HDAC1 regulates the chromatin landscape to establish transcriptional dependencies in chronic lymphocytic leukemia

• DOI: 10.1101/2020.08.03.232561
• Publication Date: 2020-08-03T20:45:21Z
• Authors: Tzung-Huei Lai; Hatice Gulcin Ozer; Pierluigi Gasparini; Giovanni Nigita; Rosario Destefano; Lianbo Yu; Janani Ravikrishnan; Tzung-Lin Tsai; Rosa Lapalombella; Jennifer Woyach; Vinay Puduvalli; James Blachly; John C Byrd; Deepa Sampath
• Keywords: HDAC1; BRD4; Chromatin immunoprecipitation

Abstract HDAC1 is a key regulator of gene expression in cancer. We identified critical role for establishing the transcriptional dependencies essential survival chronic lymphocytic leukemia (CLL) by profiling with BRD4, H3K27Ac superenhancers, H4K9Ac, chromatin accessibility signatures, Pol2 measurements and signatures to generate regulatory landscape. Superenhancers marked high levels acetylation BRD4 paradoxically also recruited highest HDAC1. HDAC inhibition poisoned transcription at these loci selectively disrupt B-cell factors receptor signaling. was genome-wide promoters without superenhancers repress expression; induces genes which include microRNA networks that reciprocally downregulate CLL specific driver genes. Our work provides compelling rationale across cancers characterize its driving dysregulation hallmark most develop epigenetic therapeutic strategies. Significance definitively establishes composition enables function as an activator repressor distinct target within same tumor drive allow B cell signaling are survival.