bims-crepig 2023-07-30 papers

bims-crepig

Biomed News

on Chromatin regulation and epigenetics in cell fate and cancer

Issue of 2023–07–30
fiveteen papers selected by
Connor Rogerson, University of Cambridge

Modeling epigenetic lesions that cause gliomas.
Identification of mammalian transcription factors that bind to inaccessible chromatin.
The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates.
Nucleosome retention by histone chaperones and remodelers occludes pervasive DNA-protein binding.
RNA polymerase II pausing regulates chromatin organization in erythrocytes.
Transcription factor expression repertoire basis for epigenetic and transcriptional subtypes of colorectal cancers.
Integrated single-cell chromatin and transcriptomic analyses of human scalp identify gene-regulatory programs and critical cell types for hair and skin diseases.
Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.
Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma.
Phosphorylated nuclear DICER1 promotes open chromatin state and lineage plasticity of AT2 tumor cells in lung adenocarcinomas.
Robust enhancer-gene regulation identified by single-cell transcriptomes and epigenomes.
Molecular features driving condensate formation and gene expression by the BRD4-NUT fusion oncoprotein are overlapping but distinct.
Dynamic network-guided CRISPRi screen identifies CTCF-loop-constrained nonlinear enhancer gene regulatory activity during cell state transitions.
14-3-3σ-NEDD4L axis promotes ubiquitination and degradation of HIF-1α in colorectal cancer.
ISW1a modulates cohesin distribution in centromeric and pericentromeric regions.

Cell. 2023 Jul 20. pii: S0092-8674(23)00729-8. [Epub ahead of print]

Modeling epigenetic lesions that cause gliomas.

Gilbert J Rahme, Nauman M Javed, Kaitlyn L Puorro, Shouhui Xin, Volker Hovestadt, Sarah E Johnstone, Bradley E Bernstein.

  Epigenetic lesions that disrupt regulatory elements represent potential cancer drivers. However, we lack experimental models for validating their tumorigenic impact. Here, we model aberrations arising in isocitrate dehydrogenase-mutant gliomas, which exhibit DNA hypermethylation. We focus on a CTCF insulator near the PDGFRA oncogene that is recurrently disrupted by methylation in these tumors. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. We show that a second lesion, methylation-dependent silencing of the Cdkn2a tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Despite locus synteny, the insulator is CpG-rich only in humans, a feature that may confer human glioma risk but complicates mouse modeling. Our study demonstrates the capacity of recurrent epigenetic lesions to drive OPC proliferation in vitro and gliomagenesis in vivo.

Keywords:  CDKN2A; DNA methylation; IDH mutation; PDGFRA; cell of origin; chromatin; genome topology; glioma; nuclear architecture; oligodendrocyte progenitor cells

DOI:  https://doi.org/10.1016/j.cell.2023.06.022
Nucleic Acids Res. 2023 Jul 24. pii: gkad614. [Epub ahead of print]

Identification of mammalian transcription factors that bind to inaccessible chromatin.

Romana T Pop, Alessandra Pisante, Dorka Nagy, Patrick C N Martin, Liudmila A Mikheeva, Ateequllah Hayat, Gabriella Ficz, Nicolae Radu Zabet.

Transcription factors (TFs) are proteins that affect gene expression by binding to regulatory regions of DNA in a sequence specific manner. The binding of TFs to DNA is controlled by many factors, including the DNA sequence, concentration of TF, chromatin accessibility and co-factors. Here, we systematically investigated the binding mechanism of hundreds of TFs by analysing ChIP-seq data with our explainable statistical model, ChIPanalyser. This tool uses as inputs the DNA sequence binding motif; the capacity to distinguish between strong and weak binding sites; the concentration of TF; and chromatin accessibility. We found that approximately one third of TFs are predicted to bind the genome in a DNA accessibility independent fashion, which includes TFs that can open the chromatin, their co-factors and TFs with similar motifs. Our model predicted this to be the case when the TF binds to its strongest binding regions in the genome, and only a small number of TFs have the capacity to bind dense chromatin at their weakest binding regions, such as CTCF, USF2 and CEBPB. Our study demonstrated that the binding of hundreds of human and mouse TFs is predicted by ChIPanalyser with high accuracy and showed that many TFs can bind dense chromatin.

