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

Carlos A. Toro, Hollis Wright, Carlos F. Aylwin, Sergio R. Ojeda () and Alejandro Lomniczi ()
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Carlos A. Toro: Oregon National Primate Research Center/Oregon Health and Science University
Hollis Wright: Oregon National Primate Research Center/Oregon Health and Science University
Carlos F. Aylwin: Oregon National Primate Research Center/Oregon Health and Science University
Sergio R. Ojeda: Oregon National Primate Research Center/Oregon Health and Science University
Alejandro Lomniczi: Oregon National Primate Research Center/Oregon Health and Science University

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02512-1

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