bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2024‒04‒14
twenty papers selected by
Connor Rogerson, University of Cambridge
  1. Integrative analysis of transcriptomic and epigenomic data reveals distinct patterns for developmental and housekeeping gene regulation.
  2. Nucleation and spreading maintain Polycomb domains every cell cycle.
  3. Three-step mechanism of promoter escape by RNA polymerase II.
  4. Enhancer switching in cell lineage priming is linked to eRNA, Brg1's AT-hook, and SWI/SNF recruitment.
  5. scifi-ATAC-seq: massive-scale single-cell chromatin accessibility sequencing using combinatorial fluidic indexing.
  6. TEAD2 initiates ground-state pluripotency by mediating chromatin looping.
  7. Mutant FOXO1 controls an oncogenic network via enhancer accessibility.
  8. Deciphering cell types by integrating scATAC-seq data with genome sequences.
  9. Transcription bodies regulate gene expression by sequestering CDK9.
  10. Inferring gene regulatory networks from single-cell multiome data using atlas-scale external data.
  11. Tissue-specific enhancer-gene maps from multimodal single-cell data identify causal disease alleles.
  12. Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer.
  13. TATA-binding associated factors have distinct roles during early mammalian development.
  14. ARID1A regulates DNA repair through chromatin organization and its deficiency triggers DNA damage-mediated anti-tumor immune response.
  15. ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer.
  16. The dynamic landscape of enhancer-derived RNA during mouse early embryo development.
  17. Arabidopsis transcription factor TCP4 controls the identity of the apical gynoecium.
  18. Chromatin context-dependent regulation and epigenetic manipulation of prime editing.
  19. An RNA-dependent and phase-separated active subnuclear compartment safeguards repressive chromatin domains.
  20. Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function.
  1. BMC Biol. 2024 Apr 10. 22(1): 78
    Integrative analysis of transcriptomic and epigenomic data reveals distinct patterns for developmental and housekeeping gene regulation.
    Irina Abnizova, Carine Stapel, Rene Te Boekhorst, Jimmy Tsz Hang Lee, Martin Hemberg.
      BACKGROUND: Regulation of transcription is central to the emergence of new cell types during development, and it often involves activation of genes via proximal and distal regulatory regions. The activity of regulatory elements is determined by transcription factors (TFs) and epigenetic marks, but despite extensive mapping of such patterns, the extraction of regulatory principles remains challenging.RESULTS: Here we study differentially and similarly expressed genes along with their associated epigenomic profiles, chromatin accessibility and DNA methylation, during lineage specification at gastrulation in mice. Comparison of the three lineages allows us to identify genomic and epigenomic features that distinguish the two classes of genes. We show that differentially expressed genes are primarily regulated by distal elements, while similarly expressed genes are controlled by proximal housekeeping regulatory programs. Differentially expressed genes are relatively isolated within topologically associated domains, while similarly expressed genes tend to be located in gene clusters. Transcription of differentially expressed genes is associated with differentially open chromatin at distal elements including enhancers, while that of similarly expressed genes is associated with ubiquitously accessible chromatin at promoters.
    CONCLUSION: Based on these associations of (linearly) distal genes' transcription start sites (TSSs) and putative enhancers for developmental genes, our findings allow us to link putative enhancers to their target promoters and to infer lineage-specific repertoires of putative driver transcription factors, within which we define subgroups of pioneers and co-operators.
    Keywords:  Developmental and housekeeping genes; Differentially and similarly expressed genes; Epigenomics; Gene regulation programs; Pioneer TFs; Transcriptional architecture
    DOI:  https://doi.org/10.1186/s12915-024-01869-2
  2. Cell Rep. 2024 Apr 11. pii: S2211-1247(24)00418-2. [Epub ahead of print]43(4): 114090
    Nucleation and spreading maintain Polycomb domains every cell cycle.
    Giovana M B Veronezi, Srinivas Ramachandran.
