bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2022‒01‒09
eighteen papers selected by
Connor Rogerson
University of Cambridge, MRC Cancer Unit
  1. Establishment of developmental gene silencing by ordered polycomb complex recruitment in early zebrafish embryos.
  2. Computational modeling of chromatin accessibility identified important epigenomic regulators.
  3. The pioneer factor hypothesis is not necessary to explain ectopic liver gene activation.
  4. Integrative analysis of 3604 GWAS reveals multiple novel cell type-specific regulatory associations.
  5. PRC1 sustains the integrity of neural fate in the absence of PRC2 function.
  6. Chromatin remodeling induced by ARID1A loss in lung cancer promotes glycolysis and confers JQ1 vulnerability.
  7. Three classes of epigenomic regulators converge to hyperactivate the essential maternal gene deadhead within a heterochromatin mini-domain.
  8. Decoding gene regulation in the fly brain.
  9. DNMT1 regulates the timing of DNA methylation by DNMT3 in an enzymatic activity-dependent manner in mouse embryonic stem cells.
  10. Universal annotation of the human genome through integration of over a thousand epigenomic datasets.
  11. The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasion in vivo.
  12. N4-acetyldeoxycytosine DNA modification marks euchromatin regions in Arabidopsis thaliana.
  13. Release of linker histone from the nucleosome driven by polyelectrolyte competition with a disordered protein.
  14. Glucose starvation induces a switch in the histone acetylome for activation of gluconeogenic and fat metabolism genes.
  15. Transcriptional regulation of neural stem cell expansion in adult hippocampus.
  16. Highly rigid H3.1/H3.2-H3K9me3 domains set a barrier for cell fate reprogramming in trophoblast stem cells.
  17. RB1 loss in castration-resistant prostate cancer confers vulnerability to LSD1 inhibition.
  18. FoxO-KLF15 pathway switches the flow of macronutrients under the control of insulin.
  1. Elife. 2022 Jan 04. pii: e67738. [Epub ahead of print]11
    Establishment of developmental gene silencing by ordered polycomb complex recruitment in early zebrafish embryos.
    Graham Jm Hickey, Candice L Wike, Xichen Nie, Yixuan Guo, Mengyao Tan, Patrick J Murphy, Bradley R Cairns.
      Vertebrate embryos achieve developmental competency during zygotic genome activation (ZGA) by establishing chromatin states that silence yet poise developmental genes for subsequent lineage-specific activation. Here, we reveal the order of chromatin states in establishing developmental gene poising in preZGA zebrafish embryos. Poising is established at promoters and enhancers that initially contain open/permissive chromatin with 'Placeholder' nucleosomes (bearing H2A.Z, H3K4me1, and H3K27ac), and DNA hypomethylation. Silencing is initiated by the recruitment of Polycomb Repressive Complex 1 (PRC1), and H2Aub1 deposition by catalytic Rnf2 during preZGA and ZGA stages. During postZGA, H2Aub1 enables Aebp2-containing PRC2 recruitment and H3K27me3 deposition. Notably, preventing H2Aub1 (via Rnf2 inhibition) eliminates recruitment of Aebp2-PRC2 and H3K27me3, and elicits transcriptional upregulation of certain developmental genes during ZGA. However, upregulation is independent of H3K27me3 - establishing H2Aub1 as the critical silencing modification at ZGA. Taken together, we reveal the logic and mechanism for establishing poised/silent developmental genes in early vertebrate embryos.
    Keywords:  chromosomes; developmental biology; gene expression; zebrafish
    DOI:  https://doi.org/10.7554/eLife.67738
  2. BMC Genomics. 2022 Jan 08. 23(1): 19
    Computational modeling of chromatin accessibility identified important epigenomic regulators.
    Yanding Zhao, Yadong Dong, Wei Hong, Chongming Jiang, Kevin Yao, Chao Cheng.
      Chromatin accessibility is essential for transcriptional activation of genomic regions. It is well established that transcription factors (TFs) and histone modifications (HMs) play critical roles in chromatin accessibility regulation. However, there is a lack of studies that quantify these relationships. Here we constructed a two-layer model to predict chromatin accessibility by integrating DNA sequence, TF binding, and HM signals. By applying the model to two human cell lines (GM12878 and HepG2), we found that DNA sequences had limited power for accessibility prediction, while both TF binding and HM signals predicted chromatin accessibility with high accuracy. According to the HM model, HM features determined chromatin accessibility in a cell line shared manner, with the prediction power attributing to five core HM types. Results from the TF model indicated that chromatin accessibility was determined by a subset of informative TFs including both cell line-specific and generic TFs. The combined model of both TF and HM signals did not further improve the prediction accuracy, indicating that they provide redundant information in terms of chromatin accessibility prediction. The TFs and HM models can also distinguish the chromatin accessibility of proximal versus distal transcription start sites with high accuracy.
    Keywords:  Chromatin accessibility; ENCODE; Histone modifications; Machine learning; Transcription factor
    DOI:  https://doi.org/10.1186/s12864-021-08234-5
  3. Elife. 2022 Jan 05. pii: e73358. [Epub ahead of print]11
    The pioneer factor hypothesis is not necessary to explain ectopic liver gene activation.
    Jeffrey L Hansen, Kaiser J Loell, Barak A Cohen.
      The Pioneer Factor Hypothesis (PFH) states that pioneer factors (PFs) are a subclass of transcription factors (TFs) that bind to and open inaccessible sites and then recruit non-pioneer factors (nonPFs) that activate batteries of silent genes. The PFH predicts that ectopic gene activation requires the sequential activity of qualitatively different TFs. We tested the PFH by expressing the endodermal PF FOXA1 and nonPF HNF4A in K562 lymphoblast cells. While co-expression of FOXA1 and HNF4A activated a burst of endoderm-specific gene expression, we found no evidence for a functional distinction between these two TFs. When expressed independently, both TFs bound and opened inaccessible sites, activated endodermal genes, and 'pioneered' for each other, although FOXA1 required fewer copies of its motif for binding. A subset of targets required both TFs, but the predominant mode of action at these targets did not conform to the sequential activity predicted by the PFH. From these results we hypothesize an alternative to the PFH where 'pioneer activity' depends not on categorically different TFs but rather on the affinity of interaction between TF and DNA.
    Keywords:  chromosomes; gene expression; genetics; genomics
    DOI:  https://doi.org/10.7554/eLife.73358
  4. Genome Biol. 2022 Jan 07. 23(1): 13
    Integrative analysis of 3604 GWAS reveals multiple novel cell type-specific regulatory associations.
    Charles E Breeze, Eric Haugen, Alex Reynolds, Andrew Teschendorff, Jenny van Dongen, Qing Lan, Nathaniel Rothman, Guillaume Bourque, Ian Dunham, Stephan Beck, John Stamatoyannopoulos, Nora Franceschini, Sonja I Berndt.
      BACKGROUND: Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are known to preferentially co-locate to active regulatory elements in tissues and cell types relevant to disease aetiology. Further characterisation of associated cell type-specific regulation can broaden our understanding of how GWAS signals may contribute to disease risk.RESULTS: To gain insight into potential functional mechanisms underlying GWAS associations, we developed FORGE2 ( https://forge2.altiusinstitute.org/ ), which is an updated version of the FORGE web tool. FORGE2 uses an expanded atlas of cell type-specific regulatory element annotations, including DNase I hotspots, five histone mark categories and 15 hidden Markov model (HMM) chromatin states, to identify tissue- and cell type-specific signals. An analysis of 3,604 GWAS from the NHGRI-EBI GWAS catalogue yielded at least one significant disease/trait-tissue association for 2,057 GWAS, including > 400 associations specific to epigenomic marks in immune tissues and cell types, > 30 associations specific to heart tissue, and > 60 associations specific to brain tissue, highlighting the key potential of tissue- and cell type-specific regulatory elements. Importantly, we demonstrate that FORGE2 analysis can separate previously observed accessible chromatin enrichments into different chromatin states, such as enhancers or active transcription start sites, providing a greater understanding of underlying regulatory mechanisms. Interestingly, tissue-specific enrichments for repressive chromatin states and histone marks were also detected, suggesting a role for tissue-specific repressed regions in GWAS-mediated disease aetiology.
    CONCLUSION: In summary, we demonstrate that FORGE2 has the potential to uncover previously unreported disease-tissue associations and identify new candidate mechanisms. FORGE2 is a transparent, user-friendly web tool for the integrative analysis of loci discovered from GWAS.
