Histone demethylome map reveals combinatorial gene regulatory functions in embryonic stem cells
Author Identifier (ORCID)
Andrew J. Woo: https://orcid.org/0000-0003-1198-6373
Abstract
Epigenetic regulators and transcription factors establish distinct regulatory networks for gene regulation to maintain the embryonic stem cell (ESC) state. Although much has been learned regarding individual epigenetic regulators, their combinatorial functions remain elusive. Here, we report previously unknown combinatorial functions of histone demethylases (HDMs) in gene regulation of mouse ESCs. Generation of a histone demethylome (HDMome) map of 20 well-characterized HDMs based on their genome-wide binding revealed co-occupancy of HDMs in different combinations: KDM1A-KDM4B-KDM6A and JARID2-KDM2B-KDM4A-KDM4C-KDM5B largely co-occupy at enhancers and promoters, respectively. Mechanistic studies uncover that KDM1A-KDM6A combinatorially modulates P300/H3K27ac, H3K4me2 deposition and OCT4 recruitment that directs the OCT4/CORE regulatory network for target gene expression; while co-operative actions of JARID2-KDM2B-KDM4A-KDM4C-KDM5B control H2AK119ub1 and bivalent marks of polycomb-repressive complexes that facilitate the PRC regulatory network for target gene repression. Thus, combinatorial functions of HDMs differentially impact gene expression programs in mESCs.
Document Type
Report
Date of Publication
2022
Publisher
Cold Spring Harbor Laboratory
School
School of Medical and Health Sciences
RAS ID
82667
Funders
National Health and Medical Research Council (NHMRC) of Australia National Human Genome Research Institute (NHGRI) Career Development Award (R00HG008399) Genomic Innovator Award (R35HG010717)
Grant Number
NHMRC Numbers: APP1159461, APP1182804