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PAX8 interacts with the SWI/SNF complex at enhancers to drive proliferation in ovarian cancer

ABSTRACT: Activation of lineage-specific gene expression programs is mediated by the sequence-specific recruitment of transcriptional coactivators to chromatin. This occurs via interaction with lineage specific DNA binding transcription factors. The lineage factor PAX8 drives essential gene expression in ovarian cancer cells and is required for tumor proliferation. However, the molecular details surrounding co-factor recruitment and specific activation of transcription by PAX8 remain unknow. Here, we identify an important functional interaction between PAX8 and the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. We show that PAX8 can recruit SWI/SNF complexes to DNA, where they function to open chromatin and facilitate expression of PAX8 target genes. Genetic deletion of PAX8 results in loss of SWI/SNF from PAX8 bound enhancers, loss of expression of associated target genes, and reduced proliferation. These results can be phenocopied by pharmacological inhibition of SWI/SNF ATPase activity. These data indicate that PAX8 mediates the expression of an essential ovarian cancer proliferative program in part by the recruitment of chromatin remodelers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272992 | GEO | 2024/08/04

REPOSITORIES: GEO

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PAX8 interacts with the SWI/SNF complex at enhancers to drive proliferation in ovarian cancer [ChIP-seq]

Project description:Activation of lineage-specific gene expression programs is mediated by the sequence-specific recruitment of transcriptional coactivators to chromatin. This occurs via interaction with lineage specific DNA binding transcription factors. The lineage factor PAX8 drives essential gene expression in ovarian cancer cells and is required for tumor proliferation. However, the molecular details surrounding co-factor recruitment and specific activation of transcription by PAX8 remain unknow. Here, we identify an important functional interaction between PAX8 and the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. We show that PAX8 can recruit SWI/SNF complexes to DNA, where they function to open chromatin and facilitate expression of PAX8 target genes. Genetic deletion of PAX8 results in loss of SWI/SNF from PAX8 bound enhancers, loss of expression of associated target genes, and reduced proliferation. These results can be phenocopied by pharmacological inhibition of SWI/SNF ATPase activity. These data indicate that PAX8 mediates the expression of an essential ovarian cancer proliferative program in part by the recruitment of chromatin remodelers.

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SWI/SNF is positively auto-regulated by an AT-hook in the catalytic subunit

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PAX8 interacts with the SWI/SNF complex at enhancers to drive proliferation in ovarian cancer

Project description:PAX8 interacts with the SWI/SNF complex at enhancers to drive proliferation in ovarian cancer

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Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells [RNA-seq]

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Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells [ChIP-seq]

2019-02-10 | GSE110448 | GEO

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Project description:Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cancer types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 megabases downstream of Myc that are occupied by SWI/SNF, as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in 3% of acute myeloid leukemia. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs In order to understanding the lineage specific requirement of coactivaor, such as Brg1 and Brd4, in AML, we performed ChIP-seq with Brg1, Brd4 together with histone modification marks in murine MLL-AF9/NrasG12D AML cell line to search tissue specific cis regulation element that can be accounted for the leukemia specific dependence.

2013-12-02 | E-GEOD-52277 | biostudies-arrayexpress

Brd7, a novel PBAF-specific SWI/SNF subunit, is required for gene activation and repression in embryonic stem cells

Project description:The composition of chromatin remodeling complexes dictates how these enzymes control transcriptional programs and cellular identity. Here, we investigate the composition of SWI/SNF complexes in embryonic stem cells (ESCs). In contrast to differentiated cells, ESCs have a biased incorporation of certain paralogous SWI/SNF subunits, with low levels of Brm, BAF170 and ARID1B. Upon differentiation, the expression of these subunits increases, resulting in a higher diversity of compositionally distinct SWI/SNF enzymes. We also identify Brd7 as a novel component of the PBAF complex in both ESCs and differentiated cells. Using shRNA-mediated depletion of Brg1, we show that SWI/SNF can function as both a repressor and an activator in pluripotent cells, regulating expression of developmental modifiers and signaling components such as Nodal, ADAMTS1, Bmi-1, CRABP1 and TRH. Knock-down studies of PBAF-specific Brd7 and of a signature subunit within the BAF complex, ARID1A, show that these two sub-complexes affect SWI/SNF target genes differentially, in some cases even antagonistically. This may be due to their different biochemical properties. Finally, we examine the role of SWI/SNF in regulating its target genes during differentiation. We find that SWI/SNF affects recruitment of components of the pre-initiation complex in a promoter-specific manner, to modulate transcription positively or negatively. Taken together, our results provide insight into the function of compositionally diverse SWI/SNF enzymes that underlie their inherent gene-specific mode of action. R1 ESCs were infected in duplicates with shRNA targeting Brg1 or GLUT4 (as a control). Knockdown of Brg1 mRNA affected Brg1 protein levels efficiently. RNA was isolated 67 hours post-infection and analyzed using microarrays.

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