    DOI:  https://doi.org/10.1186/s13059-021-02560-3
  5. Elife. 2022 Jan 07. pii: e72769. [Epub ahead of print]11
    PRC1 sustains the integrity of neural fate in the absence of PRC2 function.
    Ayana Sawai, Sarah Pfennig, Milica Bulajić, Alexander Miller, Alireza Khodadadi-Jamayran, Esteban Orlando Mazzoni, Jeremy S Dasen.
      Polycomb repressive complexes (PRCs) 1 and 2 maintain stable cellular memories of early fate decisions by establishing heritable patterns of gene repression. PRCs repress transcription through histone modifications and chromatin compaction, but their roles in neuronal subtype diversification are poorly defined. We found that PRC1 is essential for the specification of segmentally-restricted spinal motor neuron (MN) subtypes, while PRC2 activity is dispensable to maintain MN positional identities during terminal differentiation. Mutation of the core PRC1 component Ring1 in mice leads to increased chromatin accessibility and ectopic expression of a broad variety of fates determinants, including Hox transcription factors, while neuronal class-specific features are maintained. Loss of MN subtype identities in Ring1 mutants is due to the suppression of Hox-dependent specification programs by derepressed Hox13 paralogs (Hoxa13, Hoxb13, Hoxc13, Hoxd13). These results indicate that PRC1 can function in the absence of de novo PRC2-dependent histone methylation to maintain chromatin topology and postmitotic neuronal fate.
    Keywords:  chicken; developmental biology; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.72769
  6. Cancer Res. 2022 Jan 05. pii: canres.0763.2021. [Epub ahead of print]
    Chromatin remodeling induced by ARID1A loss in lung cancer promotes glycolysis and confers JQ1 vulnerability.
    Xiaoyu Liu, Zhi Li, Zhongmin Wang, Fei Liu, Linling Zhang, Jingjing Ke, Xu Xu, Yuefang Zhang, Yiting Yuan, Tao Wei, Qungang Shan, Yingjie Chen, Wei Huang, Jie Gao, Nan Wu, Fuliang Chen, Lunquan Sun, Zilong Qiu, Yuezhen Deng, Wang Xiaojing.
      ARID1A is a key mammalian SWI/SNF complex subunit that is mutated in 5%-11% of lung cancers. Although recent studies have elucidated the mechanism underlying dysregulation of SWI/SNF complexes in cancers, the significance of ARID1A loss and its implications in lung cancers remain poorly defined. This study investigates how ARID1A loss affects initiation and progression of lung cancer. In genetically engineered mouse models bearing mutant Kras and a deficient Trp53 allele (KP), ARID1A loss (KPA) promoted lung tumorigenesis. Analysis of the transcriptome profiles of KP and KPA tumors suggested enhanced glycolysis following ARID1A loss, and expression of the glycolytic regulators Pgam1, Pkm, and Pgk1 was significantly increased in ARID1A-deficient lung tumors. Furthermore, ARID1A loss increased chromatin accessibility and enhanced HIF1α binding to the promoter regions of Pgam1, Pkm, and Pgk1. Loss of ARID1A in lung adenocarcinoma also resulted in loss of histone deacetylase 1 (HDAC1) recruitment, increasing acetylation of histone 4 lysine at the promoters of Pgam1, Pkm, and Pgk1 and subsequently enhancing BRD4-driven transcription of these genes. Metabolic analyses confirmed that glycolysis is enhanced in ARID1A-deficient tumors, and genetic or pharmacologic inhibition of glycolysis inhibited lung tumorigenesis in KPA mice. Treatment with the small molecule bromodomain and extra terminal protein (BET) inhibitor JQ1 compromised both initiation and progression of ARID1A-deficient lung adenocarcinoma. ARID1A negatively correlated with glycolysis-related genes in human lung adenocarcinoma. Overall, ARID1A loss leads to metabolic reprogramming that supports tumorigenesis but also confers a therapeutic vulnerability that could be harnessed to improve the treatment of ARID1A-deficient lung cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0763
  7. PLoS Genet. 2022 Jan 04. 18(1): e1009615
    Three classes of epigenomic regulators converge to hyperactivate the essential maternal gene deadhead within a heterochromatin mini-domain.
    Daniela Torres-Campana, Béatrice Horard, Sandrine Denaud, Gérard Benoit, Benjamin Loppin, Guillermo A Orsi.
