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

Carlos A. Toro, Hollis Wright, Carlos F. Aylwin, Sergio Ojeda, Alejandro Lomniczi

    Research output: Contribution to journalArticle

    12 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Article number02512
    JournalNature Communications
    Volume9
    Issue number1
    DOIs
    StatePublished - Dec 1 2018

    Fingerprint

    chromatin
    Puberty
    Genetic Promoter Regions
    Chromatin
    leukemias
    Clustered Regularly Interspaced Short Palindromic Repeats
    Genes
    Polycomb-Group Proteins
    genes
    Arcuate Nucleus of Hypothalamus
    time measurement
    Neurons
    Machinery
    nuclei
    Epigenomics
    Chemical activation
    Switches
    machinery
    neurons
    Leukemia

    ASJC Scopus subject areas

    • Chemistry(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Physics and Astronomy(all)

    Cite this

    Trithorax dependent changes in chromatin landscape at enhancer and promoter regions drive female puberty. / Toro, Carlos A.; Wright, Hollis; Aylwin, Carlos F.; Ojeda, Sergio; Lomniczi, Alejandro.

    In: Nature Communications, Vol. 9, No. 1, 02512, 01.12.2018.

    Research output: Contribution to journalArticle

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    AU - Lomniczi, Alejandro

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