bims-crepig 2024-04-28 papers

bims-crepig

Biomed News

on Chromatin regulation and epigenetics in cell fate and cancer

Issue of 2024–04–28
thirty-one papers selected by
Connor Rogerson, University of Cambridge

Imputation of 3D genome structure by genetic-epigenetic interaction modeling in mice.
Individual transcription factors modulate both the micromovement of chromatin and its long-range structure.
Uncovering uncharacterized binding of transcription factors from ATAC-seq footprinting data.
Lineage specific transcription factor waves reprogram neuroblastoma from self-renewal to differentiation.
Emergence of enhancers at late DNA replicating regions.
Linker histone H1 regulates homeostasis of heterochromatin-associated cRNAs.
Comprehensive genomic features indicative for Notch responsiveness.
BRG1 programs PRC2-complex repression and controls oligodendrocyte differentiation and remyelination.
EZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition.
Sequence basis of transcription initiation in the human genome.
TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.
ISWI catalyzes nucleosome sliding in condensed nucleosome arrays.
Cis-regulatory control of transcriptional timing and noise in response to estrogen.
Interplay of condensation and chromatin binding underlies BRD4 targeting.
YY1 binding is a gene-intrinsic barrier to Xist-mediated gene silencing.
DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.
Predicting A/B compartments from histone modifications using deep learning.
Rummagene: massive mining of gene sets from supporting materials of biomedical research publications.
Class IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation.
The Drosophila Hippo pathway transcription factor Scalloped and its co-factors alter each other's chromatin binding dynamics and transcription in vivo.
Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.
Principles of chromosome organization for meiotic recombination.
A logic-incorporated gene regulatory network deciphers principles in cell fate decisions.
Dependence of nucleosome mechanical stability on DNA mismatches.
The MYCN 5' UTR as a therapeutic target in neuroblastoma.
Chromatin landscape instructs precise transcription factor regulome during embryonic lineage specification.
Polycomb protein binding and looping in the ON transcriptional state.
Extensive long-range polycomb interactions and weak compartmentalization are hallmarks of human neuronal 3D genome.
Temporal coordination of the transcription factor response to H2O2 stress.
Characterization of the genetic determinants of context-specific DNA methylation in primary monocytes.
KLF5 regulates actin remodeling to enhance the metastasis of nasopharyngeal carcinoma.

Elife. 2024 Apr 26. pii: RP88222. [Epub ahead of print]12

Imputation of 3D genome structure by genetic-epigenetic interaction modeling in mice.

Lauren Kuffler, Daniel A Skelly, Anne Czechanski, Haley J Fortin, Steven C Munger, Christopher L Baker, Laura G Reinholdt, Gregory W Carter.

  Gene expression is known to be affected by interactions between local genetic variation and DNA accessibility, with the latter organized into three-dimensional chromatin structures. Analyses of these interactions have previously been limited, obscuring their regulatory context, and the extent to which they occur throughout the genome. Here, we undertake a genome-scale analysis of these interactions in a genetically diverse population to systematically identify global genetic-epigenetic interaction, and reveal constraints imposed by chromatin structure. We establish the extent and structure of genotype-by-epigenotype interaction using embryonic stem cells derived from Diversity Outbred mice. This mouse population segregates millions of variants from eight inbred founders, enabling precision genetic mapping with extensive genotypic and phenotypic diversity. With 176 samples profiled for genotype, gene expression, and open chromatin, we used regression modeling to infer genetic-epigenetic interactions on a genome-wide scale. Our results demonstrate that statistical interactions between genetic variants and chromatin accessibility are common throughout the genome. We found that these interactions occur within the local area of the affected gene, and that this locality corresponds to topologically associated domains (TADs). The likelihood of interaction was most strongly defined by the three-dimensional (3D) domain structure rather than linear DNA sequence. We show that stable 3D genome structure is an effective tool to guide searches for regulatory elements and, conversely, that regulatory elements in genetically diverse populations provide a means to infer 3D genome structure. We confirmed this finding with CTCF ChIP-seq that revealed strain-specific binding in the inbred founder mice. In stem cells, open chromatin participating in the most significant regression models demonstrated an enrichment for developmental genes and the TAD-forming CTCF-binding complex, providing an opportunity for statistical inference of shifting TAD boundaries operating during early development. These findings provide evidence that genetic and epigenetic factors operate within the context of 3D chromatin structure.

Keywords:  chromatin accessibility; computational biology; embryonic stem cells; genetic interaction; genetics; genomics; mouse; systems biology; topologically associating domains

DOI:  https://doi.org/10.7554/eLife.88222
Proc Natl Acad Sci U S A. 2024 Apr 30. 121(18): e2311374121

Individual transcription factors modulate both the micromovement of chromatin and its long-range structure.

Haitham A Shaban, Elias T Friman, Cédric Deluz, Armelle Tollenaere, Natalya Katanayeva, David M Suter.

  The control of eukaryotic gene expression is intimately connected to highly dynamic chromatin structures. Gene regulation relies on activator and repressor transcription factors (TFs) that induce local chromatin opening and closing. However, it is unclear how nucleus-wide chromatin organization responds dynamically to the activity of specific TFs. Here, we examined how two TFs with opposite effects on local chromatin accessibility modulate chromatin dynamics nucleus-wide. We combine high-resolution diffusion mapping and dense flow reconstruction and correlation in living cells to obtain an imaging-based, nanometer-scale analysis of local diffusion processes and long-range coordinated movements of both chromatin and TFs. We show that the expression of either an individual transcriptional activator (CDX2) or repressor (SIX6) with large numbers of binding sites increases chromatin mobility nucleus-wide, yet they induce opposite coherent chromatin motions at the micron scale. Hi-C analysis of higher-order chromatin structures shows that induction of the pioneer factor CDX2 leads both to changes in local chromatin interactions and the distribution of A and B compartments, thus relating the micromovement of chromatin with changes in compartmental structures. Given that inhibition of transcription initiation and elongation by RNA Pol II has a partial impact on the global chromatin dynamics induced by CDX2, we suggest that CDX2 overexpression alters chromatin structure dynamics both dependently and independently of transcription. Our biophysical analysis shows that sequence-specific TFs can influence chromatin structure on multiple architectural levels, arguing that local chromatin changes brought by TFs alter long-range chromatin mobility and its organization.

