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

• Published in: Nature communications 2018-01, Vol.9 (1), p.57-16, Article 57
• Main Authors: Toro, Carlos A., Wright, Hollis, Aylwin, Carlos F., Ojeda, Sergio R., Lomniczi, Alejandro
• Format: Article
• Language: English
• Subjects: 13/1; 13/51; 13/89; 14; 14/32; 45; 45/15; 45/22; 45/23; 45/29; 45/41; 45/44; 45/47; 45/77; 45/88; 45/90; 49; 49/91; 631/136; 631/208/176; 631/208/4041/3196; 631/378/2584; 64; 64/86; 96; 96/106; 96/109; 96/31; 96/63; Animals; Arcuate nucleus; Chromatin; CRISPR; CRISPR-Cas Systems; Epigenesis, Genetic; Epigenetics; Female; Gene Expression Regulation, Developmental - genetics; Gene Knockdown Techniques; Gene Silencing; Humanities and Social Sciences; Hypothalamus; Hypothalamus - metabolism; Kiss1 protein; Kisspeptins - genetics; Leukemia; Macaca mulatta; Machinery and equipment; multidisciplinary; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Polycomb group proteins; Polycomb-Group Proteins - metabolism; Promoter Regions, Genetic; Proteins; Puberty; Puberty - genetics; Rats; Rats, Sprague-Dawley; Regulatory mechanisms (biology); RNA-mediated interference; Science; Science (multidisciplinary); Tachykinins - genetics; Transcription activation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02512-1

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. Before the onset of puberty, Polycomb proteins repress the expression of Kiss1 in KNDy neurons of the arcuate nucleus. Here, by CRISPR-Cas9-directed epigenome editing and RNAi, the authors show that coordinated action of Mll proteins at the Kiss1 promoter and enhancer is required for correct timing of puberty.