bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2024–07–28
24 papers selected by
Connor Rogerson, University of Cambridge
  1. 3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression.
  2. Cohesin prevents cross-domain gene coactivation.
  3. USP11 promotes prostate cancer progression by up-regulating AR and c-Myc activity.
  4. Epigenetic memory is governed by an effector recruitment specificity toggle in Heterochromatin Protein 1.
  5. Swi/Snf chromatin remodeling regulates transcriptional interference and gene repression.
  6. Single gene analysis in yeast suggests nonequilibrium regulatory dynamics for transcription.
  7. Tuning cohesin trajectories enables differential readout of the Pcdhα cluster across neurons.
  8. Hippo pathway-mediated YAP1/TAZ inhibition is essential for proper pancreatic endocrine specification and differentiation.
  9. Generating information-dense promoter sequences with optimal string packing.
  10. Remodeling of perturbed chromatin can initiate de novo transcriptional and post-transcriptional silencing.
  11. IRF8 and MAFB drive distinct transcriptional machineries in different resident macrophages of the central nervous system.
  12. 3D chromatin structures associated with ncRNA roX2 for hyperactivation and coactivation across the entire X chromosome.
  13. Engineering mouse cell fate controller by rational design.
  14. YAP/TAZ enhances P-body formation to promote tumorigenesis.
  15. Interpretable deep residual network uncovers nucleosome positioning and associated features.
  16. Structural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction.
  17. Nuclear pyruvate dehydrogenase complex regulates histone acetylation and transcriptional regulation in the ethylene response.
  18. HYENA detects oncogenes activated by distal enhancers in cancer.
  19. Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.
  20. Elf1 promotes transcription-coupled repair in yeast by using its C-terminal domain to bind TFIIH.
  21. Assembly mechanism of Integrator's RNA cleavage module.
  22. HIRA complex deposition of histone H3.3 is driven by histone tetramerization and histone-DNA binding.
  23. Single-cell multi-omic and spatial profiling of human kidneys implicates the fibrotic microenvironment in kidney disease progression.
  24. MYB-related transcription factors control chloroplast biogenesis.
  1. Nat Commun. 2024 Jul 20. 15(1): 6130
    3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression.
    Katelyn L Mortenson, Courtney Dawes, Emily R Wilson, Nathan E Patchen, Hailey E Johnson, Jason Gertz, Swneke D Bailey, Yang Liu, Katherine E Varley, Xiaoyang Zhang.
      Cancer genomes are composed of many complex structural alterations on chromosomes and extrachromosomal DNA (ecDNA), making it difficult to identify non-coding enhancer regions that are hijacked to activate oncogene expression. Here, we describe a 3D genomics-based analysis called HAPI (Highly Active Promoter Interactions) to characterize enhancer hijacking. HAPI analysis of HiChIP data from 34 cancer cell lines identified enhancer hijacking events that activate both known and potentially novel oncogenes such as MYC, CCND1, ETV1, CRKL, and ID4. Furthermore, we found enhancer hijacking among multiple oncogenes from different chromosomes, often including MYC, on the same complex amplicons such as ecDNA. We characterized a MYC-ERBB2 chimeric ecDNA, in which ERBB2 heavily hijacks MYC's enhancers. Notably, CRISPRi of the MYC promoter led to increased interaction of ERBB2 with MYC enhancers and elevated ERBB2 expression. Our HAPI analysis tool provides a robust strategy to detect enhancer hijacking and reveals novel insights into oncogene activation.
    DOI:  https://doi.org/10.1038/s41467-024-50387-w
  2. Nat Genet. 2024 Jul 24.
    Cohesin prevents cross-domain gene coactivation.
    Peng Dong, Shu Zhang, Valentina Gandin, Liangqi Xie, Lihua Wang, Andrew L Lemire, Wenhong Li, Hideo Otsuna, Takashi Kawase, Arthur D Lander, Howard Y Chang, Zhe J Liu.
      The contrast between the disruption of genome topology after cohesin loss and the lack of downstream gene expression changes instigates intense debates regarding the structure-function relationship between genome and gene regulation. Here, by analyzing transcriptome and chromatin accessibility at the single-cell level, we discover that, instead of dictating population-wide gene expression levels, cohesin supplies a general function to neutralize stochastic coexpression tendencies of cis-linked genes in single cells. Notably, cohesin loss induces widespread gene coactivation and chromatin co-opening tens of million bases apart in cis. Spatial genome and protein imaging reveals that cohesin prevents gene co-bursting along the chromosome and blocks spatial mixing of transcriptional hubs. Single-molecule imaging shows that cohesin confines the exploration of diverse enhancer and core promoter binding transcriptional regulators. Together, these results support that cohesin arranges nuclear topology to control gene coexpression in single cells.
