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Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription control (ChiP-Seq 2)

ABSTRACT: Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A and RAD21, cohesin contains in somatic cells one of two orthologous STAG subunits, STAG1 or STAG2. How these variable subunits affect the function of the cohesin complex is still unclear. STAG1- and STAG2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of STAG1 and STAG2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either STAG1 or STAG2. Following rapid depletion of either subunit, we perform high resolution Hi-C, RNA-sequencing and sequential ChIP studies to show that STAG1 and STAG2 do not co-occupy individual binding sites and have distinct ways how they affect looping and gene expression. These findings are supported at the single cell level by single-molecule localizations via dSTORM super-resolution imaging. Since somatic and congenital mutations of the STAG subunits are associated with cancer (STAG2) and intellectual disability syndromes with congenital abnormalities (STAG1 and STAG2), we verified STAG1-/STAG2-dependencies using human neural stem cells, hence highlighting their importance for understanding particular disease contexts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140751 | GEO | 2020/03/06

REPOSITORIES: GEO

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Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription control (ChIP-Seq)

Project description:Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A and RAD21, cohesin contains in somatic cells one of two orthologous STAG subunits, SA1 or SA2. How these variable subunits affect the function of the cohesin complex is still unclear. SA1- and SA2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of SA1 and SA2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either SA1 or SA2. Following rapid depletion of either subunit, we perform high resolution Hi-C, RNA-sequencing and sequential ChIP studies to show that SA1 and SA2 do not co-occupy individual binding sites and have distinct ways how they affect looping and gene expression. These findings are supported at the single cell level by single-molecule localizations via dSTORM super-resolution imaging. Since somatic and congenital mutations of the SA subunits are associated with cancer (SA2) and intellectual disability syndromes with congenital abnormalities (SA1 and SA2), we verified SA1-/SA2-dependencies using human neural stem cells, hence highlighting their importance for understanding particular disease contexts.

2020-03-06 | GSE133021 | GEO

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Distinct and overlapping roles of STAG1 and STAG2 in cohesin localization and gene expression in embryonic stem cells [RNA-seq]

Project description:Purpose: Cohesin is a ring-shaped complex that is critical to genome organization and is an important regulator of gene expression. How cohesin accessory proteins contribute to cohesin function remain unclear. The purpose of this study is to assess the roles of cohesin accessory proteins, STAG1 and STAG2, in cohesin localization and gene expression. Method: The role of STAG1 and STAG2 in gene regulation was assessed by performing RNA-seq in wildtype and CRISPR-Cas9 genome edited STAG knockout mouse embryonic stem cells (mESCs). The redundancy of the STAGs was addressed by using siRNA against STAG1 in a STAG2-knockout background.

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Distinct and overlapping roles of STAG1 and STAG2 in cohesin localization and gene expression in embryonic stem cells [ChIP-seq]

Project description:Purpose: Cohesin is a ring-shaped complex that is critical to genome organization and is an important regulator of gene expression. How cohesin accessory proteins contribute to cohesin function remains unclear. The purpose of this study is to assess the roles of cohesin accessory proteins, STAG1 and STAG2, in cohesin localization and gene expression. Method: Genome wide binding patterns of the STAGs and cohesin in wildtype cells as well as in STAG CRISPR/Cas9 genome edited knockout cells were assessed via chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq). The redundancy of the STAGs was addressed by using siRNA against STAG1 in a STAG2-knockout background.

2020-08-10 | GSE144114 | GEO

Response of cohesin STAG1 and STAG2 to reduction of NIPBL levels [Hi-C]

Project description:Cohesin mediates sister chromatid cohesion and organizes the genome through the formation of chromatin loops. Two versions of the complex carrying either STAG1 or STAG2 show overlapping and specific functions and both are required to fulfill embryonic development. Cohesin-STAG1 displays longer residence time on chromatin that depends on CTCF and ESCO1 and establishes longer, long-lived chromatin loops together with CTCF. Cohesin-STAG2 shows a preferential interaction with WAPL and mediates shorter loops involved in tissue-specific transcription independently of CTCF. Here we show that the two variants respond in opposite ways to knock down of NIPBL, the putative cohesin loader that is also essential for loop extrusion. Cohesin-STAG1 levels increase on chromatin under this condition and the complex accumulates further at CTCF positions while cohesin-STAG2 is diminished genome-wide. Our data support a model in which NIPBL is not required for association of cohesin with chromatin but it is for loop extrusion, which in turn facilitates stabilization of cohesin-STAG2 at CTCF positions after being loaded elsewhere. In contrast, cohesin-STAG1 is preferentially loaded at CTCF sites independently of NIPBL. Nevertheless, loop formation by these chromatin-bound complexes is impaired and gene expression is severely affected, resembling alterations in Cornelia de Lange patients

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Response of cohesin STAG1 and STAG2 to reduction of NIPBL levels [ChIP-Seq]

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Genome-wide map of cohesin positions in RT112 bladder cancer cells

Project description:Bladder cancer is one of the most common genitourinary malignancies worldwide. It is a heterogeneous disease at the clinical, pathological, and genetic levels. In an exome-sequencing study of bladder cancer, we identified genes mutated in bladder cancer coding for proteins involved in chromatin modification, cell division, and DNA repair. STAG2, a constituent of the cohesin complex, was commonly mutated or lost, mainly in tumors of low stage or grade. Loss of STAG2 expression was often observed in genomically stable tumors, suggesting that STAG2 may act as a tumor suppressor through mechanisms other than chromosome segregation (Balbás-Martínez et al. 2013). In addition to mediating sister chromatid cohesion, cohesin plays a central role in DNA looping and organization of the genome into Topologically Associating Domains (TADs). Two variant cohesin complexes that contain either STAG1 or STAG2 are present in all cell type. Here we addressed their genome wide binding in bladder cancer cells.

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Identification of the protein interaction network of Stag proteins

Project description:This study involves the identification of specific Stag1 interactors with and without Cohesin loss. Stag1 was immunoprecipiated from human HCT116 cells, under 4 treatments - untreated (UTR), Non-specific siRNA treatment (SiCON), SA1 siRNA treatment (SiSA1) and Auxin treatment for Cohesin loss (IAA). An unspecific IgG pulldown was also conducted to assess for unspecific protein binding to the bead system (Mock). Significant proteins were determined by label-free quantification and statistical analysis using MaxQuant and MSstats.

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