      Gene repression by the Polycomb pathway is essential for metazoan development. Polycomb domains, characterized by trimethylation of histone H3 lysine 27 (H3K27me3), carry the memory of repression and hence need to be maintained to counter the dilution of parental H3K27me3 with unmodified H3 during replication. Yet, how locus-specific H3K27me3 is maintained through replication is unclear. To understand H3K27me3 recovery post-replication, we first define nucleation sites within each Polycomb domain in mouse embryonic stem cells. To map dynamics of H3K27me3 domains across the cell cycle, we develop CUT&Flow (coupling cleavage under target and tagmentation with flow cytometry). We show that post-replication recovery of Polycomb domains occurs by nucleation and spreading, using the same nucleation sites used during de novo domain formation. By using Polycomb repressive complex 2 (PRC2) subunit-specific inhibitors, we find that PRC2 targets nucleation sites post-replication independent of pre-existing H3K27me3. Thus, competition between H3K27me3 deposition and nucleosome turnover drives both de novo domain formation and maintenance during every cell cycle.
    Keywords:  CP: Molecular biology; PRC2; Polycomb; chromatin dynamics; epigenomics; nucleation
    DOI:  https://doi.org/10.1016/j.celrep.2024.114090
  3. Mol Cell. 2024 Apr 05. pii: S1097-2765(24)00226-0. [Epub ahead of print]
    Three-step mechanism of promoter escape by RNA polymerase II.
    Yumeng Zhan, Frauke Grabbe, Elisa Oberbeckmann, Christian Dienemann, Patrick Cramer.
      The transition from transcription initiation to elongation is highly regulated in human cells but remains incompletely understood at the structural level. In particular, it is unclear how interactions between RNA polymerase II (RNA Pol II) and initiation factors are broken to enable promoter escape. Here, we reconstitute RNA Pol II promoter escape in vitro and determine high-resolution structures of initially transcribing complexes containing 8-, 10-, and 12-nt ordered RNAs and two elongation complexes containing 14-nt RNAs. We suggest that promoter escape occurs in three major steps. First, the growing RNA displaces the B-reader element of the initiation factor TFIIB without evicting TFIIB. Second, the rewinding of the transcription bubble coincides with the eviction of TFIIA, TFIIB, and TBP. Third, the binding of DSIF and NELF facilitates TFIIE and TFIIH dissociation, establishing the paused elongation complex. This three-step model for promoter escape fills a gap in our understanding of the initiation-elongation transition of RNA Pol II transcription.
    Keywords:  RNA polymerase II; promoter escape; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2024.03.016
  4. Mol Cell. 2024 Mar 29. pii: S1097-2765(24)00223-5. [Epub ahead of print]
    Enhancer switching in cell lineage priming is linked to eRNA, Brg1's AT-hook, and SWI/SNF recruitment.
    Dhurjhoti Saha, Srinivas Animireddy, Junwoo Lee, Anna Thommen, McKenzie M Murvin, Yue Lu, Mauro J Calabrese, Blaine Bartholomew.
      RNA transcribed from enhancers, i.e., eRNA, has been suggested to directly activate transcription by recruiting transcription factors and co-activators. Although there have been specific examples of eRNA functioning in this way, it is not clear how general this may be. We find that the AT-hook of SWI/SNF preferentially binds RNA and, as part of the esBAF complex, associates with eRNA transcribed from intronic and intergenic regions. Our data suggest that SWI/SNF is globally recruited in cis by eRNA to cell-type-specific enhancers, representative of two distinct stages that mimic early mammalian development, and not at enhancers that are shared between the two stages. In this manner, SWI/SNF facilitates recruitment and/or activation of MLL3/4, p300/CBP, and Mediator to stage-specific enhancers and super-enhancers that regulate the transcription of metabolic and cell lineage priming-related genes. These findings highlight a connection between ATP-dependent chromatin remodeling and eRNA in cell identity and typical- and super-enhancer activation.
    Keywords:  Brg1/Smarca4; EpiSCs; MLL3/4; RNAPII; SWI/SNF; eRNA; enhancer; mediator (Med1); naive; p300/CBP; primed
    DOI:  https://doi.org/10.1016/j.molcel.2024.03.013
  5. Genome Biol. 2024 Apr 08. 25(1): 90
    scifi-ATAC-seq: massive-scale single-cell chromatin accessibility sequencing using combinatorial fluidic indexing.
