Epigenetics Mondays Seminars - Fulvio Chiacchiera, Ph.D.
Loss of Arid1a reshapes tissue microenvironment promoting tumor formation
Cell identity and tissue homeostasis is preserved by the antagonistic activity of chromatin associated complexes able to positively or negatively regulate transcription in a cell type and time dependent manner. The proper structural and functional organization of the cell type specific epigenetic landscape is of crucial importance to preserve tissue architecture. Mutations affecting chromatin-modifying enzymes leads to differentiation, regeneration and cell cycle defects thus favoring tumor formation. SWI/SNF chromatin remodeling complexes are multiprotein complexes required to mobilize nucleosomes to promote tight regulation of transcriptional activation and repression. Through their mutually exclusive catalytic subunits BRG1 and BRM they catalyze the sliding and eviction of nucleosomes to promote DNA accessibility and transcription factor binding at promoter and enhancers. Crucial functional and structural SWI/SNF complexes subunits are frequently mutated in cancer. Among the different SWI/SNF subunits, tumor driving mutations affecting the structure and function of ARID1A have been identified in several different tumors and pre-tumoral lesions. Despite compelling clinical and molecular evidence, it is still debated whether Arid1a plays a tumor suppressive or oncogenic role. We will present unpublished results about a neglected role of Arid1A-containing SWI/SNF complex supporting tumor suppressive activity in adult tissues.
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