    DOI:  https://doi.org/10.1038/s41588-024-01852-1
  3. Proc Natl Acad Sci U S A. 2024 Jul 30. 121(31): e2403331121
    USP11 promotes prostate cancer progression by up-regulating AR and c-Myc activity.
    Majid Pornour, Hee-Young Jeon, Hyunju Ryu, Sudeep Khadka, Rui Xu, Hegang Chen, Arif Hussain, Hung-Ming Lam, Zhihao Zhuang, Htoo Zarni Oo, Martin Gleave, Xuesen Dong, Qianben Wang, Christopher Barbieri, Jianfei Qi.
      Androgen receptor (AR) is a main driver for castration-resistant prostate cancer (CRPC). c-Myc is an oncogene underlying prostate tumorigenesis. Here, we find that the deubiquitinase USP11 targets both AR and c-Myc in prostate cancer (PCa). USP11 expression was up-regulated in metastatic PCa and CRPC. USP11 knockdown (KD) significantly inhibited PCa cell growth. Our RNA-seq studies revealed AR and c-Myc as the top transcription factors altered after USP11 KD. ChIP-seq analysis showed that either USP11 KD or replacement of endogenous USP11 with a catalytic-inactive USP11 mutant significantly decreased chromatin binding by AR and c-Myc. We find that USP11 employs two mechanisms to up-regulate AR and c-Myc levels: namely, deubiquitination of AR and c-Myc proteins to increase their stability and deubiquitination of H2A-K119Ub, a repressive histone mark, on promoters of AR and c-Myc genes to increase their transcription. AR and c-Myc reexpression in USP11-KD PCa cells partly rescued cell growth defects. Thus, our studies reveal a tumor-promoting role for USP11 in aggressive PCa through upregulation of AR and c-Myc activities and support USP11 as a potential target against PCa.
    Keywords:  AR; c-Myc; gene expression; prostate cancer; ubiquitination
    DOI:  https://doi.org/10.1073/pnas.2403331121
  4. Nat Commun. 2024 Jul 25. 15(1): 6276
    Epigenetic memory is governed by an effector recruitment specificity toggle in Heterochromatin Protein 1.
    Amanda Ames, Melissa Seman, Ajay Larkin, Gulzhan Raiymbek, Ziyuan Chen, Alex Levashkevich, Bokyung Kim, Julie Suzanne Biteen, Kaushik Ragunathan.
      HP1 proteins are essential for establishing and maintaining transcriptionally silent heterochromatin. They dimerize, forming a binding interface to recruit diverse chromatin-associated factors. Although HP1 proteins are known to rapidly evolve, the extent of variation required to achieve functional specialization is unknown. To investigate how changes in amino acid sequence impacts heterochromatin formation, we performed a targeted mutagenesis screen of the S. pombe HP1 homolog, Swi6. Substitutions within an auxiliary surface adjacent to the HP1 dimerization interface produce Swi6 variants with divergent maintenance properties. Remarkably, substitutions at a single amino acid position lead to the persistent gain or loss of epigenetic inheritance. These substitutions increase Swi6 chromatin occupancy in vivo and altered Swi6-protein interactions that reprogram H3K9me maintenance. We show how relatively minor changes in Swi6 amino acid composition in an auxiliary surface can lead to profound changes in epigenetic inheritance providing a redundant mechanism to evolve HP1-effector specificity.
    DOI:  https://doi.org/10.1038/s41467-024-50538-z
  5. Mol Cell. 2024 Jul 12. pii: S1097-2765(24)00536-7. [Epub ahead of print]
    Swi/Snf chromatin remodeling regulates transcriptional interference and gene repression.
    Kaitlin Morse, Alena L Bishop, Sarah Swerdlow, Jessica M Leslie, Elçin Ünal.
      Alternative transcription start sites can affect transcript isoform diversity and translation levels. In a recently described form of gene regulation, coordinated transcriptional and translational interference results in transcript isoform-dependent changes in protein expression. Specifically, a long undecoded transcript isoform (LUTI) is transcribed from a gene-distal promoter, interfering with expression of the gene-proximal promoter. Although transcriptional and chromatin features associated with LUTI expression have been described, the mechanism underlying LUTI-based transcriptional interference is not well understood. Using an unbiased genetic approach followed by functional genomics, we uncovered that the Swi/Snf chromatin remodeling complex is required for co-transcriptional nucleosome remodeling that leads to LUTI-based repression. We identified genes with tandem promoters that rely on Swi/Snf function for transcriptional interference during protein folding stress, including LUTI-regulated genes. This study provides clear evidence for Swi/Snf playing a direct role in gene repression via a cis transcriptional interference mechanism.
    Keywords:  LUTI; SWI/SNF; chromatin; chromatin remodeling; gene regulation; gene repression; transcription; transcription elongation; transcriptional interference; unfolded protein response
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.029
  6. Nat Commun. 2024 Jul 23. 15(1): 6226
    Single gene analysis in yeast suggests nonequilibrium regulatory dynamics for transcription.