Keywords:  biophysics; chromatin; genome organization; nucleosome imaging; transcription factors

DOI:  https://doi.org/10.1073/pnas.2311374121
Sci Rep. 2024 04 23. 14(1): 9275

Uncovering uncharacterized binding of transcription factors from ATAC-seq footprinting data.

Hendrik Schultheis, Mette Bentsen, Vanessa Heger, Mario Looso.

  Transcription factors (TFs) are crucial epigenetic regulators, which enable cells to dynamically adjust gene expression in response to environmental signals. Computational procedures like digital genomic footprinting on chromatin accessibility assays such as ATACseq can be used to identify bound TFs in a genome-wide scale. This method utilizes short regions of low accessibility signals due to steric hindrance of DNA bound proteins, called footprints (FPs), which are combined with motif databases for TF identification. However, while over 1600 TFs have been described in the human genome, only ~ 700 of these have a known binding motif. Thus, a substantial number of FPs without overlap to a known DNA motif are normally discarded from FP analysis. In addition, the FP method is restricted to organisms with a substantial number of known TF motifs. Here we present DENIS (DE Novo motIf diScovery), a framework to generate and systematically investigate the potential of de novo TF motif discovery from FPs. DENIS includes functionality (1) to isolate FPs without binding motifs, (2) to perform de novo motif generation and (3) to characterize novel motifs. Here, we show that the framework rediscovers artificially removed TF motifs, quantifies de novo motif usage during an early embryonic development example dataset, and is able to analyze and uncover TF activity in organisms lacking canonical motifs. The latter task is exemplified by an investigation of a scATAC-seq dataset in zebrafish which covers different cell types during hematopoiesis.

Keywords:  ATAC-seq; Chromatin; De novo motif generation; Epigenetics; Footprinting; Transcription factor

DOI:  https://doi.org/10.1038/s41598-024-59989-2
Nat Commun. 2024 Apr 23. 15(1): 3432

Lineage specific transcription factor waves reprogram neuroblastoma from self-renewal to differentiation.

Deblina Banerjee, Sukriti Bagchi, Zhihui Liu, Hsien-Chao Chou, Man Xu, Ming Sun, Sara Aloisi, Zalman Vaksman, Sharon J Diskin, Mark Zimmerman, Javed Khan, Berkley Gryder, Carol J Thiele.

Temporal regulation of super-enhancer (SE) driven transcription factors (TFs) underlies normal developmental programs. Neuroblastoma (NB) arises from an inability of sympathoadrenal progenitors to exit a self-renewal program and terminally differentiate. To identify SEs driving TF regulators, we use all-trans retinoic acid (ATRA) to induce NB growth arrest and differentiation. Time-course H3K27ac ChIP-seq and RNA-seq reveal ATRA coordinated SE waves. SEs that decrease with ATRA link to stem cell development (MYCN, GATA3, SOX11). CRISPR-Cas9 and siRNA verify SOX11 dependency, in vitro and in vivo. Silencing the SOX11 SE using dCAS9-KRAB decreases SOX11 mRNA and inhibits cell growth. Other TFs activate in sequential waves at 2, 4 and 8 days of ATRA treatment that regulate neural development (GATA2 and SOX4). Silencing the gained SOX4 SE using dCAS9-KRAB decreases SOX4 expression and attenuates ATRA-induced differentiation genes. Our study identifies oncogenic lineage drivers of NB self-renewal and TFs critical for implementing a differentiation program.

DOI: https://doi.org/10.1038/s41467-024-47166-y
Nat Commun. 2024 Apr 24. 15(1): 3451

Emergence of enhancers at late DNA replicating regions.

Paola Cornejo-Páramo, Veronika Petrova, Xuan Zhang, Robert S Young, Emily S Wong.

Enhancers are fast-evolving genomic sequences that control spatiotemporal gene expression patterns. By examining enhancer turnover across mammalian species and in multiple tissue types, we uncover a relationship between the emergence of enhancers and genome organization as a function of germline DNA replication time. While enhancers are most abundant in euchromatic regions, enhancers emerge almost twice as often in late compared to early germline replicating regions, independent of transposable elements. Using a deep learning sequence model, we demonstrate that new enhancers are enriched for mutations that alter transcription factor (TF) binding. Recently evolved enhancers appear to be mostly neutrally evolving and enriched in eQTLs. They also show more tissue specificity than conserved enhancers, and the TFs that bind to these elements, as inferred by binding sequences, also show increased tissue-specific gene expression. We find a similar relationship with DNA replication time in cancer, suggesting that these observations may be time-invariant principles of genome evolution. Our work underscores that genome organization has a profound impact in shaping mammalian gene regulation.

DOI: https://doi.org/10.1038/s41467-024-47391-5
Cell Rep. 2024 Apr 24. pii: S2211-1247(24)00465-0. [Epub ahead of print]43(5): 114137

Linker histone H1 regulates homeostasis of heterochromatin-associated cRNAs.

Paula Bujosa, Oscar Reina, Adrià Caballé, Anna Casas-Lamesa, Mònica Torras-Llort, Juan Pérez-Roldán, Ana Silvina Nacht, Guillermo P Vicent, Jordi Bernués, Fernando Azorín.

  Chromatin-associated RNAs (cRNAs) are a poorly characterized fraction of cellular RNAs that co-purify with chromatin. Their full complexity and the mechanisms regulating their packaging and chromatin association remain poorly understood. Here, we address these questions in Drosophila. We find that cRNAs constitute a heterogeneous group of RNA species that is abundant in heterochromatic transcripts. We show that heterochromatic cRNAs interact with the heterogeneous nuclear ribonucleoproteins (hnRNP) hrp36/hrp48 and that depletion of linker histone dH1 impairs this interaction. dH1 depletion induces the accumulation of RNA::DNA hybrids (R-loops) in heterochromatin and, as a consequence, increases retention of heterochromatic cRNAs. These effects correlate with increased RNA polymerase II (RNAPII) occupancy at heterochromatin. Notably, impairing cRNA assembly by depletion of hrp36/hrp48 mimics heterochromatic R-loop accumulation induced by dH1 depletion. We also show that dH1 depletion alters nucleosome organization, increasing accessibility of heterochromatin. Altogether, these perturbations facilitate annealing of cRNAs to the DNA template, enhancing R-loop formation and cRNA retention at heterochromatin.