DOI: https://doi.org/10.1093/nar/gkad614
Nat Cell Biol. 2023 Jul 24.

The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates.

Yihao Yang, Nicholas Gomez, Nicole Infarinato, Rene C Adam, Megan Sribour, Inwha Baek, Mélanie Laurin, Elaine Fuchs.

During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers. Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching remains elusive. Here we tackle this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells. By engineering mice to re-activate SOX9 in adult EpdSCs, we trigger fate switching. Combining epigenetic, proteomic and functional analyses, we interrogate the ensuing chromatin and transcriptional dynamics, slowed temporally by the mature EpdSC niche microenvironment. We show that as SOX9 binds and opens key hair follicle enhancers de novo in EpdSCs, it simultaneously recruits co-factors away from epidermal enhancers, which are silenced. Unhinged from its normal regulation, sustained SOX9 subsequently activates oncogenic transcriptional regulators that chart the path to cancers typified by constitutive SOX9 expression.

DOI: https://doi.org/10.1038/s41556-023-01184-y
Nucleic Acids Res. 2023 Jul 26. pii: gkad615. [Epub ahead of print]

Nucleosome retention by histone chaperones and remodelers occludes pervasive DNA-protein binding.

Felix Jonas, Matan Vidavski, Eli Benuck, Naama Barkai, Gilad Yaakov.

DNA packaging within chromatin depends on histone chaperones and remodelers that form and position nucleosomes. Cells express multiple such chromatin regulators with overlapping in-vitro activities. Defining specific in-vivo activities requires monitoring histone dynamics during regulator depletion, which has been technically challenging. We have recently generated histone-exchange sensors in Saccharomyces cerevisiae, which we now use to define the contributions of 15 regulators to histone dynamics genome-wide. While replication-independent exchange in unperturbed cells maps to promoters, regulator depletions primarily affected gene bodies. Depletion of Spt6, Spt16 or Chd1 sharply increased nucleosome replacement sequentially at the beginning, middle or end of highly expressed gene bodies. They further triggered re-localization of chaperones to affected gene body regions, which compensated for nucleosome loss during transcription complex passage, but concurred with extensive TF binding in gene bodies. We provide a unified quantitative screen highlighting regulator roles in retaining nucleosome binding during transcription and preserving genomic packaging.

DOI: https://doi.org/10.1093/nar/gkad615
Nat Struct Mol Biol. 2023 Jul 27.

RNA polymerase II pausing regulates chromatin organization in erythrocytes.

Andrés Penagos-Puig, Sherlyn Claudio-Galeana, Aura Stephenson-Gussinye, Karina Jácome-López, Amaury Aguilar-Lomas, Rosario Pérez-Molina, Mayra Furlan-Magaril.

Chicken erythrocytes are nucleated cells often considered to be transcriptionally inactive, although the epigenetic changes and chromatin remodeling that would mediate transcriptional repression and the extent of gene silencing during avian terminal erythroid differentiation are not fully understood. Here, we characterize the changes in gene expression, chromatin accessibility, genome organization and chromatin nuclear disposition during the terminal stages of erythropoiesis in chicken and uncover complex chromatin reorganization at different genomic scales. We observe a robust decrease in transcription in erythrocytes, but a set of genes maintains their expression, including genes involved in RNA polymerase II (Pol II) promoter-proximal pausing. Erythrocytes exhibit a reoriented nuclear architecture, with accessible chromatin positioned towards the nuclear periphery together with the paused RNA Pol II. In erythrocytes, chromatin domains are partially lost genome-wide, except at minidomains retained around paused promoters. Our results suggest that promoter-proximal pausing of RNA Pol II contributes to the transcriptional regulation of the erythroid genome and highlight the role of RNA polymerase in the maintenance of local chromatin organization.