    Xuan Zhang, Alexandre P Marand, Haidong Yan, Robert J Schmitz.
      Single-cell ATAC-seq has emerged as a powerful approach for revealing candidate cis-regulatory elements genome-wide at cell-type resolution. However, current single-cell methods suffer from limited throughput and high costs. Here, we present a novel technique called scifi-ATAC-seq, single-cell combinatorial fluidic indexing ATAC-sequencing, which combines a barcoded Tn5 pre-indexing step with droplet-based single-cell ATAC-seq using the 10X Genomics platform. With scifi-ATAC-seq, up to 200,000 nuclei across multiple samples can be indexed in a single emulsion reaction, representing an approximately 20-fold increase in throughput compared to the standard 10X Genomics workflow.
    Keywords:  ATAC-seq; Chromatin accessibility; Combinatorial fluidic indexing; Massive-scale; Single-cell
    DOI:  https://doi.org/10.1186/s13059-024-03235-5
  6. EMBO J. 2024 Apr 11.
    TEAD2 initiates ground-state pluripotency by mediating chromatin looping.
    Rong Guo, Xiaotao Dong, Feng Chen, Tianrong Ji, Qiannan He, Jie Zhang, Yingliang Sheng, Yanjiang Liu, Shengxiong Yang, Weifang Liang, Yawei Song, Ke Fang, Lingling Zhang, Gongcheng Hu, Hongjie Yao.
      The transition of mouse embryonic stem cells (ESCs) between serum/LIF and 2i(MEK and GSK3 kinase inhibitor)/LIF culture conditions serves as a valuable model for exploring the mechanisms underlying ground and confused pluripotent states. Regulatory networks comprising core and ancillary pluripotency factors drive the gene expression programs defining stable naïve pluripotency. In our study, we systematically screened factors essential for ESC pluripotency, identifying TEAD2 as an ancillary factor maintaining ground-state pluripotency in 2i/LIF ESCs and facilitating the transition from serum/LIF to 2i/LIF ESCs. TEAD2 exhibits increased binding to chromatin in 2i/LIF ESCs, targeting active chromatin regions to regulate the expression of 2i-specific genes. In addition, TEAD2 facilitates the expression of 2i-specific genes by mediating enhancer-promoter interactions during the serum/LIF to 2i/LIF transition. Notably, deletion of Tead2 results in reduction of a specific set of enhancer-promoter interactions without significantly affecting binding of chromatin architecture proteins, CCCTC-binding factor (CTCF), and Yin Yang 1 (YY1). In summary, our findings highlight a novel prominent role of TEAD2 in orchestrating higher-order chromatin structures of 2i-specific genes to sustain ground-state pluripotency.
    Keywords:  Ancillary Factor; Chromatin Looping; Embryonic Stem Cells; Ground-state Pluripotency; TEAD2
    DOI:  https://doi.org/10.1038/s44318-024-00086-5
  7. Cell Genom. 2024 Apr 10. pii: S2666-979X(24)00093-4. [Epub ahead of print]4(4): 100537
    Mutant FOXO1 controls an oncogenic network via enhancer accessibility.
    Hillary M Layden, Jacob D Ellis, Monica L Bomber, Luke N Bartlett, Scott W Hiebert, Kristy R Stengel.
      Transcriptional dysregulation is a hallmark of diffuse large B cell lymphoma (DLBCL), as transcriptional regulators are frequently mutated. However, our mechanistic understanding of how normal transcriptional programs are co-opted in DLBCL has been hindered by a lack of methodologies that provide the temporal resolution required to separate direct and indirect effects on transcriptional control. We applied a chemical-genetic approach to engineer the inducible degradation of the transcription factor FOXO1, which is recurrently mutated (mFOXO1) in DLBCL. The combination of rapid degradation of mFOXO1, nascent transcript detection, and assessment of chromatin accessibility allowed us to identify the direct targets of mFOXO1. mFOXO1 was required to maintain accessibility at specific enhancers associated with multiple oncogenes, and mFOXO1 degradation impaired RNA polymerase pause-release at some targets. Wild-type FOXO1 appeared to weakly regulate many of the same targets as mFOXO1 and was able to complement the degradation of mFOXO1 in the context of AKT inhibition.