Keywords:  CP: Molecular biology; Drosophila; R-loops; RNPs; chromatin; chromosomal RNAs; epigenetics; histone H1; hrp36; hrp48

DOI:  https://doi.org/10.1016/j.celrep.2024.114137
Nucleic Acids Res. 2024 Apr 22. pii: gkae292. [Epub ahead of print]

Comprehensive genomic features indicative for Notch responsiveness.

Benedetto Daniele Giaimo, Tobias Friedrich, Francesca Ferrante, Marek Bartkuhn, Tilman Borggrefe.

Transcription factor RBPJ is the central component in Notch signal transduction and directly forms a coactivator complex together with the Notch intracellular domain (NICD). While RBPJ protein levels remain constant in most tissues, dynamic expression of Notch target genes varies depending on the given cell-type and the Notch activity state. To elucidate dynamic RBPJ binding genome-wide, we investigated RBPJ occupancy by ChIP-Seq. Surprisingly, only a small set of the total RBPJ sites show a dynamic binding behavior in response to Notch signaling. Compared to static RBPJ sites, dynamic sites differ in regard to their chromatin state, binding strength and enhancer positioning. Dynamic RBPJ sites are predominantly located distal to transcriptional start sites (TSSs), while most static sites are found in promoter-proximal regions. Importantly, gene responsiveness is preferentially associated with dynamic RBPJ binding sites and this static and dynamic binding behavior is repeatedly observed across different cell types and species. Based on the above findings we used a machine-learning algorithm to predict Notch responsiveness with high confidence in different cellular contexts. Our results strongly support the notion that the combination of binding strength and enhancer positioning are indicative of Notch responsiveness.

DOI: https://doi.org/10.1093/nar/gkae292
J Cell Biol. 2024 Jul 01. pii: e202310143. [Epub ahead of print]223(7):

BRG1 programs PRC2-complex repression and controls oligodendrocyte differentiation and remyelination.

Jiajia Wang, Lijun Yang, Yiwen Du, Jincheng Wang, Qinjie Weng, Xuezhao Liu, Eva Nicholson, Mei Xin, Qing Richard Lu.

Chromatin-remodeling protein BRG1/SMARCA4 is pivotal for establishing oligodendrocyte (OL) lineage identity. However, its functions for oligodendrocyte-precursor cell (OPC) differentiation within the postnatal brain and during remyelination remain elusive. Here, we demonstrate that Brg1 loss profoundly impairs OPC differentiation in the brain with a comparatively lesser effect in the spinal cord. Moreover, BRG1 is critical for OPC remyelination after injury. Integrative transcriptomic/genomic profiling reveals that BRG1 exhibits a dual role by promoting OPC differentiation networks while repressing OL-inhibitory cues and proneuronal programs. Furthermore, we find that BRG1 interacts with EED/PRC2 polycomb-repressive-complexes to enhance H3K27me3-mediated repression at gene loci associated with OL-differentiation inhibition and neurogenesis. Notably, BRG1 depletion decreases H3K27me3 deposition, leading to the upregulation of BMP/WNT signaling and proneurogenic genes, which suppresses OL programs. Thus, our findings reveal a hitherto unexplored spatiotemporal-specific role of BRG1 for OPC differentiation in the developing CNS and underscore a new insight into BRG1/PRC2-mediated epigenetic regulation that promotes and safeguards OL lineage commitment and differentiation.

DOI: https://doi.org/10.1083/jcb.202310143
Nat Commun. 2024 Apr 24. 15(1): 3452

EZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition.

Pierre Romero, Laia Richart, Setareh Aflaki, Ambre Petitalot, Megan Burton, Audrey Michaud, Julien Masliah-Planchon, Frédérique Kuhnowski, Samuel Le Cam, Carlos Baliñas-Gavira, Céline Méaudre, Armelle Luscan, Abderaouf Hamza, Patricia Legoix, Anne Vincent-Salomon, Michel Wassef, Daniel Holoch, Raphaël Margueron.

Mutations in chromatin regulators are widespread in cancer. Among them, the histone H3 lysine 27 methyltransferase Polycomb Repressive Complex 2 (PRC2) shows distinct alterations according to tumor type. This specificity is poorly understood. Here, we model several PRC2 alterations in one isogenic system to reveal their comparative effects. Focusing then on lymphoma-associated EZH2 mutations, we show that Ezh2Y641F induces aberrant H3K27 methylation patterns even without wild-type Ezh2, which are alleviated by partial PRC2 inhibition. Remarkably, Ezh2Y641F rewires the response to PRC2 inhibition, leading to induction of antigen presentation genes. Using a unique longitudinal follicular lymphoma cohort, we further link EZH2 status to abnormal H3K27 methylation. We also uncover unexpected variability in the mutational landscape of successive biopsies, pointing to frequent co-existence of different clones and cautioning against stratifying patients based on single sampling. Our results clarify how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.

DOI: https://doi.org/10.1038/s41467-024-47701-x
Science. 2024 Apr 26. 384(6694): eadj0116

Sequence basis of transcription initiation in the human genome.

Kseniia Dudnyk, Donghong Cai, Chenlai Shi, Jian Xu, Jian Zhou.

Transcription initiation is a process that is essential to ensuring the proper function of any gene, yet we still lack a unified understanding of sequence patterns and rules that explain most transcription start sites in the human genome. By predicting transcription initiation at base-pair resolution from sequences with a deep learning-inspired explainable model called Puffin, we show that a small set of simple rules can explain transcription initiation at most human promoters. We identify key sequence patterns that contribute to human promoter activity, each activating transcription with distinct position-specific effects. Furthermore, we explain the sequence basis of bidirectional transcription at promoters, identify the links between promoter sequence and gene expression variation across cell types, and explore the conservation of sequence determinants of transcription initiation across mammalian species.

DOI: https://doi.org/10.1126/science.adj0116
Nat Commun. 2024 Apr 20. 15(1): 3380

TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.

