A novel dual histone mark reader ZCWPW2 regulates meiotic recombination through lactylation and transcriptional control in humans and mice

ABSTRACT: Meiotic recombination ensures proper chromosome segregation and genetic diversity during gametogenesis, and its disruption leads to infertility. It is known that the dual histone methylation writer–reader system, in which PRDM9 deposits H3K4me3 and H3K36me3 marks at nucleosomes to specify recombination hotspots and ZCWPW1 functions as a reader recognizing these marks, is essential for meiotic recombination. However, the regulatory mechanism of this system remains unclear. Here, Deficiency of ZCWPW2 causes recombination defects, with impairment in homologous synapsis and DNA double-strand break repair. CUT&Tag and mass spectrometry analyses revealed that ZCWPW2 recognizes PRDM9-mediated dual histone methylation and interacts with ZCWPW1 to form a complex that recruits recombination-associated proteins to hotspots. Additionally, ZCWPW2 independently binds to promoter regions to regulate meiotic transcription. Lactylome and proteome analyses demonstrated that the ZCWPW1–ZCWPW2 complex interacts with and maintains the activity of lactate dehydrogenase LDHA, and together with ZCWPW2-driven transcription of lactylation writer EP300, to promote lactylation of recombination-associated proteins and stabilize their expression at hotspots. Collectively, we identified ZCWPW2 as a previously unrecognized yet indispensable factor supporting the function of PRDM9/ZCWPW1 during meiotic recombination, elucidated the molecular mechanism of the PRDM9/ZCWPW1/ZCWPW2 system in regulating recombination, and uncovered a critical role for lactylation in meiosis.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Testis

SUBMITTER: Ying Shen  

LAB HEAD: Ying Shen

PROVIDER: PXD070427 | Pride | 2026-01-07

REPOSITORIES: Pride