    Robert Shelansky, Sara Abrahamsson, Christopher R Brown, Michael Doody, Tineke L Lenstra, Daniel R Larson, Hinrich Boeger.
      Fluctuations in the initiation rate of transcription, the first step in gene expression, ensue from the stochastic behavior of the molecular process that controls transcription. In steady state, the regulatory process is often assumed to operate reversibly, i.e., in equilibrium. However, reversibility imposes fundamental limits to information processing. For instance, the assumption of equilibrium is difficult to square with the precision with which the regulatory process executes its task in eukaryotes. Here we provide evidence - from microscopic analyses of the transcription dynamics at a single gene copy of yeast - that the regulatory process for transcription is cyclic and irreversible (out of equilibrium). The necessary coupling to reservoirs of free energy occurs via sequence-specific transcriptional activators and the recruitment, in part, of ATP-dependent chromatin remodelers. Our findings may help explain how eukaryotic cells reconcile the dual but opposing requirements for fast regulatory kinetics and high regulatory specificity.
    DOI:  https://doi.org/10.1038/s41467-024-50419-5
  7. Science. 2024 Jul 26. 385(6707): eadm9802
    Tuning cohesin trajectories enables differential readout of the Pcdhα cluster across neurons.
    Lea Kiefer, Simon Gaudin, Sandy M Rajkumar, Gabrielle Isabelle F Servito, Jennifer Langen, Michael H Mui, Shayra Nawsheen, Daniele Canzio.
      Expression of Protocadherin (Pcdh) genes is critical to the generation of neuron identity and wiring of the nervous system. Pcdhα genes are arranged in clusters and exhibit a range of expression profiles, from stochastic to deterministic. Because Pcdhα promoters have high sequence identity and share distal enhancers, how distinct neurons choose which gene to express remains unclear. We show that the interplay between multiple enhancers, epigenetics, and genome folding orchestrates differential readouts of the locus across neurons. The probability of Pcdhα promoter choice depends on enhancer/promoter encounters catalyzed by cohesin, whose extrusion trajectories determine the likelihood that an individual promoter can "escape" heterochromatin-mediated silencing. We propose that tunable locus-specific regulatory elements and cell type-specific cohesin activity underlie the generation of cellular diversity by Pcdh genes.
    DOI:  https://doi.org/10.1126/science.adm9802
  8. Elife. 2024 Jul 25. pii: e84532. [Epub ahead of print]13
    Hippo pathway-mediated YAP1/TAZ inhibition is essential for proper pancreatic endocrine specification and differentiation.
    Yifan Wu, Kunhua Qin, Yi Xu, Shreya Rajhans, Truong Vo, Kevin M Lopez, Jun Liu, Michael H Nipper, Janice Deng, Xue Yin, Logan R Ramjit, Zhenqing Ye, Yu Luan, H Efsun Arda, Pei Wang.
      The Hippo pathway plays a central role in tissue development and homeostasis. However, the function of Hippo in pancreatic endocrine development remains obscure. Here, we generated novel conditional genetically engineered mouse models to examine the roles of Hippo pathway-mediated YAP1/TAZ inhibition in the development stages of endocrine specification and differentiation. While YAP1 protein was localized to the nuclei in bipotent progenitor cells, Neurogenin 3 expressing endocrine progenitors completely lost YAP1 expression. Using genetically engineered mouse models, we found that inactivation of YAP1 requires both an intact Hippo pathway and Neurogenin 3 protein. Gene deletion of Lats1 and 2 kinases (Lats1&2) in endocrine progenitor cells of developing mouse pancreas using Neurog3Cre blocked endocrine progenitor cell differentiation and specification, resulting in reduced islets size and a disorganized pancreas at birth. Loss of Lats1&2 in Neurogenin 3 expressing cells activated YAP1/TAZ transcriptional activity and recruited macrophages to the developing pancreas. These defects were rescued by deletion of Yap1/Wwtr1 genes, suggesting that tight regulation of YAP1/TAZ by Hippo signaling is crucial for pancreatic endocrine specification. In contrast, deletion of Lats1&2 using β-cell-specific Ins1CreER resulted in a phenotypically normal pancreas, indicating that Lats1&2 are indispensable for differentiation of endocrine progenitors but not for that of β-cells. Our results demonstrate that loss of YAP1/TAZ expression in the pancreatic endocrine compartment is not a passive consequence of endocrine specification. Rather, Hippo pathway-mediated inhibition of YAP1/TAZ in endocrine progenitors is a prerequisite for endocrine specification and differentiation.