Manon Baudic, Hiroshige Murata, Fernanda M Bosada, Uirá Souto Melo, Takanori Aizawa, Pierre Lindenbaum, Lieve E van der Maarel, Amaury Guedon, Estelle Baron, Enora Fremy, Adrien Foucal, Taisuke Ishikawa, Hiroya Ushinohama, Sean J Jurgens, Seung Hoan Choi, Florence Kyndt, Solena Le Scouarnec, Vincent Wakker, Aurélie Thollet, Annabelle Rajalu, Tadashi Takaki, Seiko Ohno, Wataru Shimizu, Minoru Horie, Takeshi Kimura, Patrick T Ellinor, Florence Petit, Yves Dulac, Paul Bru, Anne Boland, Jean-François Deleuze, Richard Redon, Hervé Le Marec, Thierry Le Tourneau, Jean-Baptiste Gourraud, Yoshinori Yoshida, Naomasa Makita, Claude Vieyres, Takeru Makiyama, Stephan Mundlos, Vincent M Christoffels, Vincent Probst, Jean-Jacques Schott, Julien Barc.

While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.

DOI: https://doi.org/10.1038/s41467-024-47739-x
Nat Struct Mol Biol. 2024 Apr 25.

ISWI catalyzes nucleosome sliding in condensed nucleosome arrays.

Petra Vizjak, Dieter Kamp, Nicola Hepp, Alessandro Scacchetti, Mariano Gonzalez Pisfil, Joseph Bartho, Mario Halic, Peter B Becker, Michaela Smolle, Johannes Stigler, Felix Mueller-Planitz.

How chromatin enzymes work in condensed chromatin and how they maintain diffusional mobility inside remains unexplored. Here we investigated these challenges using the Drosophila ISWI remodeling ATPase, which slides nucleosomes along DNA. Folding of chromatin fibers did not affect sliding in vitro. Catalytic rates were also comparable in- and outside of chromatin condensates. ISWI cross-links and thereby stiffens condensates, except when ATP hydrolysis is possible. Active hydrolysis is also required for ISWI's mobility in condensates. Energy from ATP hydrolysis therefore fuels ISWI's diffusion through chromatin and prevents ISWI from cross-linking chromatin. Molecular dynamics simulations of a 'monkey-bar' model in which ISWI grabs onto neighboring nucleosomes, then withdraws from one before rebinding another in an ATP hydrolysis-dependent manner, qualitatively agree with our data. We speculate that monkey-bar mechanisms could be shared with other chromatin factors and that changes in chromatin dynamics caused by mutations in remodelers could contribute to pathologies.

DOI: https://doi.org/10.1038/s41594-024-01290-x
Cell Genom. 2024 Apr 22. pii: S2666-979X(24)00098-3. [Epub ahead of print] 100542

Cis-regulatory control of transcriptional timing and noise in response to estrogen.

Matthew Ginley-Hidinger, Hosiana Abewe, Kyle Osborne, Alexandra Richey, Noel Kitchen, Katelyn L Mortenson, Erin M Wissink, John Lis, Xiaoyang Zhang, Jason Gertz.

  Cis-regulatory elements control transcription levels, temporal dynamics, and cell-cell variation or transcriptional noise. However, the combination of regulatory features that control these different attributes is not fully understood. Here, we used single-cell RNA-seq during an estrogen treatment time course and machine learning to identify predictors of expression timing and noise. We found that genes with multiple active enhancers exhibit faster temporal responses. We verified this finding by showing that manipulation of enhancer activity changes the temporal response of estrogen target genes. Analysis of transcriptional noise uncovered a relationship between promoter and enhancer activity, with active promoters associated with low noise and active enhancers linked to high noise. Finally, we observed that co-expression across single cells is an emergent property associated with chromatin looping, timing, and noise. Overall, our results indicate a fundamental tradeoff between a gene's ability to quickly respond to incoming signals and maintain low variation across cells.

Keywords:  cis-regulatory elements; epigenetic editing; estrogen receptor; expression noise; gene regulation; single-cell RNA-seq; transcription dynamics

DOI:  https://doi.org/10.1016/j.xgen.2024.100542
Mol Biol Cell. 2024 Apr 24. mbcE24010046

Interplay of condensation and chromatin binding underlies BRD4 targeting.

Amy R Strom, Jorine M Eeftens, Yury Polyachenko, Claire J Weaver, Hans-Frederick Watanabe, Dan Bracha, Natalia D Orlovsky, Chanelle C Jumper, William M Jacobs, Clifford P Brangwynne.

Nuclear compartments form via biomolecular phase separation, mediated through multivalent properties of biomolecules concentrated within condensates. Certain compartments are associated with specific chromatin regions, including transcriptional initiation condensates, which are composed of transcription factors and transcriptional machinery, and form at acetylated regions including enhancer and promoter loci. While protein self-interactions, especially within low-complexity and intrinsically disordered regions, are known to mediate condensation, the role of substrate-binding interactions in regulating the formation and function of biomolecular condensates is under-explored. Here, utilizing live-cell experiments in parallel with coarse-grained simulations, we investigate how chromatin interaction of the transcriptional activator BRD4 modulates its condensate formation. We find that both kinetic and thermodynamic properties of BRD4 condensation are affected by chromatin binding: nucleation rate is sensitive to BRD4-chromatin interactions, providing an explanation for the selective formation of BRD4 condensates at acetylated chromatin regions, and thermodynamically, multivalent acetylated chromatin sites provide a platform for BRD4 clustering below the concentration required for off-chromatin condensation. This provides a molecular and physical explanation of the relationship between nuclear condensates and epigenetically modified chromatin that results in their mutual spatiotemporal regulation, suggesting that epigenetic modulation is an important mechanism by which the cell targets transcriptional condensates to specific chromatin loci. [Media: see text].

DOI: https://doi.org/10.1091/mbc.E24-01-0046
EMBO Rep. 2024 Apr 23.

YY1 binding is a gene-intrinsic barrier to Xist-mediated gene silencing.

Joseph S Bowness, Mafalda Almeida, Tatyana B Nesterova, Neil Brockdorff.

  X chromosome inactivation (XCI) in mammals is mediated by Xist RNA which functions in cis to silence genes on a single X chromosome in XX female cells, thereby equalising levels of X-linked gene expression relative to XY males. XCI progresses over a period of several days, with some X-linked genes silencing faster than others. The chromosomal location of a gene is an important determinant of silencing rate, but uncharacterised gene-intrinsic features also mediate resistance or susceptibility to silencing. In this study, we examine mouse embryonic stem cell lines with an inducible Xist allele (iXist-ChrX mESCs) and integrate allele-specific data of gene silencing and decreasing inactive X (Xi) chromatin accessibility over time courses of Xist induction with cellular differentiation. Our analysis reveals that motifs bound by the transcription factor YY1 are associated with persistently accessible regulatory elements, including many promoters and enhancers of slow-silencing genes. We further show that YY1 is evicted relatively slowly from target sites on Xi, and that silencing of X-linked genes is increased upon YY1 degradation. Together our results suggest that YY1 acts as a barrier to Xist-mediated silencing until the late stages of the XCI process.

Keywords:  Chromatin; Gene Silencing; Transcription Factor; X Inactivation; Xist

DOI:  https://doi.org/10.1038/s44319-024-00136-3
Cell. 2024 Apr 17. pii: S0092-8674(24)00318-0. [Epub ahead of print]

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Mariko Takahashi, Harrison B Chong, Siwen Zhang, Tzu-Yi Yang, Matthew J Lazarov, Stefan Harry, Michelle Maynard, Brendan Hilbert, Ryan D White, Heather E Murrey, Chih-Chiang Tsou, Kira Vordermark, Jonathan Assaad, Magdy Gohar, Benedikt R Dürr, Marianne Richter, Himani Patel, Gregory Kryukov, Natasja Brooijmans, Aliyu Sidi Omar Alghali, Karla Rubio, Antonio Villanueva, Junbing Zhang, Maolin Ge, Farah Makram, Hanna Griesshaber, Drew Harrison, Ann-Sophie Koglin, Samuel Ojeda, Barbara Karakyriakou, Alexander Healy, George Popoola, Inbal Rachmin, Neha Khandelwal, Jason R Neil, Pei-Chieh Tien, Nicholas Chen, Tobias Hosp, Sanne van den Ouweland, Toshiro Hara, Lillian Bussema, Rui Dong, Lei Shi, Martin Q Rasmussen, Ana Carolina Domingues, Aleigha Lawless, Jacy Fang, Satoshi Yoda, Linh Phuong Nguyen, Sarah Marie Reeves, Farrah Nicole Wakefield, Adam Acker, Sarah Elizabeth Clark, Taronish Dubash, John Kastanos, Eugene Oh, David E Fisher, Shyamala Maheswaran, Daniel A Haber, Genevieve M Boland, Moshe Sade-Feldman, Russell W Jenkins, Aaron N Hata, Nabeel M Bardeesy, Mario L Suvà, Brent R Martin, Brian B Liau, Christopher J Ott, Miguel N Rivera, Michael S Lawrence, Liron Bar-Peled.

  Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.

Keywords:  chemical proteomics; covalent inhibitors; cysteine ligandability; transcription factors

DOI:  https://doi.org/10.1016/j.cell.2024.03.027
iScience. 2024 May 17. 27(5): 109570

Predicting A/B compartments from histone modifications using deep learning.

Suchen Zheng, Nitya Thakkar, Hannah L Harris, Susanna Liu, Megan Zhang, Mark Gerstein, Erez Lieberman Aiden, M Jordan Rowley, William Stafford Noble, Gamze Gürsoy, Ritambhara Singh.

  The three-dimensional organization of genomes plays a crucial role in essential biological processes. The segregation of chromatin into A and B compartments highlights regions of activity and inactivity, providing a window into the genomic activities specific to each cell type. Yet, the steep costs associated with acquiring Hi-C data, necessary for studying this compartmentalization across various cell types, pose a significant barrier in studying cell type specific genome organization. To address this, we present a prediction tool called compartment prediction using recurrent neural networks (CoRNN), which predicts compartmentalization of 3D genome using histone modification enrichment. CoRNN demonstrates robust cross-cell-type prediction of A/B compartments with an average AuROC of 90.9%. Cell-type-specific predictions align well with known functional elements, with H3K27ac and H3K36me3 identified as highly predictive histone marks. We further investigate our mispredictions and found that they are located in regions with ambiguous compartmental status. Furthermore, our model's generalizability is validated by predicting compartments in independent tissue samples, which underscores its broad applicability.

Keywords:  Chromosome organization; Genomics; Machine learning

DOI:  https://doi.org/10.1016/j.isci.2024.109570
Commun Biol. 2024 Apr 20. 7(1): 482

Rummagene: massive mining of gene sets from supporting materials of biomedical research publications.

Daniel J B Clarke, Giacomo B Marino, Eden Z Deng, Zhuorui Xie, John Erol Evangelista, Avi Ma'ayan.

Many biomedical research publications contain gene sets in their supporting tables, and these sets are currently not available for search and reuse. By crawling PubMed Central, the Rummagene server provides access to hundreds of thousands of such mammalian gene sets. So far, we scanned 5,448,589 articles to find 121,237 articles that contain 642,389 gene sets. These sets are served for enrichment analysis, free text, and table title search. Investigating statistical patterns within the Rummagene database, we demonstrate that Rummagene can be used for transcription factor and kinase enrichment analyses, and for gene function predictions. By combining gene set similarity with abstract similarity, Rummagene can find surprising relationships between biological processes, concepts, and named entities. Overall, Rummagene brings to surface the ability to search a massive collection of published biomedical datasets that are currently buried and inaccessible. The Rummagene web application is available at https://rummagene.com .

DOI: https://doi.org/10.1038/s42003-024-06177-7
Proc Natl Acad Sci U S A. 2024 Apr 30. 121(18): e2312111121

Class IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation.

Ka Lung Cheung, Li Zhao, Rajal Sharma, Anurupa Abhijit Ghosh, Michael Appiah, Yifei Sun, Anbalagan Jaganathan, Yuan Hu, Alannah LeJeune, Feihong Xu, Xinye Han, Xueting Wang, Fan Zhang, Chunyan Ren, Martin J Walsh, Huabao Xiong, Alexander Tsankov, Ming-Ming Zhou.

  Class II histone deacetylases (HDACs) are important in regulation of gene transcription during T cell development. However, our understanding of their cell-specific functions is limited. In this study, we reveal that class IIa Hdac4 and Hdac7 (Hdac4/7) are selectively induced in transcription, guiding the lineage-specific differentiation of mouse T-helper 17 (Th17) cells from naive CD4+ T cells. Importantly, Hdac4/7 are functionally dispensable in other Th subtypes. Mechanistically, Hdac4 interacts with the transcription factor (TF) JunB, facilitating the transcriptional activation of Th17 signature genes such as Il17a/f. Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators, including Il2, in Th17 cell differentiation. Inhibiting Hdac4/7 through pharmacological or genetic methods effectively mitigates Th17 cell-mediated intestinal inflammation in a colitis mouse model. Our study uncovers molecular mechanisms where HDAC4 and HDAC7 function distinctively yet cooperatively in regulating ordered gene transcription during Th17 cell differentiation. These findings suggest a potential therapeutic strategy of targeting HDAC4/7 for treating Th17-related inflammatory diseases, such as ulcerative colitis.

Keywords:  HDAC4 and HDAC7; Th17 cell differentiation; drug discovery; gene transcription

DOI:  https://doi.org/10.1073/pnas.2312111121
Dev Cell. 2024 Apr 23. pii: S1534-5807(24)00231-4. [Epub ahead of print]

The Drosophila Hippo pathway transcription factor Scalloped and its co-factors alter each other's chromatin binding dynamics and transcription in vivo.

Samuel A Manning, Benjamin Kroeger, Qiji Deng, Elliot Brooks, Yoshana Fonseka, Elizabeth Hinde, Kieran F Harvey.

  The Hippo pathway is an important regulator of organ growth and cell fate. The major mechanism by which Hippo is known to control transcription is by dictating the nucleo-cytoplasmic shuttling rate of Yorkie, a transcription co-activator, which promotes transcription with the DNA binding protein Scalloped. The nuclear biophysical behavior of Yorkie and Scalloped, and whether this is regulated by the Hippo pathway, remains unexplored. Using multiple live-imaging modalities on Drosophila tissues, we found that Scalloped interacts with DNA on a broad range of timescales, and enrichment of Scalloped at sites of active transcription is mediated by longer DNA dwell times. Further, Yorkie increased Scalloped's DNA dwell time, whereas the repressors Nervous fingers 1 (Nerfin-1) and Tondu-domain-containing growth inhibitor (Tgi) decreased it. Therefore, the Hippo pathway influences transcription not only by controlling nuclear abundance of Yorkie but also by modifying the DNA binding kinetics of the transcription factor Scalloped.

Keywords:  Drosophila; Hippo signaling; biophysical behavior; live imaging; transcription; transcription factor

DOI:  https://doi.org/10.1016/j.devcel.2024.04.006
Nat Commun. 2024 Apr 25. 15(1): 3483

Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.

Noha A M Shendy, Melissa Bikowitz, Logan H Sigua, Yang Zhang, Audrey Mercier, Yousef Khashana, Stephanie Nance, Qi Liu, Ian M Delahunty, Sarah Robinson, Vanshita Goel, Matthew G Rees, Melissa A Ronan, Tingjian Wang, Mustafa Kocak, Jennifer A Roth, Yingzhe Wang, Burgess B Freeman, Brent A Orr, Brian J Abraham, Martine F Roussel, Ernst Schonbrunn, Jun Qi, Adam D Durbin.

Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.

DOI: https://doi.org/10.1038/s41467-024-47102-0
Mol Cell. 2024 Apr 18. pii: S1097-2765(24)00279-X. [Epub ahead of print]

Principles of chromosome organization for meiotic recombination.

Mathilde Biot, Attila Toth, Christine Brun, Leon Guichard, Bernard de Massy, Corinne Grey.

  In meiotic cells, chromosomes are organized as chromatin loop arrays anchored to a protein axis. This organization is essential to regulate meiotic recombination, from DNA double-strand break (DSB) formation to their repair. In mammals, it is unknown how chromatin loops are organized along the genome and how proteins participating in DSB formation are tethered to the chromosome axes. Here, we identify three categories of axis-associated genomic sites: PRDM9 binding sites, where DSBs form; binding sites of the insulator protein CTCF; and H3K4me3-enriched sites. We demonstrate that PRDM9 promotes the recruitment of MEI4 and IHO1, two proteins essential for DSB formation. In turn, IHO1 anchors DSB sites to the axis components HORMAD1 and SYCP3. We discovered that IHO1, HORMAD1, and SYCP3 are associated at the DSB ends during DSB repair. Our results highlight how interactions of proteins with specific genomic elements shape the meiotic chromosome organization for recombination.

Keywords:  ChIP-seq; chromosome structure; genome stability; germline; meiosis; recombination; reproduction

DOI:  https://doi.org/10.1016/j.molcel.2024.04.001
Elife. 2024 Apr 23. pii: RP88742. [Epub ahead of print]12

A logic-incorporated gene regulatory network deciphers principles in cell fate decisions.

Gang Xue, Xiaoyi Zhang, Wanqi Li, Lu Zhang, Zongxu Zhang, Xiaolin Zhou, Di Zhang, Lei Zhang, Zhiyuan Li.

  Organisms utilize gene regulatory networks (GRN) to make fate decisions, but the regulatory mechanisms of transcription factors (TF) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision-making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top-down fate-decision studies and a practical approach to the taxonomy of cell fate decisions.

Keywords:  cell dynamics; cell fate decision; computational biology; developmental biology; driving force; gene expression noise; gene regulatory logic; gene regulatory network; human; mouse; systems biology

DOI:  https://doi.org/10.7554/eLife.88742
Elife. 2024 Apr 24. pii: RP95514. [Epub ahead of print]13

Dependence of nucleosome mechanical stability on DNA mismatches.

Thuy T M Ngo, Bailey Liu, Feng Wang, Aakash Basu, Carl Wu, Taekjip Ha.

  The organization of nucleosomes into chromatin and their accessibility are shaped by local DNA mechanics. Conversely, nucleosome positions shape genetic variations, which may originate from mismatches during replication and chemical modification of DNA. To investigate how DNA mismatches affect the mechanical stability and the exposure of nucleosomal DNA, we used an optical trap combined with single-molecule FRET and a single-molecule FRET cyclization assay. We found that a single base-pair C-C mismatch enhances DNA bendability and nucleosome mechanical stability for the 601-nucleosome positioning sequence. An increase in force required for DNA unwrapping from the histone core is observed for single base-pair C-C mismatches placed at three tested positions: at the inner turn, at the outer turn, or at the junction of the inner and outer turn of the nucleosome. The results support a model where nucleosomal DNA accessibility is reduced by mismatches, potentially explaining the preferred accumulation of single-nucleotide substitutions in the nucleosome core and serving as the source of genetic variation during evolution and cancer progression. Mechanical stability of an intact nucleosome, that is mismatch-free, is also dependent on the species as we find that yeast nucleosomes are mechanically less stable and more symmetrical in the outer turn unwrapping compared to Xenopus nucleosomes.

Keywords:  DNA mismatch; DNA repair; S. cerevisiae; fluorescence resonance energy transfer; molecular biophysics; nucleosome; optical tweezers; single molecule biophysics; structural biology; xenopus

DOI:  https://doi.org/10.7554/eLife.95514
Cell Rep. 2024 Apr 23. pii: S2211-1247(24)00462-5. [Epub ahead of print]43(5): 114134

The MYCN 5' UTR as a therapeutic target in neuroblastoma.

Marina P Volegova, Lauren E Brown, Ushashi Banerjee, Ruben Dries, Bandana Sharma, Alyssa Kennedy, John A Porco, Rani E George.

  Tumor MYCN amplification is seen in high-risk neuroblastoma, yet direct targeting of this oncogenic transcription factor has been challenging. Here, we take advantage of the dependence of MYCN-amplified neuroblastoma cells on increased protein synthesis to inhibit the activity of eukaryotic translation initiation factor 4A1 (eIF4A1) using an amidino-rocaglate, CMLD012824. Consistent with the role of this RNA helicase in resolving structural barriers in 5' untranslated regions (UTRs), CMLD012824 increased eIF4A1 affinity for polypurine-rich 5' UTRs, including that of the MYCN and associated transcripts with critical roles in cell proliferation. CMLD012824-mediated clamping of eIF4A1 spanned the full lengths of mRNAs, while translational inhibition was mediated through 5' UTR binding in a cap-dependent and -independent manner. Finally, CMLD012824 led to growth inhibition in MYCN-amplified neuroblastoma models without generalized toxicity. Our studies highlight the key role of eIF4A1 in MYCN-amplified neuroblastoma and demonstrate the therapeutic potential of disrupting its function.

Keywords:  CP: Cancer; CP: Molecular biology; MYCN; MYCN amplification; PAR-CLIP; amidino-rocaglate; eIF4A1; neuroblastoma; ribosome profiling; rocaglate; translation; translation regulation

DOI:  https://doi.org/10.1016/j.celrep.2024.114134
Cell Rep. 2024 Apr 20. pii: S2211-1247(24)00464-9. [Epub ahead of print]43(5): 114136

Chromatin landscape instructs precise transcription factor regulome during embryonic lineage specification.

Liping Wang, Shanru Yi, Xinyu Cui, Zhenxiang Guo, Mengting Wang, Xiaochen Kou, Yanhong Zhao, Hong Wang, Cizhong Jiang, Shaorong Gao, Guang Yang, Jiayu Chen, Rui Gao.

  Embryos, originating from fertilized eggs, undergo continuous cell division and differentiation, accompanied by dramatic changes in transcription, translation, and metabolism. Chromatin regulators, including transcription factors (TFs), play indispensable roles in regulating these processes. Recently, the trophoblast regulator TFAP2C was identified as crucial in initiating early cell fate decisions. However, Tfap2c transcripts persist in both the inner cell mass and trophectoderm of blastocysts, prompting inquiry into Tfap2c's function in post-lineage establishment. In this study, we delineate the dynamics of TFAP2C during the mouse peri-implantation stage and elucidate its collaboration with the key lineage regulators CDX2 and NANOG. Importantly, we propose that de novo formation of H3K9me3 in the extraembryonic ectoderm during implantation antagonizes TFAP2C binding to crucial developmental genes, thereby maintaining its lineage identity. Together, these results highlight the plasticity of the chromatin environment in designating the genomic binding of highly adaptable lineage-specific TFs and regulating embryonic cell fates.

Keywords:  CP: Molecular biology; CP: Stem cell research; CUT&RUN; chromatin landscape; embryo development; heterochromatin; lineage specification; peri-implantation; super bivalency; transcription factor

DOI:  https://doi.org/10.1016/j.celrep.2024.114136
Sci Adv. 2024 Apr 26. 10(17): eadn1837

Polycomb protein binding and looping in the ON transcriptional state.

J Lesley Brown, Liangliang Zhang, Pedro P Rocha, Judith A Kassis, Ming-An Sun.

Polycomb group (PcG) proteins mediate epigenetic silencing of important developmental genes by modifying histones and compacting chromatin through two major protein complexes, PRC1 and PRC2. These complexes are recruited to DNA by CpG islands (CGIs) in mammals and Polycomb response elements (PREs) in Drosophila. When PcG target genes are turned OFF, PcG proteins bind to PREs or CGIs, and PREs serve as anchors that loop together and stabilize gene silencing. Here, we address which PcG proteins bind to PREs and whether PREs mediate looping when their targets are in the ON transcriptional state. While the binding of most PcG proteins decreases at PREs in the ON state, one PRC1 component, Ph, remains bound. Further, PREs can loop to each other and with presumptive enhancers in the ON state and, like CGIs, may act as tethering elements between promoters and enhancers. Overall, our data suggest that PREs are important looping elements for developmental loci in both the ON and OFF states.

DOI: https://doi.org/10.1126/sciadv.adn1837
Nucleic Acids Res. 2024 Apr 22. pii: gkae271. [Epub ahead of print]

Extensive long-range polycomb interactions and weak compartmentalization are hallmarks of human neuronal 3D genome.

