Accession Number:

AD1093439

Title:

Defining the Consequence of CHD1 Loss on Transcriptional Regulation and Therapeutic Response

Descriptive Note:

Technical Report,01 Jun 2017,31 May 2019

Corporate Author:

Joan and Sanford I Weill Medical College of Cornell University New York United States

Personal Author(s):

Report Date:

2019-09-01

Pagination or Media Count:

34.0

Abstract:

Genome wide studies have identified a high prevalence of inactivating genomic alterations associated with nucleosome remodeling and modifying enzymes, suggesting that deregulation of chromatin architecture is critical in tumor initiationprogression. CHD1 is a founding member of the chromatin remodeling family, characterized by tandem Chromo-domains, a DNA Helicase domain, and DNA binding domain CHD1. A multitude of studies have demonstrated that CHD1 is recruited to the promoters of highly transcribed genes by the epigenetic mark H3K4me3, where it redistributes local nucleosomes ahead of RNA polymerase to facilitate efficient transcriptional initiation and RNA processing. While a majority of cell types appear to be dependent upon the function of CHD1, a subclass of primary PCa is characterized by the genomic loss of this chromatin remodeler. Given that PCa is a disease driven by aberrant transcriptional regulation mediated by oncogenic transcriptional factors e.g. AR and MYC, it is imperative to understand the molecular underpinnings of CHD1 loss in driving these oncogenic programs. For the first time, our preliminary data demonstrate that in a prostate-specific background, CHD1 localizes to enhancer-like regions of the genome specifically occupied by AR and its associated transcriptional regulators FOXA1 and HOXB13. This CHD1 binding signature is highly consistent with epigenetic marks identifying these enhancer sites, suggesting that CHD1 remodels enhancer-like chromatin to define a unique AR cistrome. Furthermore, CHD1 was found to be dispensable for global transcriptional output in prostate derived models, but was essential for efficient transcriptional processing. Thus, loss of CHD1 may have a global impact on the AR transcriptional network, deregulating both genomic binding and resultant transcriptional output, via distinct molecular mechanisms.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE