RLF/ZFP292 stabilize CoREST-linked LSD1 engagement at bivalent promoters to safeguard pluripotency

How CoREST-linked chromatin activities are regulated at promoters independently of canonical REST repression remains unclear. Here, we identify the zinc-finger proteins rearranged L-myc fusion (RLF) and ZFP292 as redundant promoter-associated factors that stabilize CoREST-linked LSD1 engagement within RCOR2-containing CoREST assemblies at active and bivalent promoters in embryonic stem cells. Loss of RLF/ZFP292 reduces ZMYM3 occupancy while diminishing LSD1 enrichment at target promoters, whereas RCOR2 and HDAC1 occupancy remain largely unchanged, consistent with a role in stabilizing enzymatic engagement rather than in complex recruitment. Loss of RLF/ZFP292 increases promoter-associated active chromatin features at both promoter classes, but transcriptional upregulation is most evident at genes with bivalent promoters. At a subset of active promoters, selective loss of ZMYM3 coincides with reduced transcription despite retained RCOR2-HDAC1-LSD1 signals. Together, these findings reveal a REST-independent mechanism in which RLF/ZFP292 modulate the functional output of promoter-associated CoREST assemblies to maintain transcriptional balance in pluripotent cells.