    Keywords:  ATAC-seq; DLBCL; FOXO1; PRO-seq; chromatin remodeling; dark zone; enhancer; therapeutics
    DOI:  https://doi.org/10.1016/j.xgen.2024.100537
  8. Nat Comput Sci. 2024 Apr 10.
    Deciphering cell types by integrating scATAC-seq data with genome sequences.
    Yuansong Zeng, Mai Luo, Ningyuan Shangguan, Peiyu Shi, Junxi Feng, Jin Xu, Ken Chen, Yutong Lu, Weijiang Yu, Yuedong Yang.
      The single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) technology provides insight into gene regulation and epigenetic heterogeneity at single-cell resolution, but cell annotation from scATAC-seq remains challenging due to high dimensionality and extreme sparsity within the data. Existing cell annotation methods mostly focus on the cell peak matrix without fully utilizing the underlying genomic sequence. Here we propose a method, SANGO, for accurate single-cell annotation by integrating genome sequences around the accessibility peaks within scATAC data. The genome sequences of peaks are encoded into low-dimensional embeddings, and then iteratively used to reconstruct the peak statistics of cells through a fully connected network. The learned weights are considered as regulatory modes to represent cells, and utilized to align the query cells and the annotated cells in the reference data through a graph transformer network for cell annotations. SANGO was demonstrated to consistently outperform competing methods on 55 paired scATAC-seq datasets across samples, platforms and tissues. SANGO was also shown to be able to detect unknown tumor cells through attention edge weights learned by the graph transformer. Moreover, from the annotated cells, we found cell-type-specific peaks that provide functional insights/biological signals through expression enrichment analysis, cis-regulatory chromatin interaction analysis and motif enrichment analysis.
    DOI:  https://doi.org/10.1038/s43588-024-00622-7
  9. Nat Cell Biol. 2024 Apr 08.
    Transcription bodies regulate gene expression by sequestering CDK9.
    Martino Ugolini, Maciej A Kerlin, Ksenia Kuznetsova, Haruka Oda, Hiroshi Kimura, Nadine L Vastenhouw.
      The localization of transcriptional activity in specialized transcription bodies is a hallmark of gene expression in eukaryotic cells. It remains unclear, however, if and how transcription bodies affect gene expression. Here we disrupted the formation of two prominent endogenous transcription bodies that mark the onset of zygotic transcription in zebrafish embryos and analysed the effect on gene expression using enriched SLAM-seq and live-cell imaging. We find that the disruption of transcription bodies results in the misregulation of hundreds of genes. Here we focus on genes that are upregulated. These genes have accessible chromatin and are poised to be transcribed in the presence of the two transcription bodies, but they do not go into elongation. Live-cell imaging shows that disruption of the two large transcription bodies enables these poised genes to be transcribed in ectopic transcription bodies, suggesting that the large transcription bodies sequester a pause release factor. Supporting this hypothesis, we find that CDK9-the kinase that releases paused polymerase II-is highly enriched in the two large transcription bodies. Overexpression of CDK9 in wild-type embryos results in the formation of ectopic transcription bodies and thus phenocopies the removal of the two large transcription bodies. Taken together, our results show that transcription bodies regulate transcription by sequestering machinery, thereby preventing genes elsewhere in the nucleus from being transcribed.
    DOI:  https://doi.org/10.1038/s41556-024-01389-9
  10. Nat Biotechnol. 2024 Apr 12.
    Inferring gene regulatory networks from single-cell multiome data using atlas-scale external data.
    Qiuyue Yuan, Zhana Duren.
      Existing methods for gene regulatory network (GRN) inference rely on gene expression data alone or on lower resolution bulk data. Despite the recent integration of chromatin accessibility and RNA sequencing data, learning complex mechanisms from limited independent data points still presents a daunting challenge. Here we present LINGER (Lifelong neural network for gene regulation), a machine-learning method to infer GRNs from single-cell paired gene expression and chromatin accessibility data. LINGER incorporates atlas-scale external bulk data across diverse cellular contexts and prior knowledge of transcription factor motifs as a manifold regularization. LINGER achieves a fourfold to sevenfold relative increase in accuracy over existing methods and reveals a complex regulatory landscape of genome-wide association studies, enabling enhanced interpretation of disease-associated variants and genes. Following the GRN inference from reference single-cell multiome data, LINGER enables the estimation of transcription factor activity solely from bulk or single-cell gene expression data, leveraging the abundance of available gene expression data to identify driver regulators from case-control studies.
