Biology subjects

Bando, M.

Publications and source records attributed to Bando, M..

7 recordsLinked to original sources

bioRxiv2026

Region-specific generation and retention of acetylated cohesin shape the genome-wide pattern of sister chromatid cohesion

Sister chromatid cohesion depends on ESCO2-mediated acetylation of the cohesin subunit SMC3, yet how this modification is established and maintained across the genome remains poorly understood. Here, we examined the chromatin-binding dynamics of ESCO2 and its enzymatic activity using quantitative ChIP-seq of human cells synchronously progressing through S phase. ESCO2 bound broadly along chromosomes without forming discrete peaks and preferentially localized to transcriptionally inactive regions, but was not confined to H3K9me3- or H3K27me3-enriched heterochromatin. Consistent with this binding pattern, ESCO2-dependent SMC3 acetylation showed a similarly broad distribution in these regions. In contrast, ESCO1, a paralog of ESCO2, primarily mediated SMC3 acetylation at cohesin peak sites. Notably, most of the broadly distributed, ESCO2-dependent SMC3 acetylation generated during S phase was progressively lost from chromatin after replication, whereas the fraction that persisted into late G2 accumulated in domains enriched for the repressive H3K27me3 modification. Our work identifies selective post-replicative retention of acetylated cohesin as a previously unappreciated step in shaping the genome-wide architecture of sister chromatid cohesion.

molecular biology↗

bioRxiv2025

Cohesin acts as a transcriptional gatekeeper by restraining pause-release to promote processive elongation

Cohesin organizes 3D chromatin architecture, including promoter-enhancer loops, yet its loss has surprisingly modest effects on steady-state gene expression. We address this paradox by demonstrating that cohesin acts at different stages of transcription. First, it promotes Pol II promoter recruitment by facilitating enhancer-promoter communication that maintains active promoter chromatin states. Second, it delays pause release by transiently associating with the transcriptional machinery during the pause-release transition. Kinetic modelling suggests that reduced Pol II recruitment and enhanced pause release have compensatory effects, contributing to minimal changes in steady-state gene expression across genes upon cohesin loss. In contrast, cohesin depletion impairs robust transcriptional induction in response to external stimuli. Moreover, cohesin ensures sufficient pausing duration as a quality-control-like step to promote elongation complex assembly and transcription processivity. Here, we show that cohesin regulates multiple steps of transcription, offering mechanistic insight into cohesin-related diseases, including cancers and cohesinopathies.

molecular biology↗

bioRxiv2024

Cohesin regulates promoter-proximal pausing of RNA Polymerase II by limiting recruitment of super elongation complex

Cohesin is a ring-shaped complex, responsible for establishing sister chromatid cohesion and forming topologically associating domains (TADs) and chromatin loops. Loss-of-function mutations in cohesin subunits and its regulatory factors can cause Cornelia de Lange syndrome (CdLS). Because dysregulated gene expression was observed in CdLS, it has long been thought that cohesin plays a regulatory role in transcription. Here, we investigated the effect of acute cohesin depletion on transcription and observed that a small number of genes exhibited differential expression. Analysis of RNA polymerase II (Pol II) distribution revealed that the depletion reduced Pol II promoter binding and pausing simultaneously at the majority of genes. This implies that at most genes, the two decreases counterbalance each other, resulting in unchanged gene expression. Additionally, we find that cohesin loss increased promoter binding of super elongation complex (SEC), which mediates the release of Pol II from paused state. Moreover, the reduction in pausing caused by cohesin depletion was no longer observed when SEC was inhibited. These observations suggest that cohesin regulates Pol II pausing by restricting SEC recruitment to promoters. Together, our study demonstrates the involvement of cohesin in transcriptional regulation, particularly in Pol II pause and release.

molecular biology↗

bioRxiv2022

Context-dependent 3D genome regulation by cohesin and related factors

Cohesin plays vital roles in chromatin folding and gene expression regulation, cooperating with such factors as cohesin loaders, unloaders, acetyltransferase, and the insulation factor CTCF. Although various models of regulation have been proposed (e.g., loop extrusion), how cohesin and related factors collectively or individually regulate the hierarchical chromatin structure and gene expression remains unclear. In this study, we have depleted cohesin and related factors and then conducted a comprehensive evaluation of the resulting 3D genome, transcriptome and epigenome data. We observed substantial variation in depletion effects among factors at topologically associating domain (TAD) boundaries and on interTAD interactions, which were partly related to epigenomic status. Gene expression changes were highly correlated with direct cohesin binding and gain of TAD boundaries than with the loss of boundaries. Our results suggested that cohesin positively regulates gene expression, whereas other mechanisms (e.g., cohesin turnover and acetylation) add to the diversity of this pattern of dysregulation. Moreover, cohesin was broadly enriched in active compartment A, but not in compartment B, which were retained even after CTCF depletion. Our rich dataset and the subsequent data-driven analysis support the context-specific regulation of chromatin folding by cohesin and related factors.