DOI: https://doi.org/10.1038/s41594-023-01037-0
Proc Natl Acad Sci U S A. 2023 08;120(31): e2301536120

Transcription factor expression repertoire basis for epigenetic and transcriptional subtypes of colorectal cancers.

Yuba R Bhandari, Vinod Krishna, Rachael Powers, Sehej Parmar, Sara-Jayne Thursby, Ekta Gupta, Ozlem Kulak, Prashanth Gokare, Joke Reumers, Liesbeth Van Wesenbeeck, Kurtis E Bachman, Stephen B Baylin, Hariharan Easwaran.

  Colorectal cancers (CRCs) form a heterogenous group classified into epigenetic and transcriptional subtypes. The basis for the epigenetic subtypes, exemplified by varying degrees of promoter DNA hypermethylation, and its relation to the transcriptional subtypes is not well understood. We link cancer-specific transcription factor (TF) expression alterations to methylation alterations near TF-binding sites at promoter and enhancer regions in CRCs and their premalignant precursor lesions to provide mechanistic insights into the origins and evolution of the CRC molecular subtypes. A gradient of TF expression changes forms a basis for the subtypes of abnormal DNA methylation, termed CpG-island promoter DNA methylation phenotypes (CIMPs), in CRCs and other cancers. CIMP is tightly correlated with cancer-specific hypermethylation at enhancers, which we term CpG-enhancer methylation phenotype (CEMP). Coordinated promoter and enhancer methylation appears to be driven by downregulation of TFs with common binding sites at the hypermethylated enhancers and promoters. The altered expression of TFs related to hypermethylator subtypes occurs early during CRC development, detectable in premalignant adenomas. TF-based profiling further identifies patients with worse overall survival. Importantly, altered expression of these TFs discriminates the transcriptome-based consensus molecular subtypes (CMS), thus providing a common basis for CIMP and CMS subtypes.

Keywords:  DNA methylation; colorectal cancers; epigenetics; promoters enhancers; transcriptional subtypes

DOI:  https://doi.org/10.1073/pnas.2301536120
Nat Genet. 2023 Jul 27.

Integrated single-cell chromatin and transcriptomic analyses of human scalp identify gene-regulatory programs and critical cell types for hair and skin diseases.

Benjamin Ober-Reynolds, Chen Wang, Justin M Ko, Eon J Rios, Sumaira Z Aasi, Mark M Davis, Anthony E Oro, William J Greenleaf.

Genome-wide association studies have identified many loci associated with hair and skin disease, but identification of causal variants requires deciphering of gene-regulatory networks in relevant cell types. We generated matched single-cell chromatin profiles and transcriptomes from scalp tissue from healthy controls and patients with alopecia areata, identifying diverse cell types of the hair follicle niche. By interrogating these datasets at multiple levels of cellular resolution, we infer 50-100% more enhancer-gene links than previous approaches and show that aggregate enhancer accessibility for highly regulated genes predicts expression. We use these gene-regulatory maps to prioritize cell types, genes and causal variants implicated in the pathobiology of androgenetic alopecia (AGA), eczema and other complex traits. AGA genome-wide association studies signals are enriched in dermal papilla regulatory regions, supporting the role of these cells as drivers of AGA pathogenesis. Finally, we train machine learning models to nominate single-nucleotide polymorphisms that affect gene expression through disruption of transcription factor binding, predicting candidate functional single-nucleotide polymorphism for AGA and eczema.

DOI: https://doi.org/10.1038/s41588-023-01445-4
Nat Struct Mol Biol. 2023 Jul 24.

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.

Yuxiang Zhang, David Remillard, Ugoma Onubogu, Barbara Karakyriakou, Joshua N Asiaban, Anissa R Ramos, Kirsten Bowland, Timothy R Bishop, Paige A Barta, Stephanie Nance, Adam D Durbin, Christopher J Ott, Michalina Janiszewska, Benjamin F Cravatt, Michael A Erb.

Transcriptional co-regulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which limits their therapeutic window. Here we unveil a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2, wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal deletions that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic disruption or dTAG-mediated degradation, we show that targeting HDAC2 suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2-NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders that could leverage HDAC1/2 synthetic lethality to target NuRD vulnerabilities. Altogether, we identify HDAC1/2 collateral synthetic lethality as a potential therapeutic target and reveal an unexplored mechanism for targeting NuRD-associated cancer dependencies.

DOI: https://doi.org/10.1038/s41594-023-01041-4
Cell Genom. 2023 Jul 12. 3(7): 100321

Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma.

Samantha M Bevill, Salvador Casaní-Galdón, Chadi A El Farran, Eli G Cytrynbaum, Kevin A Macias, Sylvie E Oldeman, Kayla J Oliveira, Molly M Moore, Esmat Hegazi, Carmen Adriaens, Fadi J Najm, George D Demetri, Sonia Cohen, John T Mullen, Nicolò Riggi, Sarah E Johnstone, Bradley E Bernstein.

  Amplification of MDM2 on supernumerary chromosomes is a common mechanism of P53 inactivation across tumors. Here, we investigated the impact of MDM2 overexpression on chromatin, gene expression, and cellular phenotypes in liposarcoma. Three independent regulatory circuits predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind mesenchymal gene enhancers. P53 and MDM2 co-occupy enhancers and promoters associated with P53 signaling. When highly expressed, MDM2 also binds thousands of P53-independent growth and stress response genes, whose promoters engage in multi-way topological interactions. Overexpressed MDM2 concentrates within nuclear foci that co-localize with PML and YY1 and could also contribute to P53-independent phenotypes associated with supraphysiologic MDM2. Importantly, we observe striking cell-to-cell variability in MDM2 copy number and expression in tumors and models. Whereas liposarcoma cells are generally sensitive to MDM2 inhibitors and their combination with pro-apoptotic drugs, MDM2-high cells tolerate them and may underlie the poor clinical efficacy of these agents.

Keywords:  MDM2; P53 independent; epigenetics; genome topology; liposarcoma; sarcoma; therapeutic resistance

DOI:  https://doi.org/10.1016/j.xgen.2023.100321
Sci Adv. 2023 Jul 28. 9(30): eadf6210

Phosphorylated nuclear DICER1 promotes open chromatin state and lineage plasticity of AT2 tumor cells in lung adenocarcinomas.

Raisa A Reyes-Castro, Shin-Yu Chen, Jacob Seemann, Samrat T Kundu, Don L Gibbons, Swathi Arur.

KRAS/ERK pathway phosphorylates DICER1, causing its nuclear translocation, and phosphomimetic Dicer1 contributes to tumorigenesis in mice. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. While DICER1 canonically regulates microRNAs (miRNA) and epithelial-to-mesenchymal transition (EMT), we found that phosphorylated nuclear DICER1 (phospho-nuclear DICER1) promotes late-stage tumor progression in mice with oncogenic Kras, independent of miRNAs and EMT. Instead, we observe that the murine AT2 tumor cells exhibit altered chromatin compaction, and cells from disorganized advanced tumors, but not localized tumors, express gastric genes. Collectively, this results in subpopulations of tumor cells transitioning from a restricted alveolar to a broader endodermal lineage state. In human LUADs, we observed expression of phospho-nuclear DICER1 in advanced tumors together with the expression of gastric genes. We define a multimeric chromatin-DICER1 complex composed of the Mediator complex subunit 12, CBX1, MACROH2A.1, and transcriptional regulators supporting the model that phospho-nuclear DICER1 leads to lineage reprogramming of AT2 tumor cells to mediate lung cancer progression.

DOI: https://doi.org/10.1126/sciadv.adf6210
Cell Genom. 2023 Jul 12. 3(7): 100342

Robust enhancer-gene regulation identified by single-cell transcriptomes and epigenomes.