      The formation of a diploid zygote is a highly complex cellular process that is entirely controlled by maternal gene products stored in the egg cytoplasm. This highly specialized transcriptional program is tightly controlled at the chromatin level in the female germline. As an extreme case in point, the massive and specific ovarian expression of the essential thioredoxin Deadhead (DHD) is critically regulated in Drosophila by the histone demethylase Lid and its partner, the histone deacetylase complex Sin3A/Rpd3, via yet unknown mechanisms. Here, we identified Snr1 and Mod(mdg4) as essential for dhd expression and investigated how these epigenomic effectors act with Lid and Sin3A to hyperactivate dhd. Using Cut&Run chromatin profiling with a dedicated data analysis procedure, we found that dhd is intriguingly embedded in an H3K27me3/H3K9me3-enriched mini-domain flanked by DNA regulatory elements, including a dhd promoter-proximal element essential for its expression. Surprisingly, Lid, Sin3a, Snr1 and Mod(mdg4) impact H3K27me3 and this regulatory element in distinct manners. However, we show that these effectors activate dhd independently of H3K27me3/H3K9me3, and that dhd remains silent in the absence of these marks. Together, our study demonstrates an atypical and critical role for chromatin regulators Lid, Sin3A, Snr1 and Mod(mdg4) to trigger tissue-specific hyperactivation within a unique heterochromatin mini-domain.
    DOI:  https://doi.org/10.1371/journal.pgen.1009615
  8. Nature. 2022 Jan 05.
    Decoding gene regulation in the fly brain.
    Jasper Janssens, Sara Aibar, Ibrahim Ihsan Taskiran, Joy N Ismail, Alicia Estacio Gomez, Gabriel Aughey, Katina I Spanier, Florian V De Rop, Carmen Bravo González-Blas, Marc Dionne, Krista Grimes, Xiao Jiang Quan, Dafni Papasokrati, Gert Hulselmans, Samira Makhzami, Maxime De Waegeneer, Valerie Christiaens, Tony Southall, Stein Aerts.
      The Drosophila brain is a frequently used model in neuroscience. Single-cell transcriptome analysis1-6, three-dimensional morphological classification7 and electron microscopy mapping of the connectome8,9 have revealed an immense diversity of neuronal and glial cell types that underlie an array of functional and behavioural traits in the fly. The identities of these cell types are controlled by gene regulatory networks (GRNs), involving combinations of transcription factors that bind to genomic enhancers to regulate their target genes. Here, to characterize GRNs at the cell-type level in the fly brain, we profiled the chromatin accessibility of 240,919 single cells spanning 9 developmental timepoints and integrated these data with single-cell transcriptomes. We identify more than 95,000 regulatory regions that are used in different neuronal cell types, of which 70,000 are linked to developmental trajectories involving neurogenesis, reprogramming and maturation. For 40 cell types, uniquely accessible regions were associated with their expressed transcription factors and downstream target genes through a combination of motif discovery, network inference and deep learning, creating enhancer GRNs. The enhancer architectures revealed by DeepFlyBrain lead to a better understanding of neuronal regulatory diversity and can be used to design genetic driver lines for cell types at specific timepoints, facilitating their characterization and manipulation.
    DOI:  https://doi.org/10.1038/s41586-021-04262-z
  9. PLoS One. 2022 ;17(1): e0262277
    DNMT1 regulates the timing of DNA methylation by DNMT3 in an enzymatic activity-dependent manner in mouse embryonic stem cells.
    Takamasa Ito, Musashi Kubiura-Ichimaru, Yuri Murakami, Aaron B Bogutz, Louis Lefebvre, Isao Suetake, Shoji Tajima, Masako Tada.