    DOI:  https://doi.org/10.1038/s41587-024-02182-7
  11. Nat Genet. 2024 Apr 09.
    Tissue-specific enhancer-gene maps from multimodal single-cell data identify causal disease alleles.
    Accelerating Medicines Partnership® RA/SLE Program and Network
      Translating genome-wide association study (GWAS) loci into causal variants and genes requires accurate cell-type-specific enhancer-gene maps from disease-relevant tissues. Building enhancer-gene maps is essential but challenging with current experimental methods in primary human tissues. Here we developed a nonparametric statistical method, SCENT (single-cell enhancer target gene mapping), that models association between enhancer chromatin accessibility and gene expression in single-cell or nucleus multimodal RNA sequencing and ATAC sequencing data. We applied SCENT to 9 multimodal datasets including >120,000 single cells or nuclei and created 23 cell-type-specific enhancer-gene maps. These maps were highly enriched for causal variants in expression quantitative loci and GWAS for 1,143 diseases and traits. We identified likely causal genes for both common and rare diseases and linked somatic mutation hotspots to target genes. We demonstrate that application of SCENT to multimodal data from disease-relevant human tissue enables the scalable construction of accurate cell-type-specific enhancer-gene maps, essential for defining noncoding variant function.
    DOI:  https://doi.org/10.1038/s41588-024-01682-1
  12. Nature. 2024 Apr 08.
    Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer.
    Urszula N Wasko, Jingjing Jiang, Tanner C Dalton, Alvaro Curiel-Garcia, A Cole Edwards, Yingyun Wang, Bianca Lee, Margo Orlen, Sha Tian, Clint A Stalnecker, Kristina Drizyte-Miller, Marie Menard, Julien Dilly, Stephen A Sastra, Carmine F Palermo, Marie C Hasselluhn, Amanda R Decker-Farrell, Stephanie Chang, Lingyan Jiang, Xing Wei, Yu C Yang, Ciara Helland, Haley Courtney, Yevgeniy Gindin, Karl Muonio, Ruiping Zhao, Samantha B Kemp, Cynthia Clendenin, Rina Sor, William P Vostrejs, Priya S Hibshman, Amber M Amparo, Connor Hennessey, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Jens Brodbeck, Lorenzo Tomassoni, Basil Bakir, Nicholas D Socci, Laura E Herring, Natalie K Barker, Junning Wang, James M Cleary, Brian M Wolpin, John A Chabot, Michael D Kluger, Gulam A Manji, Kenneth Y Tsai, Miroslav Sekulic, Stephen M Lagana, Andrea Califano, Elsa Quintana, Zhengping Wang, Jacqueline A M Smith, Matthew Holderfield, David Wildes, Scott W Lowe, Michael A Badgley, Andrew J Aguirre, Robert H Vonderheide, Ben Z Stanger, Timour Baslan, Channing J Der, Mallika Singh, Kenneth P Olive.
      Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants (RAS(ON) multi-selective)3. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS4, we assessed the therapeutic potential of the RAS(ON) multi-selective inhibitor RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumor activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumors identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.
    DOI:  https://doi.org/10.1038/s41586-024-07379-z
  13. Dev Biol. 2024 Apr 07. pii: S0012-1606(24)00091-5. [Epub ahead of print]511 53-62
    TATA-binding associated factors have distinct roles during early mammalian development.
    Xinjian Doris He, Shelby Phillips, Kaito Hioki, Prabin Dhangada Majhi, Courtney Babbitt, Kimberly D Tremblay, Leonid A Pobezinsky, Jesse Mager.