Fangming Xie, Ethan J Armand, Zizhen Yao, Hanqing Liu, Anna Bartlett, M Margarita Behrens, Yang Eric Li, Jacinta D Lucero, Chongyuan Luo, Joseph R Nery, Antonio Pinto-Duarte, Olivier B Poirion, Sebastian Preissl, Angeline C Rivkin, Bosiljka Tasic, Hongkui Zeng, Bing Ren, Joseph R Ecker, Eran A Mukamel.

  Single-cell sequencing could help to solve the fundamental challenge of linking millions of cell-type-specific enhancers with their target genes. However, this task is confounded by patterns of gene co-expression in much the same way that genetic correlation due to linkage disequilibrium confounds fine-mapping in genome-wide association studies (GWAS). We developed a non-parametric permutation-based procedure to establish stringent statistical criteria to control the risk of false-positive associations in enhancer-gene association studies (EGAS). We applied our procedure to large-scale transcriptome and epigenome data from multiple tissues and species, including the mouse and human brain, to predict enhancer-gene associations genome wide. We tested the functional validity of our predictions by comparing them with chromatin conformation data and causal enhancer perturbation experiments. Our study shows how controlling for gene co-expression enables robust enhancer-gene linkage using single-cell sequencing data.

Keywords:  DNA methylation; brain; chromatin accessibility; enhancer; epigenome

DOI:  https://doi.org/10.1016/j.xgen.2023.100342
Sci Rep. 2023 07 24. 13(1): 11907

Molecular features driving condensate formation and gene expression by the BRD4-NUT fusion oncoprotein are overlapping but distinct.

Martyna Kosno, Simon L Currie, Ashwani Kumar, Chao Xing, Michael K Rosen.

Aberrant formation of biomolecular condensates has been proposed to play a role in several cancers. The oncogenic fusion protein BRD4-NUT forms condensates and drives changes in gene expression in Nut Carcinoma. Here we sought to understand the molecular elements of BRD4-NUT and its associated histone acetyltransferase (HAT), p300, that promote these activities. We determined that a minimal fragment of NUT (MIN) in fusion with BRD4 is necessary and sufficient to bind p300 and form condensates. Furthermore, a BRD4-p300 fusion protein also forms condensates and drives gene expression similarly to BRD4-NUT(MIN), suggesting the p300 fusion may mimic certain features of BRD4-NUT. The intrinsically disordered regions, transcription factor-binding domains, and HAT activity of p300 all collectively contribute to condensate formation by BRD4-p300, suggesting that these elements might contribute to condensate formation by BRD4-NUT. Conversely, only the HAT activity of BRD4-p300 appears necessary to mimic the transcriptional profile of cells expressing BRD4-NUT. Our results suggest a model for condensate formation by the BRD4-NUT:p300 complex involving a combination of positive feedback and phase separation, and show that multiple overlapping, yet distinct, regions of p300 contribute to condensate formation and transcriptional regulation.

DOI: https://doi.org/10.1038/s41598-023-39102-9
Nat Genet. 2023 Jul 24.

Dynamic network-guided CRISPRi screen identifies CTCF-loop-constrained nonlinear enhancer gene regulatory activity during cell state transitions.

Renhe Luo, Jielin Yan, Jin Woo Oh, Wang Xi, Dustin Shigaki, Wilfred Wong, Hyein S Cho, Dylan Murphy, Ronald Cutler, Bess P Rosen, Julian Pulecio, Dapeng Yang, Rachel A Glenn, Tingxu Chen, Qing V Li, Thomas Vierbuchen, Simone Sidoli, Effie Apostolou, Danwei Huangfu, Michael A Beer.

Comprehensive enhancer discovery is challenging because most enhancers, especially those contributing to complex diseases, have weak effects on gene expression. Our gene regulatory network modeling identified that nonlinear enhancer gene regulation during cell state transitions can be leveraged to improve the sensitivity of enhancer discovery. Using human embryonic stem cell definitive endoderm differentiation as a dynamic transition system, we conducted a mid-transition CRISPRi-based enhancer screen. We discovered a comprehensive set of enhancers for each of the core endoderm-specifying transcription factors. Many enhancers had strong effects mid-transition but weak effects post-transition, consistent with the nonlinear temporal responses to enhancer perturbation predicted by the modeling. Integrating three-dimensional genomic information, we were able to develop a CTCF-loop-constrained Interaction Activity model that can better predict functional enhancers compared to models that rely on Hi-C-based enhancer-promoter contact frequency. Our study provides generalizable strategies for sensitive and systematic enhancer discovery in both normal and pathological cell state transitions.

