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A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE153576 | GEO | 2021/02/23

REPOSITORIES: GEO

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A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression.

Project description:The cohesin complex spatially organizes interphase chromatin by bringing distal genomic loci into close physical proximity, looping out the intervening DNA. Mutation of cohesin complex subunits is observed in cancer and developmental disorders, but the mechanisms through which these mutations may contribute to disease remain poorly understood. Here, we investigate a recurrent missense mutation to the hinge domain of the cohesin subunit SMC1A, observed in acute myeloid leukemia. Engineering this mutation into murine embryonic stem cells caused widespread changes in gene expression, including dysregulation of the pluripotency gene expression program. This mutation reduced cohesin levels at promoters and enhancers, decreased DNA loops and interactions across short genomic distances, and weakened insulation at CTCF-mediated DNA loops. These findings provide insight into how altered cohesin function contributes to disease and identify a requirement for the cohesin hinge domain in three-dimensional chromatin structure.

| S-EPMC7990204 | biostudies-literature

A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression [RNA-seq]

Project description:Purpose: Chromatin loop formation and maintenance is regulated by the cohesin complex. Here, we investigate whether a cancer mutation to a cohesin complex subunit, SMC1A-R586W, alters genome architecture and gene expression. Method: Global gene expression was assessed using RNA-seq in wildtype and CRISPR-Cas9 genome edited SMC1A-R586W mouse embryonic stem cells (mESCs).

2021-02-23 | GSE153575 | GEO

A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression [Hi-C]

Project description:Purpose: Chromatin loop formation and maintenance is regulated by the cohesin complex. Here, we investigate whether a cancer mutation to a cohesin complex subunit, SMC1A-R586W, alters genome architecture. Method: Genome wide chromatin looping patterns were assessed via Hi-C in both wildtype and CRISPR-Cas9 genome edited SMC1A-R586W mouse embryonic stem cells (mESCs).

2021-02-23 | GSE153574 | GEO

A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression [ChIP-seq]

Project description:Purpose: Chromatin loop formation and maintenance is regulated by the cohesin complex. Here, we investigate whether a cancer mutation to a cohesin complex subunit, SMC1A-R586W, alters genome architecture and gene expression. Method: Genome wide binding patterns of known architectural proteins and histone PTMs were assessed in WT and SMC1A-R586W mESCs by ChIP-seq.

2021-02-23 | GSE153573 | GEO

A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression

Project description:A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression

| PRJNA643259 | ENA

A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression [Hi-C]

Project description:A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression [Hi-C]

| PRJNA643261 | ENA

A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression [RNA-seq]

Project description:A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression [RNA-seq]

| PRJNA643262 | ENA

A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression [ChIP-seq]

Project description:A cohesin cancer mutation reveals a role for the hinge domain in genome organization and gene expression [ChIP-seq]

| PRJNA643260 | ENA

Suppressor screening reveals common kleisin-hinge interaction in condensin and cohesin, but different modes of regulation.

Project description:Cohesin and condensin play fundamental roles in sister chromatid cohesion and chromosome segregation, respectively. Both consist of heterodimeric structural maintenance of chromosomes (SMC) subunits, which possess a head (containing ATPase) and a hinge, intervened by long coiled coils. Non-SMC subunits (Cnd1, Cnd2, and Cnd3 for condensin; Rad21, Psc3, and Mis4 for cohesin) bind to the SMC heads. Here, we report a large number of spontaneous extragenic suppressors for fission yeast condensin and cohesin mutants, and their sites were determined by whole-genome sequencing. Mutants of condensin's non-SMC subunits were rescued by impairing the SUMOylation pathway. Indeed, SUMOylation of Cnd2, Cnd3, and Cut3 occurs in midmitosis, and Cnd3 K870 SUMOylation functionally opposes Cnd subunits. In contrast, cohesin mutants rad21 and psc3 were rescued by loss of the RNA elimination pathway (Erh1, Mmi1, and Red1), and loader mutant mis4 was rescued by loss of Hrp1-mediated chromatin remodeling. In addition, distinct regulations were discovered for condensin and cohesin hinge mutants. Mutations in the N-terminal helix bundle [containing a helix-turn-helix (HTH) motif] of kleisin subunits (Cnd2 and Rad21) rescue virtually identical hinge interface mutations in cohesin and condensin, respectively. These mutations may regulate kleisin's interaction with the coiled coil at the SMC head, thereby revealing a common, but previously unknown, suppression mechanism between the hinge and the kleisin N domain, which is required for successful chromosome segregation. We propose that in both condensin and cohesin, the head (or kleisin) and hinge may interact and collaboratively regulate the resulting coiled coils to hold and release chromosomal DNAs.

| S-EPMC6561158 | biostudies-literature

A SIR-independent role for cohesin in subtelomeric silencing and organization.

Project description:Cohesin is a key determinant of chromosome architecture due to its DNA binding and tethering ability. Cohesin binds near centromeres and chromosome arms and also close to telomeres, but its role near telomeres remains elusive. In budding yeast, transcription within 20 kb of telomeres is repressed, in part by the histone-modifying silent information regulator (SIR) complex. However, extensive subtelomeric repressed domains lie outside the SIR-binding region, but the mechanism of silencing in these regions remains poorly understood. Here, we report a role for cohesin in subtelomeric silencing that extends even beyond the zone of SIR binding. Clusters of subtelomeric genes were preferentially derepressed in a cohesin mutant, whereas SIR binding was unaltered. Genetic interactions with known telomere silencing factors indicate that cohesin operates independent of the SIR-mediated pathway for telomeric silencing. Mutant cells exhibited Mpk1-dependent Sir3 hyperphosphorylation that contributes to subtelomeric derepression to a limited extent. Compaction of subtelomeric domains and tethering to the nuclear envelope were impaired in mutant cells. Our findings provide evidence for a unique SIR-independent mechanism of subtelomeric repression mediated by cohesin.

| S-EPMC6431164 | biostudies-literature

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