    Keywords:  Hippo signaling; development; developmental biology; differentiation; endocrine progenitors; mouse; pancreas; specification
    DOI:  https://doi.org/10.7554/eLife.84532
  9. PLoS Comput Biol. 2024 Jul;20(7): e1012276
    Generating information-dense promoter sequences with optimal string packing.
    Virgile Andreani, Eric J South, Mary J Dunlop.
      Dense arrangements of binding sites within nucleotide sequences can collectively influence downstream transcription rates or initiate biomolecular interactions. For example, natural promoter regions can harbor many overlapping transcription factor binding sites that influence the rate of transcription initiation. Despite the prevalence of overlapping binding sites in nature, rapid design of nucleotide sequences with many overlapping sites remains a challenge. Here, we show that this is an NP-hard problem, coined here as the nucleotide String Packing Problem (SPP). We then introduce a computational technique that efficiently assembles sets of DNA-protein binding sites into dense, contiguous stretches of double-stranded DNA. For the efficient design of nucleotide sequences spanning hundreds of base pairs, we reduce the SPP to an Orienteering Problem with integer distances, and then leverage modern integer linear programming solvers. Our method optimally packs sets of 20-100 binding sites into dense nucleotide arrays of 50-300 base pairs in 0.05-10 seconds. Unlike approximation algorithms or meta-heuristics, our approach finds provably optimal solutions. We demonstrate how our method can generate large sets of diverse sequences suitable for library generation, where the frequency of binding site usage across the returned sequences can be controlled by modulating the objective function. As an example, we then show how adding additional constraints, like the inclusion of sequence elements with fixed positions, allows for the design of bacterial promoters. The nucleotide string packing approach we present can accelerate the design of sequences with complex DNA-protein interactions. When used in combination with synthesis and high-throughput screening, this design strategy could help interrogate how complex binding site arrangements impact either gene expression or biomolecular mechanisms in varied cellular contexts.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012276
  10. Proc Natl Acad Sci U S A. 2024 Jul 30. 121(31): e2402944121
    Remodeling of perturbed chromatin can initiate de novo transcriptional and post-transcriptional silencing.
    Florian Carlier, Sebastian Castro Ramirez, Jaafar Kilani, Sara Chehboub, Isabelle Loïodice, Angela Taddei, Eugene Gladyshev.
      In eukaryotes, repetitive DNA can become silenced de novo, either transcriptionally or post-transcriptionally, by processes independent of strong sequence-specific cues. The mechanistic nature of such processes remains poorly understood. We found that in the fungus Neurospora crassa, de novo initiation of both transcriptional and post-transcriptional silencing was linked to perturbed chromatin, which was produced experimentally by the aberrant activity of transcription factors at the tetO operator array. Transcriptional silencing was mediated by canonical constitutive heterochromatin. On the other hand, post-transcriptional silencing resembled repeat-induced quelling but occurred normally when homologous recombination was inactivated. All silencing of the tetO array was dependent on SAD-6, fungal ortholog of the SWI/SNF chromatin remodeler ATRX (Alpha Thalassemia/Mental Retardation Syndrome X-Linked), which was required to maintain nucleosome occupancy at the perturbed locus. In addition, we found that two other types of sequences (the lacO array and native AT-rich DNA) could also undergo recombination-independent quelling associated with perturbed chromatin. These results suggested a model in which the de novo initiation of transcriptional and post-transcriptional silencing is coupled to the remodeling of perturbed chromatin.
    Keywords:  Neurospora; constitutive heterochromatin; post-transcriptional gene silencing; quelling; transcriptional gene silencing
    DOI:  https://doi.org/10.1073/pnas.2402944121
  11. Commun Biol. 2024 Jul 24. 7(1): 896
    IRF8 and MAFB drive distinct transcriptional machineries in different resident macrophages of the central nervous system.
    Ayato Yamasaki, Iroha Imanishi, Kaori Tanaka, Yasuyuki Ohkawa, Makoto Tsuda, Takahiro Masuda.
      The central nervous system (CNS) includes anatomically distinct macrophage populations including parenchyma microglia and CNS-associated macrophages (CAMs) localized at the interfaces like meninges and perivascular space, which play specialized roles for the maintenance of the CNS homeostasis with the help of precisely controlled gene expressions. However, the transcriptional machinery that determines their cell-type specific states of microglia and CAMs remains poorly understood. Here we show, by myeloid cell-specific deletion of transcription factors, IRF8 and MAFB, that both adult microglia and CAMs utilize IRF8 to maintain their core gene signatures, although the genes altered by IRF8 deletion are different in the two macrophage populations. By contrast, MAFB deficiency robustly affected the gene expression profile of adult microglia, whereas CAMs are almost independent of MAFB. Our data suggest that distinct transcriptional machineries regulate different macrophages in the CNS.
