SUMMARYEpigenetic regulators and transcription factors establish distinct regulatory networks for gene regulation to maintain the embryonic stem cells (ESC) state. Although much has been learned regarding individual epigenetic regulators, their combinatorial functions remain elusive. Here, we report combinatorial functions of histone demethylases (HDMs) in gene regulation of mouse ESCs that are currently unknown. We generated a histone demethylome (HDMome) map of 20 well-characterized HDMs based on their genome-wide binding. This revealed co-occupancy of HDMs in different combinations; predominantly, KDM1A-KDM4B-KDM6A and JARID2-KDM4A-KDM4C-KDM5B co-occupy at enhancers and promoters, respectively. Comprehensive mechanistic studies uncover that KDM1A-KDM6A combinatorially modulates P300/H3K27ac, H3K4me1, H3K4me2 deposition and OCT4 recruitment that eventually directs the OCT4/CORE regulatory network for target gene expression; while co-operative actions of JARID2-KDM4A-KDM4C-KDM5B control H2AK119ub1 and bivalent marks of polycomb-repressive complexes that facilitates the PRC regulatory network for target gene repression. Thus, combinatorial functions of HDMs impact gene expression programs to maintain the ESC state.
Transcriptional Regulatory Networks in Embryonic Stem Cells