      DNA methylation (DNAme; 5-methylcytosine, 5mC) plays an essential role in mammalian development, and the 5mC profile is regulated by a balance of opposing enzymatic activities: DNA methyltransferases (DNMTs) and Ten-eleven translocation dioxygenases (TETs). In mouse embryonic stem cells (ESCs), de novo DNAme by DNMT3 family enzymes, demethylation by the TET-mediated conversion of 5mC to 5-hydroxymethylation (5hmC), and maintenance of the remaining DNAme by DNMT1 are actively repeated throughout cell cycles, dynamically forming a constant 5mC profile. Nevertheless, the detailed mechanism and physiological significance of this active cyclic DNA modification in mouse ESCs remain unclear. Here by visualizing the localization of DNA modifications on metaphase chromosomes and comparing whole-genome methylation profiles before and after the mid-S phase in ESCs lacking Dnmt1 (1KO ESCs), we demonstrated that in 1KO ESCs, DNMT3-mediated remethylation was interrupted during and after DNA replication. This results in a marked asymmetry in the distribution of 5hmC between sister chromatids at mitosis, with one chromatid being almost no 5hmC. When introduced in 1KO ESCs, the catalytically inactive form of DNMT1 (DNMT1CI) induced an increase in DNAme in pericentric heterochromatin and the DNAme-independent repression of IAPEz, a retrotransposon family, in 1KO ESCs. However, DNMT1CI could not restore the ability of DNMT3 to methylate unmodified dsDNA de novo in S phase in 1KO ESCs. Furthermore, during in vitro differentiation into epiblasts, 1KO ESCs expressing DNMT1CI showed an even stronger tendency to differentiate into the primitive endoderm than 1KO ESCs and were readily reprogrammed into the primitive streak via an epiblast-like cell state, reconfirming the importance of DNMT1 enzymatic activity at the onset of epiblast differentiation. These results indicate a novel function of DNMT1, in which DNMT1 actively regulates the timing and genomic targets of de novo methylation by DNMT3 in an enzymatic activity-dependent and independent manner, respectively.
    DOI:  https://doi.org/10.1371/journal.pone.0262277
  10. Genome Biol. 2022 Jan 06. 23(1): 9
    Universal annotation of the human genome through integration of over a thousand epigenomic datasets.
    Ha Vu, Jason Ernst.
      BACKGROUND: Genome-wide maps of chromatin marks such as histone modifications and open chromatin sites provide valuable information for annotating the non-coding genome, including identifying regulatory elements. Computational approaches such as ChromHMM have been applied to discover and annotate chromatin states defined by combinatorial and spatial patterns of chromatin marks within the same cell type. An alternative "stacked modeling" approach was previously suggested, where chromatin states are defined jointly from datasets of multiple cell types to produce a single universal genome annotation based on all datasets. Despite its potential benefits for applications that are not specific to one cell type, such an approach was previously applied only for small-scale specialized purposes. Large-scale applications of stacked modeling have previously posed scalability challenges.RESULTS: Using a version of ChromHMM enhanced for large-scale applications, we apply the stacked modeling approach to produce a universal chromatin state annotation of the human genome using over 1000 datasets from more than 100 cell types, with the learned model denoted as the full-stack model. The full-stack model states show distinct enrichments for external genomic annotations, which we use in characterizing each state. Compared to per-cell-type annotations, the full-stack annotations directly differentiate constitutive from cell type-specific activity and is more predictive of locations of external genomic annotations.
    CONCLUSIONS: The full-stack ChromHMM model provides a universal chromatin state annotation of the genome and a unified global view of over 1000 datasets. We expect this to be a useful resource that complements existing per-cell-type annotations for studying the non-coding human genome.
    DOI:  https://doi.org/10.1186/s13059-021-02572-z
  11. PLoS Genet. 2022 Jan 04. 18(1): e1009981
    The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasion in vivo.
    Jayson J Smith, Yutong Xiao, Nithin Parsan, Taylor N Medwig-Kinney, Michael A Q Martinez, Frances E Q Moore, Nicholas J Palmisano, Abraham Q Kohrman, Mana Chandhok Delos Reyes, Rebecca C Adikes, Simeiyun Liu, Sydney A Bracht, Wan Zhang, Kailong Wen, Paschalis Kratsios, David Q Matus.