      Early embryonic development is a finely orchestrated process that requires precise regulation of gene expression coordinated with morphogenetic events. TATA-box binding protein-associated factors (TAFs), integral components of transcription initiation coactivators like TFIID and SAGA, play a crucial role in this intricate process. Here we show that disruptions in TAF5, TAF12 and TAF13 individually lead to embryonic lethality in the mouse, resulting in overlapping yet distinct phenotypes. Taf5 and Taf12 mutant embryos exhibited a failure to implant post-blastocyst formation, and Taf5 mutants have aberrant lineage specification within the inner cell mass. In contrast, Taf13 mutant embryos successfully implant and form egg-cylinder stages but fail to initiate gastrulation. Strikingly, we observed a depletion of pluripotency factors in TAF13-deficient embryos, including OCT4, NANOG and SOX2, highlighting an indispensable role of TAF13 in maintaining pluripotency. Transcriptomic analysis revealed distinct gene targets affected by the loss of TAF5, TAF12 and TAF13. Thus, we propose that TAF5, TAF12 and TAF13 convey locus specificity to the TFIID complex throughout the mouse genome.
    Keywords:  Gastrulation; Pluripotency; Preimplantation; SAGA; Taf12; Taf13, TFIID; Taf5
    DOI:  https://doi.org/10.1016/j.ydbio.2024.04.002
  14. Nucleic Acids Res. 2024 Apr 08. pii: gkae233. [Epub ahead of print]
    ARID1A regulates DNA repair through chromatin organization and its deficiency triggers DNA damage-mediated anti-tumor immune response.
    Ali Bakr, Giuditta Della Corte, Olivera Veselinov, Simge Kelekçi, Mei-Ju May Chen, Yu-Yu Lin, Gianluca Sigismondo, Marika Iacovone, Alice Cross, Rabail Syed, Yunhee Jeong, Etienne Sollier, Chun-Shan Liu, Pavlo Lutsik, Jeroen Krijgsveld, Dieter Weichenhan, Christoph Plass, Odilia Popanda, Peter Schmezer.
      AT-rich interaction domain protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. Loss of ARID1A leads to DNA repair defects. Here, we show that ARID1A plays epigenetic roles to promote both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates chromatin loops formation by recruiting RAD21 and CTCF to DSBs. Simultaneously, ARID1A facilitates transcription silencing at DSBs in transcriptionally active chromatin by recruiting HDAC1 and RSF1 to control the distribution of activating histone marks, chromatin accessibility, and eviction of RNAPII. ARID1A depletion resulted in enhanced accumulation of micronuclei, activation of cGAS-STING pathway, and an increased expression of immunomodulatory cytokines upon ionizing radiation. Furthermore, low ARID1A expression in cancer patients receiving radiotherapy was associated with higher infiltration of several immune cells. The high mutation rate of ARID1A in various cancer types highlights its clinical relevance as a promising biomarker that correlates with the level of immune regulatory cytokines and estimates the levels of tumor-infiltrating immune cells, which can predict the response to the combination of radio- and immunotherapy.
    DOI:  https://doi.org/10.1093/nar/gkae233
  15. Cancer Discov. 2024 Apr 08.
    ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer.
    Yaru Xu, Yuqiu Yang, Zhaoning Wang, Martin Sjostrom, Yuyin Jiang, Yitao Tang, Siyuan Cheng, Su Deng, Choushi Wang, Julisa Gonzalez, Nickolas A Johnson, Xiang Li, Xiaoling Li, Lauren A Metang, Atreyi Mukherji, Quanhui Xu, Carla Rodriguez Tirado, Garrett Wainwright, Xinzhe Yu, Spencer Barnes, Mia Hofstad, Yu Chen, Hong Zhu, Ariella B Hanker, Ganesh V Raj, Guanghui Zhu, Housheng Hansen He, Zhao Wang, Carlos L Arteaga, Han Liang, Felix Y Feng, Yunguan Wang, Tao Wang, Ping Mu.
      Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the resistance to AR targeted therapies in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0539
  16. Cell Rep. 2024 Apr 08. pii: S2211-1247(24)00405-4. [Epub ahead of print]43(4): 114077
    The dynamic landscape of enhancer-derived RNA during mouse early embryo development.
