TY - JOUR
T1 - Trithorax dependent changes in chromatin landscape at enhancer and promoter regions drive female puberty
AU - Toro, Carlos A.
AU - Wright, Hollis
AU - Aylwin, Carlos F.
AU - Ojeda, Sergio R.
AU - Lomniczi, Alejandro
N1 - Funding Information:
This work was supported by grants from the US National Science Foundation (NSF: IOS1121691) to S.R.O., and the National Institute of Health (NIH 1R01HD084542) to S. R.O. and A.L., and 8P51OD011092 for the operation of the Oregon National Primate Research Center. C.A.T. was supported by NIH NRSA grant F32-HD-86904. C.A.T. and H.W. were supported by NIH Training grants T32-HD007133 and T32-DK 7680. We thank Ali Shilatifard (Feinberg School of Medicine, Northwestern University, Chicago, IL) for providing us with COMPASS protein antibodies for ChIP assays.
Funding Information:
This work was supported by grants from the US National Science Foundation (NSF: IOS1121691) to S.R.O., and the National Institute of Health (NIH 1R01HD084542) to S. R.O. and A.L., and 8P51OD011092 for the operation of the Oregon National Primate Research Center. C.A.T. was supported by NIH NRSA grant F32-HD-86904. C.A.T. and H.W. were supported by NIH Training grants T32-HD007133 and T32-DK 7680. We thank Ali Shilatifard (Feinberg School of Medicine, Northwestern University, Chicago, IL) for providing us with COMPASS protein antibodies for ChIP assays
Publisher Copyright:
© 2017 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-02512-1
DO - 10.1038/s41467-017-02512-1
M3 - Article
C2 - 29302059
AN - SCOPUS:85040253439
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 57
ER -