      Chromatin remodelers such as the SWI/SNF complex coordinate metazoan development through broad regulation of chromatin accessibility and transcription, ensuring normal cell cycle control and cellular differentiation in a lineage-specific and temporally restricted manner. Mutations in genes encoding the structural subunits of chromatin, such as histone subunits, and chromatin regulating factors are associated with a variety of disease mechanisms including cancer metastasis, in which cancer co-opts cellular invasion programs functioning in healthy cells during development. Here we utilize Caenorhabditis elegans anchor cell (AC) invasion as an in vivo model to identify the suite of chromatin agents and chromatin regulating factors that promote cellular invasiveness. We demonstrate that the SWI/SNF ATP-dependent chromatin remodeling complex is a critical regulator of AC invasion, with pleiotropic effects on both G0 cell cycle arrest and activation of invasive machinery. Using targeted protein degradation and enhanced RNA interference (RNAi) vectors, we show that SWI/SNF contributes to AC invasion in a dose-dependent fashion, with lower levels of activity in the AC corresponding to aberrant cell cycle entry and increased loss of invasion. Our data specifically implicate the SWI/SNF BAF assembly in the regulation of the G0 cell cycle arrest in the AC, whereas the SWI/SNF PBAF assembly promotes AC invasion via cell cycle-independent mechanisms, including attachment to the basement membrane (BM) and activation of the pro-invasive fos-1/FOS gene. Together these findings demonstrate that the SWI/SNF complex is necessary for two essential components of AC invasion: arresting cell cycle progression and remodeling the BM. The work here provides valuable single-cell mechanistic insight into how the SWI/SNF assemblies differentially contribute to cellular invasion and how SWI/SNF subunit-specific disruptions may contribute to tumorigeneses and cancer metastasis.
    DOI:  https://doi.org/10.1371/journal.pgen.1009981
  12. Genome Biol. 2022 Jan 03. 23(1): 5
    N4-acetyldeoxycytosine DNA modification marks euchromatin regions in Arabidopsis thaliana.
    Shuai Wang, Hairong Xie, Fei Mao, Haiyan Wang, Shu Wang, Zhenglin Chen, Yuxia Zhang, Zhihui Xu, Jinming Xing, Zhaokang Cui, Xiquan Gao, Hongmei Jin, Jian Hua, Bo Xiong, Yufeng Wu.
      BACKGROUND: Direct analogs of chemically modified bases that carry important epigenetic information, such as 5-methylcytosine (m5C)/5-methyldeoxycytosine (5mC), 5-hydroxymethylcytosine (hm5C)/5-hydroxymethyldeoxycytosine (5hmC), and N6-methyladenosine (m6A)/N6-methyldeoxyadenosine (6mA), are detected in both RNA and DNA, respectively. The modified base N4-acetylcytosine (ac4C) is well studied in RNAs, but its presence and epigenetic roles in cellular DNA have not been explored.RESULTS: Here, we demonstrate the existence of N4-acetyldeoxycytosine (4acC) in genomic DNA of Arabidopsis with multiple detection methods. Genome-wide profiling of 4acC modification reveals that 4acC peaks are mostly distributed in euchromatin regions and present in nearly half of the expressed protein-coding genes in Arabidopsis. 4acC is mainly located around transcription start sites and positively correlates with gene expression levels. Imbalance of 5mC does not directly affect 4acC modification. We also characterize the associations of 4acC with 5mC and histone modifications that cooperatively regulate gene expression. Moreover, 4acC is also detected in genomic DNA of rice, maize, mouse, and human by mass spectrometry.
    CONCLUSIONS: Our findings reveal 4acC as a hitherto unknown DNA modification in higher eukaryotes. We identify potential interactions of this mark with other epigenetic marks in gene expression regulation.
    Keywords:  5mC; Arabidopsis thaliana; Gene expression; Histone modification; N 4-acetyldeoxycytosine (4acC)
    DOI:  https://doi.org/10.1186/s13059-021-02578-7
  13. Nat Chem. 2022 Jan 06.
    Release of linker histone from the nucleosome driven by polyelectrolyte competition with a disordered protein.
    Pétur O Heidarsson, Davide Mercadante, Andrea Sottini, Daniel Nettels, Madeleine B Borgia, Alessandro Borgia, Sinan Kilic, Beat Fierz, Robert B Best, Benjamin Schuler.
      Highly charged intrinsically disordered proteins are essential regulators of chromatin structure and transcriptional activity. Here we identify a surprising mechanism of molecular competition that relies on the pronounced dynamical disorder present in these polyelectrolytes and their complexes. The highly positively charged human linker histone H1.0 (H1) binds to nucleosomes with ultrahigh affinity, implying residence times incompatible with efficient biological regulation. However, we show that the disordered regions of H1 retain their large-amplitude dynamics when bound to the nucleosome, which enables the highly negatively charged and disordered histone chaperone prothymosin α to efficiently invade the H1-nucleosome complex and displace H1 via a competitive substitution mechanism, vastly accelerating H1 dissociation. By integrating experiments and simulations, we establish a molecular model that rationalizes the remarkable kinetics of this process structurally and dynamically. Given the abundance of polyelectrolyte sequences in the nuclear proteome, this mechanism is likely to be widespread in cellular regulation.