DOI: https://doi.org/10.1038/s41588-023-01450-7
Cell Rep. 2023 Jul 25. pii: S2211-1247(23)00881-1. [Epub ahead of print]42(8): 112870

14-3-3σ-NEDD4L axis promotes ubiquitination and degradation of HIF-1α in colorectal cancer.

Sicheng Liu, Rui Guo, Hui Xu, Jinneng Yang, Haidan Luo, Sai-Ching Jim Yeung, Kai Li, Mong-Hong Lee, Runxiang Yang.

  A hypoxic microenvironment contributes to tumor progression, with hypoxia-inducible factor-1α (HIF-1α) being a critical regulator. We have reported that 14-3-3σ is negatively associated with HIF-1α expression; however, its role in hypoxia-induced tumor progression remains poorly characterized. Here we show that 14-3-3σ suppresses cancer hypoxia-induced metastasis and angiogenesis in colorectal cancer (CRC). 14-3-3σ opposes HIF-1α expression by regulating the protein stability of HIF-1α, thereby decreasing HIF-1α transcriptional activity and suppressing tumor progression. Mechanistic studies show that the 14-3-3σ-interacting protein neural precursor cell-expressed developmentally down-regulated 4-like (NEDD4L) is an E3 ligase that targets HIF-1α. 14-3-3σ promotes the binding of S448-phosphorylated NEDD4L to HIF-1α, thereby enhancing HIF-1α poly-ubiquitination and subsequent proteasome-mediated degradation. Consistent with this anti-tumorigenic function for 14-3-3σ, low 14-3-3σ expression levels correlate with poor CRC patient survival, and 14-3-3σ enhances the response of CRC to bevacizumab. These results reveal an important mechanism for 14-3-3σ in tumor suppression through HIF-1α regulation.

Keywords:  14-3-3σ; CP: Cancer; HIF-1α; NEDD4L; bevacizumab; colorectal cancer; ubiquitination

DOI:  https://doi.org/10.1016/j.celrep.2023.112870
Nucleic Acids Res. 2023 Jul 24. pii: gkad612. [Epub ahead of print]

ISW1a modulates cohesin distribution in centromeric and pericentromeric regions.

Ireneusz Litwin, Małgorzata Nowicka, Katarzyna Markowska, Ewa Maciaszczyk-Dziubińska, Paulina Tomaszewska, Robert Wysocki, Karol Kramarz.

Cohesin is a highly conserved, multiprotein complex whose canonical function is to hold sister chromatids together to ensure accurate chromosome segregation. Cohesin association with chromatin relies on the Scc2-Scc4 cohesin loading complex that enables cohesin ring opening and topological entrapment of sister DNAs. To better understand how sister chromatid cohesion is regulated, we performed a proteomic screen in budding yeast that identified the Isw1 chromatin remodeler as a cohesin binding partner. In addition, we found that Isw1 also interacts with Scc2-Scc4. Lack of Isw1 protein, the Ioc3 subunit of ISW1a or Isw1 chromatin remodeling activity resulted in increased accumulation of cohesin at centromeres and pericentromeres, suggesting that ISW1a may promote efficient translocation of cohesin from the centromeric site of loading to neighboring regions. Consistent with the role of ISW1a in the chromatin organization of centromeric regions, Isw1 was found to be recruited to centromeres. In its absence we observed changes in the nucleosomal landscape at centromeres and pericentromeres. Finally, we discovered that upon loss of RSC functionality, ISW1a activity leads to reduced cohesin binding and cohesion defect. Taken together, our results support the notion of a key role of chromatin remodelers in the regulation of cohesin distribution on chromosomes.

DOI: https://doi.org/10.1093/nar/gkad612