Ilya A Pletenev, Maria Bazarevich, Diana R Zagirova, Anna D Kononkova, Alexander V Cherkasov, Olga I Efimova, Eugenia A Tiukacheva, Kirill V Morozov, Kirill A Ulianov, Dmitriy Komkov, Anna V Tvorogova, Vera E Golimbet, Nikolay V Kondratyev, Sergey V Razin, Philipp Khaitovich, Sergey V Ulianov, Ekaterina E Khrameeva.

Chromatin architecture regulates gene expression and shapes cellular identity, particularly in neuronal cells. Specifically, polycomb group (PcG) proteins enable establishment and maintenance of neuronal cell type by reorganizing chromatin into repressive domains that limit the expression of fate-determining genes and sustain distinct gene expression patterns in neurons. Here, we map the 3D genome architecture in neuronal and non-neuronal cells isolated from the Wernicke's area of four human brains and comprehensively analyze neuron-specific aspects of chromatin organization. We find that genome segregation into active and inactive compartments is greatly reduced in neurons compared to other brain cells. Furthermore, neuronal Hi-C maps reveal strong long-range interactions, forming a specific network of PcG-mediated contacts in neurons that is nearly absent in other brain cells. These interacting loci contain developmental transcription factors with repressed expression in neurons and other mature brain cells. But only in neurons, they are rich in bivalent promoters occupied by H3K4me3 histone modification together with H3K27me3, which points to a possible functional role of PcG contacts in neurons. Importantly, other layers of chromatin organization also exhibit a distinct structure in neurons, characterized by an increase in short-range interactions and a decrease in long-range ones.

DOI: https://doi.org/10.1093/nar/gkae271
Nat Commun. 2024 Apr 23. 15(1): 3440

Temporal coordination of the transcription factor response to H2O2 stress.

Elizabeth Jose, Woody March-Steinman, Bryce A Wilson, Lisa Shanks, Chance Parkinson, Isabel Alvarado-Cruz, Joann B Sweasy, Andrew L Paek.

Oxidative stress from excess H2O2 activates transcription factors that restore redox balance and repair oxidative damage. Although many transcription factors are activated by H2O2, it is unclear whether they are activated at the same H2O2 concentration, or time. Dose-dependent activation is likely as oxidative stress is not a singular state and exhibits dose-dependent outcomes including cell-cycle arrest and cell death. Here, we show that transcription factor activation is both dose-dependent and coordinated over time. Low levels of H2O2 activate p53, NRF2 and JUN. Yet under high H2O2, these transcription factors are repressed, and FOXO1, NF-κB, and NFAT1 are activated. Time-lapse imaging revealed that the order in which these two groups of transcription factors are activated depends on whether H2O2 is administered acutely by bolus addition, or continuously through the glucose oxidase enzyme. Finally, we provide evidence that 2-Cys peroxiredoxins control which group of transcription factors are activated.

DOI: https://doi.org/10.1038/s41467-024-47837-w
Cell Genom. 2024 Apr 22. pii: S2666-979X(24)00097-1. [Epub ahead of print] 100541

Characterization of the genetic determinants of context-specific DNA methylation in primary monocytes.

James J Gilchrist, Hai Fang, Sara Danielli, Marketa Tomkova, Isar Nassiri, Esther Ng, Orion Tong, Chelsea Taylor, Dylan Muldoon, Lea R Z Cohen, Hussein Al-Mossawi, Evelyn Lau, Matt Neville, Benjamin Schuster-Boeckler, Julian C Knight, Benjamin P Fairfax.

  To better understand inter-individual variation in sensitivity of DNA methylation (DNAm) to immune activity, we characterized effects of inflammatory stimuli on primary monocyte DNAm (n = 190). We find that monocyte DNAm is site-dependently sensitive to lipopolysaccharide (LPS), with LPS-induced demethylation occurring following hydroxymethylation. We identify 7,359 high-confidence immune-modulated CpGs (imCpGs) that differ in genomic localization and transcription factor usage according to whether they represent a gain or loss in DNAm. Demethylated imCpGs are profoundly enriched for enhancers and colocalize to genes enriched for disease associations, especially cancer. DNAm is age associated, and we find that 24-h LPS exposure triggers approximately 6 months of gain in epigenetic age, directly linking epigenetic aging with innate immune activity. By integrating LPS-induced changes in DNAm with genetic variation, we identify 234 imCpGs under local genetic control. Exploring shared causal loci between LPS-induced DNAm responses and human disease traits highlights examples of disease-associated loci that modulate imCpG formation.

Keywords:  DNA methylation; LPS; cancer; epigenetic aging; genetics; innate immune activation; mQTL; monocytes

DOI:  https://doi.org/10.1016/j.xgen.2024.100541
Oncogene. 2024 Apr 22.

KLF5 regulates actin remodeling to enhance the metastasis of nasopharyngeal carcinoma.

Zhenyu Yang, Yanfu Peng, Yaqin Wang, Panyang Yang, Zhuohui Huang, Tingqiu Quan, Xudong Xu, Peng Sun, Ying Sun, Jiawei Lv, Denghui Wei, Guan-Qun Zhou.

Transcription factors (TFs) engage in various cellular essential processes including differentiation, growth and migration. However, the master TF involved in distant metastasis of nasopharyngeal carcinoma (NPC) remains largely unclear. Here we show that KLF5 regulates actin remodeling to enhance NPC metastasis. We analyzed the msVIPER algorithm-generated transcriptional regulatory networks and identified KLF5 as a master TF of metastatic NPC linked to poor clinical outcomes. KLF5 regulates actin remodeling and lamellipodia formation to promote the metastasis of NPC cells in vitro and in vivo. Mechanistically, KLF5 preferentially occupies distal enhancer regions of ACTN4 to activate its transcription, whereby decoding the informative DNA sequences. ACTN4, extensively localized within actin cytoskeleton, facilitates dense and branched actin networks and lamellipodia formation at the cell leading edge, empowering cells to migrate faster. Collectively, our findings reveal that KLF5 controls robust transcription program of ACTN4 to modulate actin remodeling and augment cell motility which enhances NPC metastasis, and provide new potential biomarkers and therapeutic interventions for NPC.

DOI: https://doi.org/10.1038/s41388-024-03033-0