    DOI:  https://doi.org/10.1038/s42003-024-06607-6
  12. Sci Adv. 2024 Jul 26. 10(30): eado5716
    3D chromatin structures associated with ncRNA roX2 for hyperactivation and coactivation across the entire X chromosome.
    Simon Zhongyuan Tian, Yang Yang, Duo Ning, Ke Fang, Kai Jing, Guangyu Huang, Yewen Xu, Pengfei Yin, Haibo Huang, Gengzhan Chen, Yuqing Deng, Shaohong Zhang, Zhimin Zhang, Zhenxia Chen, Tong Gao, Wei Chen, Guoliang Li, Ruilin Tian, Yijun Ruan, Yiming Li, Meizhen Zheng.
      The three-dimensional (3D) organization of chromatin within the nucleus is crucial for gene regulation. However, the 3D architectural features that coordinate the activation of an entire chromosome remain largely unknown. We introduce an omics method, RNA-associated chromatin DNA-DNA interactions, that integrates RNA polymerase II (RNAPII)-mediated regulome with stochastic optical reconstruction microscopy to investigate the landscape of noncoding RNA roX2-associated chromatin topology for gene equalization to achieve dosage compensation. Our findings reveal that roX2 anchors to the target gene transcription end sites (TESs) and spreads in a distinctive boot-shaped configuration, promoting a more open chromatin state for hyperactivation. Furthermore, roX2 arches TES to transcription start sites to enhance transcriptional loops, potentially facilitating RNAPII convoying and connecting proximal promoter-promoter transcriptional hubs for synergistic gene regulation. These TESs cluster as roX2 compartments, surrounded by inactive domains for coactivation of multiple genes within the roX2 territory. In addition, roX2 structures gradually form and scaffold for stepwise coactivation in dosage compensation.
    DOI:  https://doi.org/10.1126/sciadv.ado5716
  13. Nat Commun. 2024 Jul 23. 15(1): 6200
    Engineering mouse cell fate controller by rational design.
    Tao Huang, Dong Liu, Xiaomin Wang, Junqi Kuang, Manqi Wu, Beibei Wang, Zechuan Liang, Yixin Fan, Bo Chen, Zhaoyi Ma, Yu Fu, Wenhui Zhang, Jin Ming, Yue Qin, Chengchen Zhao, Bo Wang, Duanqing Pei.
      Cell fate is likely regulated by a common machinery, while components of this machine remain to be identified. Here we report the design and testing of engineered cell fate controller NanogBiD, fusing BiD or BRG1 interacting domain of SS18 with Nanog. NanogBiD promotes mouse somatic cell reprogramming efficiently in contrast to the ineffective native protein under multiple testing conditions. Mechanistic studies further reveal that it facilitates cell fate transition by recruiting the intended Brg/Brahma-associated factor (BAF) complex to modulate chromatin accessibility and reorganize cell state specific enhancers known to be occupied by canonical Nanog, resulting in precocious activation of multiple genes including Sall4, miR-302, Dppa5a and Sox15 towards pluripotency. Although we have yet to test our approach in other species, our findings suggest that engineered chromatin regulators may provide much needed tools to engineer cell fate in the cells as drugs era.
    DOI:  https://doi.org/10.1038/s41467-024-50551-2
  14. Elife. 2024 Jul 24. pii: RP88573. [Epub ahead of print]12
    YAP/TAZ enhances P-body formation to promote tumorigenesis.
    Xia Shen, Xiang Peng, YueGui Guo, Zhujiang Dai, Long Cui, Wei Yu, Yun Liu, Chen-Ying Liu.
      The role of processing bodies (P-bodies) in tumorigenesis and tumor progression is not well understood. Here, we showed that the oncogenes YAP/TAZ promote P-body formation in a series of cancer cell lines. Mechanistically, both transcriptional activation of the P-body-related genes SAMD4A, AJUBA, and WTIP and transcriptional suppression of the tumor suppressor gene PNRC1 are involved in enhancing the effects of YAP/TAZ on P-body formation in colorectal cancer (CRC) cells. By reexpression of PNRC1 or knockdown of P-body core genes (DDX6, DCP1A, and LSM14A), we determined that disruption of P-bodies attenuates cell proliferation, cell migration, and tumor growth induced by overexpression of YAP5SA in CRC. Analysis of a pancancer CRISPR screen database (DepMap) revealed co-dependencies between YAP/TEAD and the P-body core genes and correlations between the mRNA levels of SAMD4A, AJUBA, WTIP, PNRC1, and YAP target genes. Our study suggests that the P-body is a new downstream effector of YAP/TAZ, which implies that reexpression of PNRC1 or disruption of P-bodies is a potential therapeutic strategy for tumors with active YAP.
    Keywords:  Hippo pathway; P-body; PNRC1; YAP/TAZ; cancer biology; mouse
    DOI:  https://doi.org/10.7554/eLife.88573
  15. Nucleic Acids Res. 2024 Jul 22. pii: gkae623. [Epub ahead of print]
    Interpretable deep residual network uncovers nucleosome positioning and associated features.
