Pyruvate kinase M2-mediated histone lactylation alters three-dimensional genomic architecture in polycystic ovary syndrome

TL;DR

This study shows that pyruvate kinase M2 in the nucleus alters chromatin structure, contributing to PCOS, and suggests it as a potential treatment target.

Contribution

The novel finding is that nuclear PKM2 causes histone lactylation, which changes chromatin architecture and drives PCOS-related gene expression.

Findings

Nuclear PKM2 increases histone lactylation at H3K9 and H3K18, altering genomic architecture.

PKM2-mediated changes enhance expression of PCOS-related genes like CYP17A1 and CYP11A1.

Pharmacological inhibition of nuclear PKM2 reduces PCOS-like symptoms in mice.

Abstract

Polycystic ovary syndrome (PCOS) is a frequent endocrine and metabolic imbalance that typically occurs in women of reproductive age. Its molecular pathophysiology is yet unknown, especially the ovarian cellular metabolic inefficiency that causes the transcriptional dysregulation of key genes linked to PCOS. Here, we discovered that one transcriptional-like regulator that causes PCOS is nuclear pyruvate kinase M2 (nPKM2). Using multiomics techniques, we show that enhanced lactylation of histone 3 on lysine residues 9 and 18 is linked to nPKM2 binding to the genome, changing the three-dimensional architecture of the genome. Genomic compartment switching, topologically associated domain fusion, and novel enhancer–promoter interactions subsequently enhance the expression of PCOS-related genes, including CYP17A1 and CYP11A1. In mice, ectopic expression of Pkm2 in female GCs consistently presented PCOS-like traits, such as interrupted estrous cycles, hyperandrogenism, and so on. Importantly, whole-organ tracing imaging directly unfolded the number of small follicles, which increased highly in Pkm2-tdtomato transgene mice compared with control. Furthermore, pharmacological inhibition of the nuclear accumulation of PKM2 mitigated PCOS-like symptoms in mice and restored a wild-type-like transcriptome. This study demonstrates the important function of PKM2-mediated histone lactylation in regulating the three-dimensional chromatin architecture and highlights PKM2 as a potential therapeutic target for PCOS treatment.

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