    Hua Yu, Jing Zhao, Yuxuan Shen, Lu Qiao, Yuheng Liu, Guanglei Xie, Shuhui Chang, Tingying Ge, Nan Li, Ming Chen, Hu Li, Jin Zhang, Xi Wang.
      Enhancer-derived RNAs (eRNAs) play critical roles in diverse biological processes by facilitating their target gene expression. However, the abundance and function of eRNAs in early embryos are not clear. Here, we present a comprehensive eRNA atlas by systematically integrating publicly available datasets of mouse early embryos. We characterize the transcriptional and regulatory network of eRNAs and show that different embryo developmental stages have distinct eRNA expression and regulatory profiles. Paternal eRNAs are activated asymmetrically during zygotic genome activation (ZGA). Moreover, we identify an eRNA, MZGAe1, which plays an important function in regulating mouse ZGA and early embryo development. MZGAe1 knockdown leads to a developmental block from 2-cell embryo to blastocyst. We create an online data portal, M2ED2, to query and visualize eRNA expression and regulation. Our study thus provides a systematic landscape of eRNA and reveals the important role of eRNAs in regulating mouse early embryo development.
    Keywords:  CP: Developmental biology; CP: Molecular biology; CP: Stem cell research
    DOI:  https://doi.org/10.1016/j.celrep.2024.114077
  17. Plant Cell. 2024 Apr 06. pii: koae107. [Epub ahead of print]
    Arabidopsis transcription factor TCP4 controls the identity of the apical gynoecium.
    Yutao Wang, Ning Wang, Jingqiu Lan, Yige Pan, Yidan Jiang, Yongqi Wu, Xuemei Chen, Xianzhong Feng, Genji Qin.
      The style and stigma at the apical gynoecium are crucial for flowering plant reproduction. However, the mechanisms underlying specification of the apical gynoecium remain unclear. Here, we demonstrate that Class II TEOSINTE BRANCHED 1/CYCLOIDEA/PCF (TCP) transcription factors are critical for apical gynoecium specification in Arabidopsis (Arabidopsis thaliana). The septuple tcp2 tcp3 tcp4 tcp5 tcp10 tcp13 tcp17 (tcpSEP) and duodecuple tcp2 tcp3 tcp4 tcp5 tcp10 tcp13 tcp17 tcp24 tcp1 tcp12 tcp18 tcp16 (tcpDUO) mutants produce narrower and longer styles, while disruption of TCPs and CRABS CLAW (CRC) or NGATHAs (NGAs) in tcpDUO crc or tcpDUO nga1 nga2 nga4 causes the apical gynoecium to be replaced by lamellar structures with indeterminate growth. TCPs are predominantly expressed in the apex of the gynoecium. TCP4 interacts with CRC to synergistically up-regulate the expression level of NGAs, and NGAs further form high-order complexes to control the expression of auxin-related genes in the apical gynoecium by directly interacting with TCP4. Our findings demonstrate that TCP4 physically associates with CRC and NGAs to control auxin biosynthesis in forming fine structures of the apical gynoecium.
    DOI:  https://doi.org/10.1093/plcell/koae107
  18. Cell. 2024 Apr 05. pii: S0092-8674(24)00311-8. [Epub ahead of print]
    Chromatin context-dependent regulation and epigenetic manipulation of prime editing.
    Xiaoyi Li, Wei Chen, Beth K Martin, Diego Calderon, Choli Lee, Junhong Choi, Florence M Chardon, Troy A McDiarmid, Riza M Daza, Haedong Kim, Jean-Benoît Lalanne, Jenny F Nathans, David S Lee, Jay Shendure.
      We set out to exhaustively characterize the impact of the cis-chromatin environment on prime editing, a precise genome engineering tool. Using a highly sensitive method for mapping the genomic locations of randomly integrated reporters, we discover massive position effects, exemplified by editing efficiencies ranging from ∼0% to 94% for an identical target site and edit. Position effects on prime editing efficiency are well predicted by chromatin marks, e.g., positively by H3K79me2 and negatively by H3K9me3. Next, we developed a multiplex perturbational framework to assess the interaction of trans-acting factors with the cis-chromatin environment on editing outcomes. Applying this framework to DNA repair factors, we identify HLTF as a context-dependent repressor of prime editing. Finally, several lines of evidence suggest that active transcriptional elongation enhances prime editing. Consistent with this, we show we can robustly decrease or increase the efficiency of prime editing by preceding it with CRISPR-mediated silencing or activation, respectively.