    Yosef Masoudi-Sobhanzadeh, Shuxiang Li, Yunhui Peng, Anna R Panchenko.
      Nucleosomes represent elementary building units of eukaryotic chromosomes and consist of DNA wrapped around a histone octamer flanked by linker DNA segments. Nucleosomes are central in epigenetic pathways and their genomic positioning is associated with regulation of gene expression, DNA replication, DNA methylation and DNA repair, among other functions. Building on prior discoveries that DNA sequences noticeably affect nucleosome positioning, our objective is to identify nucleosome positions and related features across entire genome. Here, we introduce an interpretable framework based on the concepts of deep residual networks (NuPoSe). Trained on high-coverage human experimental MNase-seq data, NuPoSe is able to learn sequence and structural patterns associated with nucleosome organization in human genome. NuPoSe can be also applied to unseen data from different organisms and cell types. Our findings point to 43 informative features, most of them constitute tri-nucleotides, di-nucleotides and one tetra-nucleotide. Most features are significantly associated with the nucleosomal structural characteristics, namely, periodicity of nucleosomal DNA and its location with respect to a histone octamer. Importantly, we show that features derived from the 27 bp linker DNA flanking nucleosomes contribute up to 10% to the quality of the prediction model. This, along with the comprehensive training sets, deep-learning architecture, and feature selection method, may contribute to the NuPoSe's 80-89% classification accuracy on different independent datasets.
    DOI:  https://doi.org/10.1093/nar/gkae623
  16. Nat Commun. 2024 Jul 23. 15(1): 6217
    Structural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction.
    Xinyi Chen, Yiran Guo, Ting Zhao, Jiuwei Lu, Jian Fang, Yinsheng Wang, Gang Greg Wang, Jikui Song.
      Isoform 1 of DNA methyltransferase DNMT3A (DNMT3A1) specifically recognizes nucleosome monoubiquitylated at histone H2A lysine-119 (H2AK119ub1) for establishment of DNA methylation. Mis-regulation of this process may cause aberrant DNA methylation and pathogenesis. However, the molecular basis underlying DNMT3A1-nucleosome interaction remains elusive. Here we report the cryo-EM structure of DNMT3A1's ubiquitin-dependent recruitment (UDR) fragment complexed with H2AK119ub1-modified nucleosome. DNMT3A1 UDR occupies an extensive nucleosome surface, involving the H2A-H2B acidic patch, a surface groove formed by H2A and H3, nucleosomal DNA, and H2AK119ub1. The DNMT3A1 UDR's interaction with H2AK119ub1 affects the functionality of DNMT3A1 in cells in a context-dependent manner. Our structural and biochemical analysis also reveals competition between DNMT3A1 and JARID2, a cofactor of polycomb repression complex 2 (PRC2), for nucleosome binding, suggesting the interplay between different epigenetic pathways. Together, this study reports a molecular basis for H2AK119ub1-dependent DNMT3A1-nucleosome association, with important implications in DNMT3A1-mediated DNA methylation in development.
    DOI:  https://doi.org/10.1038/s41467-024-50526-3
  17. Sci Adv. 2024 Jul 26. 10(30): eado2825
    Nuclear pyruvate dehydrogenase complex regulates histone acetylation and transcriptional regulation in the ethylene response.
    Zhengyao Shao, Liangqiao Bian, Shyon K Ahmadi, Tyler J Daniel, Miguel A Belmonte, Jackson G Burns, Prashanth Kotla, Yang Bi, Zhouxin Shen, Shou-Ling Xu, Zhi-Yong Wang, Steven P Briggs, Hong Qiao.
      Ethylene plays its essential roles in plant development, growth, and defense responses by controlling the transcriptional reprograming, in which EIN2-C-directed regulation of histone acetylation is the first key step for chromatin to perceive ethylene signaling. But how the nuclear acetyl coenzyme A (acetyl CoA) is produced to ensure the ethylene-mediated histone acetylation is unknown. Here we report that ethylene triggers the accumulation of the pyruvate dehydrogenase complex (PDC) in the nucleus to synthesize nuclear acetyl CoA to regulate ethylene response. PDC is identified as an EIN2-C nuclear partner, and ethylene triggers its nuclear accumulation. Mutations in PDC lead to an ethylene hyposensitivity that results from the reduction of histone acetylation and transcription activation. Enzymatically active nuclear PDC synthesizes nuclear acetyl CoA for EIN2-C-directed histone acetylation and transcription regulation. These findings uncover a mechanism by which PDC-EIN2 converges the mitochondrial enzyme-mediated nuclear acetyl CoA synthesis with epigenetic and transcriptional regulation for plant hormone response.