    DOI:  https://doi.org/10.1038/s41557-021-00839-3
  14. Mol Cell. 2022 Jan 06. pii: S1097-2765(21)01077-7. [Epub ahead of print]82(1): 60-74.e5
    Glucose starvation induces a switch in the histone acetylome for activation of gluconeogenic and fat metabolism genes.
    Wen-Chuan Hsieh, Benjamin M Sutter, Holly Ruess, Spencer D Barnes, Venkat S Malladi, Benjamin P Tu.
      Acetyl-CoA is a key intermediate situated at the intersection of many metabolic pathways. The reliance of histone acetylation on acetyl-CoA enables the coordination of gene expression with metabolic state. Abundant acetyl-CoA has been linked to the activation of genes involved in cell growth or tumorigenesis through histone acetylation. However, the role of histone acetylation in transcription under low levels of acetyl-CoA remains poorly understood. Here, we use a yeast starvation model to observe the dramatic alteration in the global occupancy of histone acetylation following carbon starvation; the location of histone acetylation marks shifts from growth-promoting genes to gluconeogenic and fat metabolism genes. This reallocation is mediated by both the histone deacetylase Rpd3p and the acetyltransferase Gcn5p, a component of the SAGA transcriptional coactivator. Our findings reveal an unexpected switch in the specificity of histone acetylation to promote pathways that generate acetyl-CoA for oxidation when acetyl-CoA is limiting.
    Keywords:  Gcn5p; Rpd3p; SAGA; acetyl-CoA; environmental stress response; fat metabolism; gluconeogenesis; glucose starvation; histone acetylation; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2021.12.015
  15. Elife. 2022 Jan 04. pii: e72195. [Epub ahead of print]11
    Transcriptional regulation of neural stem cell expansion in adult hippocampus.
    Nannan Guo, Kelsey D McDermott, Yu-Tzu Shih, Haley Zanga, Debolina Ghosh, Charlotte Herber, William R Meara, James H Coleman, Alexia Zagouras, Lai Ping Wong, Ruslan I Sadreyev, J Tiago Gonçalves, Amar Sahay.
      Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis while amplifying RGLs to anticipate future neurogenic demands. The identities of transcription factors regulating RGL symmetric self-renewal, unlike those that regulate RGL asymmetric self-renewal, are not known. Here, we show in mice that the transcription factor Kruppel-like factor 9 (Klf9) is elevated in quiescent RGLs and inducible, deletion of Klf9 promotes RGL activation state. Clonal analysis and longitudinal intravital 2-photon imaging directly demonstrate that Klf9 functions as a brake on RGL symmetric self-renewal. In vivo translational profiling of RGLs lacking Klf9 generated a molecular blueprint for RGL symmetric self-renewal that was characterized by upregulation of genetic programs underlying Notch and mitogen signaling, cell-cycle, fatty acid oxidation and lipogenesis. Together, these observations identify Klf9 as a transcriptional regulator of neural stem cell expansion in the adult hippocampus.
    Keywords:  mouse; neuroscience; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.72195
  16. Genes Dev. 2022 Jan 06.
    Highly rigid H3.1/H3.2-H3K9me3 domains set a barrier for cell fate reprogramming in trophoblast stem cells.
    Masashi Hada, Hisashi Miura, Akie Tanigawa, Shogo Matoba, Kimiko Inoue, Narumi Ogonuki, Michiko Hirose, Naomi Watanabe, Ryuichiro Nakato, Katsunori Fujiki, Ayumi Hasegawa, Akihiko Sakashita, Hiroaki Okae, Kento Miura, Daiki Shikata, Takahiro Arima, Katsuhiko Shirahige, Ichiro Hiratani, Atsuo Ogura.