genomics↗

bioRxiv2021

Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation

Cohesin, an essential protein complex for chromosome segregation, regulates transcription through a variety of mechanisms. It is not a trivial task to genome-widely assign the diverse cohesin functions. Moreover, the context-specific roles of cohesin-mediated interactions, especially on intragenic regions, have not been thoroughly investigated. Here we performed a comprehensive characterization of cohesin binding sites in several human cell types. We integrated epigenomic, transcriptomic and chromatin interaction data with and without transcriptional stimulation, to explore context-specific functions of intragenic cohesin related to gene activation. We identified a new subset of cohesin binding sites, decreased intragenic cohesin sites (DICs), which have a different function from previously known ones. The intron-enriched DICs were negatively correlated with transcriptional regulation: a subgroup of DICs were related to enhancer markers and paused RNA polymerase II, whereas others contributed to chromatin architecture. We implemented machine learning and successfully isolated DICs with distinct genomic features. We observed DICs in various cell types, including cells from cohesinopathy patients. These results suggest a previously unidentified function of cohesin at intragenic regions for transcription regulation.

genomics↗

bioRxiv2019

Transcription-driven cohesin repositioning rewires chromatin loops in cellular senescence

Senescence is a phenotypic state of stable proliferative arrest, typically occurring in lineage-committed cells and triggered by various stimuli. It is generally accompanied by activation of a secretory program (senescence-associated secretory phenotype, SASP), which modulates both local (tissue microenvironment) and systemic (ageing) homeostasis1,2. Enhancer-promoter interactions play a key role in gene regulation3-5, facilitated by chromatin loops, mostly formed via CCCTC binding factor (CTCF) and cohesin tethering6-8. The three-dimensional chromatin structure of senescent cells has been characterised9-11 mostly in terms of macro-domain structures, but its relevance in gene expression remains elusive. Here, we use Hi-C and capture Hi-C12,13 to show that oncogenic HRAS-induced senescence (RIS) in human diploid fibroblasts (HDFs) is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks at the 3 end of a subset of active genes, reminiscent of the transcription-driven cohesin islands recently discovered in mouse embryonic fibroblasts deficient in both CTCF and the cohesin release factor Wings apart-like (Wapl)14. RIS de novo cohesin peaks are also transcription-dependent and enriched for SASP genes, as exemplified by IL1B, where de novo cohesin binding is involved in new loop formation. Cytokine induction is associated with similar cohesin islands appearance and enhancer-promoter rewiring during the terminal differentiation of monocytes to macrophages15, but not upon acute TNF treatment of HDFs16. These results suggest that RIS represents a fate-determined process in which gene expression is regulated beyond the cell type specific 3D chromatin framework, in part through cohesin redistribution.

molecular biology↗

bioRxiv2019

Dissecting the functions of NIPBL using genome editing: The importance of the N-terminus of NIPBL in transcriptional regulation

Cornelia de Lange syndrome (CdLS) is characterized by craniofacial dysmorphisms, intellectual disabilities, growth retardation, and several other systemic abnormalities. CdLS is caused by heterozygous germline mutations in structural and regulatory components of cohesin. Mutations in NIPBL, which encodes regulatory subunit of cohesin, are frequently found in individuals with CdLS. CdLS is associated with a currently unknown mechanism of global transcriptional dysregulation. In this study, NIPBL mutants were generated using the CRISPR/Cas9 system to study this mechanism. Clones with a biallelic frameshift mutation in exon 3 of NIPBL, resulting in a truncated N-terminus, displayed transcriptional dysregulation without sister chromatid separation defects. Detailed transcriptome analysis revealed the overexpression of genes in NIPBL mutants that are typically expressed at low levels in wild type and the reduced expression of genes that are typically expressed at high levels in wild type. This result suggested that NIPBL plays a role in fine-tuning gene expression levels. MAU2 protein, that closely interacts with NIPBL, was nearly absent in these clones. The reduction of MAU2 observed in NIPBL mutants points to the importance of the NIPBL N-terminus/MAU2 interaction in transcriptional regulatory role of NIPBL.

genetics↗