    DOI:  https://doi.org/10.1126/sciadv.ado2825
  18. Nucleic Acids Res. 2024 Jul 25. pii: gkae646. [Epub ahead of print]
    HYENA detects oncogenes activated by distal enhancers in cancer.
    Anqi Yu, Ali E Yesilkanal, Ashish Thakur, Fan Wang, Yang Yang, William Phillips, Xiaoyang Wu, Alexander Muir, Xin He, Francois Spitz, Lixing Yang.
      Somatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm 'HYENA' to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1146 tumors across 25 types of adult tumors and identify a total of 108 candidate oncogenes including many non-coding genes. A long non-coding RNA TOB1-AS1 is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimensional genome structure. We find that high expression of TOB1-AS1 can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression.
    DOI:  https://doi.org/10.1093/nar/gkae646
  19. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00825-8. [Epub ahead of print] 114496
    Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.
    Kan Etoh, Hirotaka Araki, Tomoaki Koga, Yuko Hino, Kanji Kuribayashi, Shinjiro Hino, Mitsuyoshi Nakao.
      The senescent microenvironment and aged cells per se contribute to tissue remodeling, chronic inflammation, and age-associated dysfunction. However, the metabolic and epigenomic bases of the senescence-associated secretory phenotype (SASP) remain largely unknown. Here, we show that ATP-citrate lyase (ACLY), a key enzyme in acetyl-coenzyme A (CoA) synthesis, is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.
    Keywords:  ACLY; CP: Cell biology; CP: Metabolism; H3K27 acetylation; SASP; acetyl-CoA; citrate metabolism; senescence; senostatics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114496
  20. Nat Commun. 2024 Jul 23. 15(1): 6223
    Elf1 promotes transcription-coupled repair in yeast by using its C-terminal domain to bind TFIIH.
    Kathiresan Selvam, Jun Xu, Hannah E Wilson, Juntaek Oh, Qingrong Li, Dong Wang, John J Wyrick.
      Transcription coupled-nucleotide excision repair (TC-NER) removes DNA lesions that block RNA polymerase II (Pol II) transcription. A key step in TC-NER is the recruitment of the TFIIH complex, which initiates DNA unwinding and damage verification; however, the mechanism by which TFIIH is recruited during TC-NER, particularly in yeast, remains unclear. Here, we show that the C-terminal domain (CTD) of elongation factor-1 (Elf1) plays a critical role in TC-NER in yeast by binding TFIIH. Analysis of genome-wide repair of UV-induced cyclobutane pyrimidine dimers (CPDs) using CPD-seq indicates that the Elf1 CTD in yeast is required for efficient TC-NER. We show that the Elf1 CTD binds to the pleckstrin homology (PH) domain of the p62 subunit of TFIIH in vitro, and identify a putative TFIIH-interaction region (TIR) in the Elf1 CTD that is important for PH binding and TC-NER. The Elf1 TIR shows functional, structural, and sequence similarities to a conserved TIR in the mammalian UV sensitivity syndrome A (UVSSA) protein, which recruits TFIIH during TC-NER in mammalian cells. These findings suggest that the Elf1 CTD acts as a functional counterpart to mammalian UVSSA in TC-NER by recruiting TFIIH in response to Pol II stalling at DNA lesions.
    DOI:  https://doi.org/10.1038/s41467-024-50539-y
  21. Mol Cell. 2024 Jul 16. pii: S1097-2765(24)00539-2. [Epub ahead of print]
    Assembly mechanism of Integrator's RNA cleavage module.
    Kevin Sabath, Chunhong Qiu, Stefanie Jonas.
      The modular Integrator complex is a transcription regulator that is essential for embryonic development. It attenuates coding gene expression via premature transcription termination and performs 3'-processing of non-coding RNAs. For both activities, Integrator requires endonuclease activity that is harbored by an RNA cleavage module consisting of INTS4-9-11. How correct assembly of Integrator modules is achieved remains unknown. Here, we show that BRAT1 and WDR73 are critical biogenesis factors for the human cleavage module. They maintain INTS9-11 inactive during maturation by physically blocking the endonuclease active site and prevent premature INTS4 association. Furthermore, BRAT1 facilitates import of INTS9-11 into the nucleus, where it is joined by INTS4. Final BRAT1 release requires locking of the mature cleavage module conformation by inositol hexaphosphate (IP6). Our data explain several neurodevelopmental disorders caused by BRAT1, WDR73, and INTS11 mutations as Integrator assembly defects and reveal that IP6 is an essential co-factor for cleavage module maturation.
    Keywords:  BRAT1; Galloway-Mowat Syndrome; NEDCAS; RNA polymerase II transcription; WDR73; inositol hexaphosphate; lethal neonatal rigidity and multifocal seizure syndrome; non-coding RNA processing; transcription attenuation
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.032
  22. J Biol Chem. 2024 Jul 24. pii: S0021-9258(24)02105-7. [Epub ahead of print] 107604
    HIRA complex deposition of histone H3.3 is driven by histone tetramerization and histone-DNA binding.