      The placenta is a highly evolved, specialized organ in mammals. It differs from other organs in that it functions only for fetal maintenance during gestation. Therefore, there must be intrinsic mechanisms that guarantee its unique functions. To address this question, we comprehensively analyzed epigenomic features of mouse trophoblast stem cells (TSCs). Our genome-wide, high-throughput analyses revealed that the TSC genome contains large-scale (>1-Mb) rigid heterochromatin architectures with a high degree of histone H3.1/3.2-H3K9me3 accumulation, which we termed TSC-defined highly heterochromatinized domains (THDs). Importantly, depletion of THDs by knockdown of CAF1, an H3.1/3.2 chaperone, resulted in down-regulation of TSC markers, such as Cdx2 and Elf5, and up-regulation of the pluripotent marker Oct3/4, indicating that THDs maintain the trophoblastic nature of TSCs. Furthermore, our nuclear transfer technique revealed that THDs are highly resistant to genomic reprogramming. However, when H3K9me3 was removed, the TSC genome was fully reprogrammed, giving rise to the first TSC cloned offspring. Interestingly, THD-like domains are also present in mouse and human placental cells in vivo, but not in other cell types. Thus, THDs are genomic architectures uniquely developed in placental lineage cells, which serve to protect them from fate reprogramming to stably maintain placental function.
    Keywords:  CAF1; H3.1/H3.2; H3K9me3; somatic cell nuclear transfer; trophoblast stem cell
    DOI:  https://doi.org/10.1101/gad.348782.121
  17. Oncogene. 2022 Jan 03.
    RB1 loss in castration-resistant prostate cancer confers vulnerability to LSD1 inhibition.
    Wanting Han, Mingyu Liu, Dong Han, Muqing Li, Anthia A Toure, Zifeng Wang, Anna Besschetnova, Susan Patalano, Jill A Macoska, Shuai Gao, Housheng Hansen He, Changmeng Cai.
      Genomic loss of RB1 is a common alteration in castration-resistant prostate cancer (CRPC) and is associated with poor patient outcomes. RB1 loss is also a critical event that promotes the neuroendocrine transdifferentiation of prostate cancer (PCa) induced by the androgen receptor (AR) signaling inhibition (ARSi). The loss of Rb protein disrupts the Rb-E2F repressor complex and thus hyperactivates E2F transcription activators. While the impact of Rb inactivation on PCa progression and linage plasticity has been previously studied, there is a pressing need to fully understand underlying mechanisms and identify vulnerabilities that can be therapeutically targeted in Rb-deficient CRPC. Using an integrated cistromic and transcriptomic analysis, we have characterized Rb activities in multiple CRPC models by identifying Rb-directly regulated genes and revealed that Rb has distinct binding sites and targets in CRPC with different genomic backgrounds. Significantly, we show that E2F1 chromatin binding and transcription activity in Rb-deficient CRPC are highly dependent on LSD1/KDM1A, and that Rb inactivation sensitizes CRPC tumor to the LSD1 inhibitor treatment. These results provide new molecular insights into Rb activity in PCa progression and suggest that targeting LSD1 activity with small molecule inhibitors may be a potential treatment strategy to treat Rb-deficient CRPC.
    DOI:  https://doi.org/10.1038/s41388-021-02135-3
  18. iScience. 2021 Dec 17. 24(12): 103446
    FoxO-KLF15 pathway switches the flow of macronutrients under the control of insulin.
    Yoshinori Takeuchi, Naoya Yahagi, Yuichi Aita, Zahra Mehrazad-Saber, Man Hei Ho, Yiren Huyan, Yuki Murayama, Akito Shikama, Yukari Masuda, Yoshihiko Izumida, Takafumi Miyamoto, Takashi Matsuzaka, Yasushi Kawakami, Hitoshi Shimano.
      KLF15 is a transcription factor that plays an important role in the activation of gluconeogenesis from amino acids as well as the suppression of lipogenesis from glucose. Here we identified the transcription start site of liver-specific KLF15 transcript and showed that FoxO1/3 transcriptionally regulates Klf15 gene expression by directly binding to the liver-specific Klf15 promoter. To achieve this, we performed a precise in vivo promoter analysis combined with the genome-wide transcription-factor-screening method "TFEL scan", using our original Transcription Factor Expression Library (TFEL), which covers nearly all the transcription factors in the mouse genome. Hepatic Klf15 expression is significantly increased via FoxOs by attenuating insulin signaling. Furthermore, FoxOs elevate the expression levels of amino acid catabolic enzymes and suppress SREBP-1c via KLF15, resulting in accelerated amino acid breakdown and suppressed lipogenesis during fasting. Thus, the FoxO-KLF15 pathway contributes to switching the macronutrient flow in the liver under the control of insulin.
    Keywords:  Diabetology; Molecular biology; Molecular network
    DOI:  https://doi.org/10.1016/j.isci.2021.103446
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