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Polycomb group (PcG) proteins control the timing of puberty by repressing the  Kiss1  gene in hypothalamic arcuate nucleus (ARC) neurons. Here we identify two members of the Trithorax group (TrxG) of modifiers, mixed-lineage leukemia 1 (MLL1), and 3 (MLL3), as central components of an activating epigenetic machinery that dynamically counteracts PcG repression. Preceding puberty, MLL1 changes the chromatin configuration at the promoters of  Kiss1  and  Tac3 , two genes required for puberty to occur, from repressive to permissive. Concomitantly, MLL3 institutes a chromatin structure that changes the functional status of a  Kiss1  enhancer from poised to active. RNAi-mediated, ARC-specific  Mll1  knockdown reduced  Kiss1  and  Tac3  expression, whereas CRISPR-Cas9-directed epigenome silencing of the  Kiss1  enhancer selectively reduced  Kiss1  activity. Both interventions delay puberty and disrupt reproductive cyclicity. Our results demonstrate that an epigenetic switch from transcriptional repression to activation is crucial to the regulatory mechanism controlling the timing of mammalian puberty.

Trithorax dependent changes in chromatin landscape at enhancer and promoter regions drive female puberty