    Austin Vogt, Mary Szurgot, Lauren Gardner, David C Schultz, Ronen Marmorstein.
      The HIRA histone chaperone complex is comprised of four protein subunits: HIRA, UBN1, CABIN1, and transiently associated ASF1a. All four subunits have been demonstrated to play a role in deposition of the histone variant H3.3 onto areas of actively transcribed euchromatin in cells. The mechanism by which these subunits function together to drive histone deposition has remained poorly understood. Here we present biochemical and biophysical data supporting a model whereby ASF1a delivers histone H3.3/H4 dimers to the HIRA complex, H3.3/H4 tetramerization drives the association of two HIRA/UBN1 complexes, and the affinity of the histones for DNA drives release of ASF1a and subsequent histone deposition. These findings have implications for understanding how other histone chaperone complexes may mediate histone deposition.
    Keywords:  ASF1a; CABIN1; Chromatin Regulation; HIRA; Histone Deposition; UBN1; histone H3.3
    DOI:  https://doi.org/10.1016/j.jbc.2024.107604
  23. Nat Genet. 2024 Jul 24.
    Single-cell multi-omic and spatial profiling of human kidneys implicates the fibrotic microenvironment in kidney disease progression.
    Amin Abedini, Jonathan Levinsohn, Konstantin A Klötzer, Bernhard Dumoulin, Ziyuan Ma, Julia Frederick, Poonam Dhillon, Michael S Balzer, Rojesh Shrestha, Hongbo Liu, Steven Vitale, Andi M Bergeson, Kishor Devalaraja-Narashimha, Paola Grandi, Tanmoy Bhattacharyya, Erding Hu, Steven S Pullen, Carine M Boustany-Kari, Paolo Guarnieri, Anil Karihaloo, Daniel Traum, Hanying Yan, Kyle Coleman, Matthew Palmer, Lea Sarov-Blat, Lori Morton, Christopher A Hunter, Klaus H Kaestner, Mingyao Li, Katalin Susztak.
      Kidneys are intricate three-dimensional structures in the body, yet the spatial and molecular principles of kidney health and disease remain inadequately understood. We generated high-quality datasets for 81 samples, including single-cell, single-nuclear, spot-level (Visium) and single-cell resolution (CosMx) spatial-RNA expression and single-nuclear open chromatin, capturing cells from healthy, diabetic and hypertensive diseased human kidneys. Combining these data, we identify cell types and map them to their locations within the tissue. Unbiased deconvolution of the spatial data identifies the following four distinct microenvironments: glomerular, immune, tubule and fibrotic. We describe the complex organization of microenvironments in health and disease and find that the fibrotic microenvironment is able to molecularly classify human kidneys and offers an improved prognosis compared to traditional histopathology. We provide a comprehensive spatially resolved molecular roadmap of the human kidney and the fibrotic process, demonstrating the clinical utility of spatial transcriptomics.
    DOI:  https://doi.org/10.1038/s41588-024-01802-x
  24. Cell. 2024 Jul 20. pii: S0092-8674(24)00713-X. [Epub ahead of print]
    MYB-related transcription factors control chloroplast biogenesis.
    Eftychios Frangedakis, Nataliya E Yelina, Kumari Billakurthi, Lei Hua, Tina Schreier, Patrick J Dickinson, Marta Tomaselli, Jim Haseloff, Julian M Hibberd.
      Chloroplast biogenesis is dependent on master regulators from the GOLDEN2-LIKE (GLK) family of transcription factors. However, glk mutants contain residual chlorophyll, indicating that other proteins must be involved. Here, we identify MYB-related transcription factors as regulators of chloroplast biogenesis in the liverwort Marchantia polymorpha and angiosperm Arabidopsis thaliana. In both species, double-mutant alleles in MYB-related genes show very limited chloroplast development, and photosynthesis gene expression is perturbed to a greater extent than in GLK mutants. Genes encoding enzymes of chlorophyll biosynthesis are controlled by MYB-related and GLK proteins, whereas those allowing CO2 fixation, photorespiration, and photosystem assembly and repair require MYB-related proteins. Regulation between the MYB-related and GLK transcription factors appears more extensive in A. thaliana than in M. polymorpha. Thus, MYB-related and GLK genes have overlapping as well as distinct targets. We conclude that MYB-related and GLK transcription factors orchestrate chloroplast development in land plants.
    Keywords:  Arabidopsis; GLK transcription factor; MYB-related transcription factor; Marchantia; chloroplast biogenesis; photosynthesis
    DOI:  https://doi.org/10.1016/j.cell.2024.06.039
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