    Keywords:  DNA damage repair; cis x trans interactions; cis-chromatin effect; epigenome editing; genome engineering; prime editing
    DOI:  https://doi.org/10.1016/j.cell.2024.03.020
  19. Mol Cell. 2024 Apr 02. pii: S1097-2765(24)00225-9. [Epub ahead of print]
    An RNA-dependent and phase-separated active subnuclear compartment safeguards repressive chromatin domains.
    Luigi Lerra, Martina Panatta, Dominik Bär, Isabella Zanini, Jennifer Yihong Tan, Agnese Pisano, Chiara Mungo, Célia Baroux, Vikram Govind Panse, Ana C Marques, Raffaella Santoro.
      The nucleus is composed of functionally distinct membraneless compartments that undergo phase separation (PS). However, whether different subnuclear compartments are connected remains elusive. We identified a type of nuclear body with PS features composed of BAZ2A that associates with active chromatin. BAZ2A bodies depend on RNA transcription and BAZ2A non-disordered RNA-binding TAM domain. Although BAZ2A and H3K27me3 occupancies anticorrelate in the linear genome, in the nuclear space, BAZ2A bodies contact H3K27me3 bodies. BAZ2A-body disruption promotes BAZ2A invasion into H3K27me3 domains, causing H3K27me3-body loss and gene upregulation. Weak BAZ2A-RNA interactions, such as with nascent transcripts, promote BAZ2A bodies, whereas the strong binder long non-coding RNA (lncRNA) Malat1 impairs them while mediating BAZ2A association to chromatin at nuclear speckles. In addition to unraveling a direct connection between nuclear active and repressive compartments through PS mechanisms, the results also showed that the strength of RNA-protein interactions regulates this process, contributing to nuclear organization and the regulation of chromatin and gene expression.
    Keywords:  BAZ2A; H3K27me3; Malat1; RNA; chromatin; ground-state pluripotency; nuclear condensates; nuclear speckles; phase separation
    DOI:  https://doi.org/10.1016/j.molcel.2024.03.015
  20. Cell Rep. 2024 Apr 10. pii: S2211-1247(24)00432-7. [Epub ahead of print]43(4): 114104
    Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function.
    Jun Takahashi, Takafumi Suzuki, Miu Sato, Shuji Nitta, Nahoko Yaguchi, Tatsuki Muta, Kouhei Tsuchida, Hiromi Suda, Masanobu Morita, Shin Hamada, Atsushi Masamune, Satoru Takahashi, Takashi Kamei, Masayuki Yamamoto.
      Clinical evidence has revealed that high-level activation of NRF2 caused by somatic mutations in NRF2 (NFE2L2) is frequently detected in esophageal squamous cell carcinoma (ESCC), whereas that caused by somatic mutations in KEAP1, a negative regulator of NRF2, is not. Here, we aspire to generate a mouse model of NRF2-activated ESCC using the cancer-derived NRF2L30F mutation and cancer driver mutant TRP53R172H. Concomitant expression of NRF2L30F and TRP53R172H results in formation of NRF2-activated ESCC-like lesions. In contrast, while squamous-cell-specific deletion of KEAP1 induces similar NRF2 hyperactivation, the loss of KEAP1 combined with expression of TRP53R172H does not elicit the formation of ESCC-like lesions. Instead, KEAP1-deleted cells disappear from the esophageal epithelium over time. These findings demonstrate that, while cellular NRF2 levels are similarly induced, NRF2 gain of function and KEAP1 loss of function elicits distinct fates of squamous cells. The NRF2L30F mutant mouse model developed here will be instrumental in elucidating the mechanistic basis leading to NRF2-activated ESCC.
    Keywords:  CP: Cancer
    DOI:  https://doi.org/10.1016/j.celrep.2024.114104
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