RESUMO
Female puberty is subject to Polycomb Group (PcG)-dependent transcriptional repression. Kiss1, a puberty-activating gene, is a key target of this silencing mechanism. Using a gain-of-function approach and a systems biology strategy we now show that EED, an essential PcG component, acts in the arcuate nucleus of the hypothalamus to alter the functional organization of a gene network involved in the stimulatory control of puberty. A central node of this network is Kdm6b, which encodes an enzyme that erases the PcG-dependent histone modification H3K27me3. Kiss1 is a first neighbor in the network; genes encoding glutamatergic receptors and potassium channels are second neighbors. By repressing Kdm6b expression, EED increases H3K27me3 abundance at these gene promoters, reducing gene expression throughout a gene network controlling puberty activation. These results indicate that Kdm6b repression is a basic mechanism used by PcG to modulate the biological output of puberty-activating gene networks.
Assuntos
Histona Desmetilases com o Domínio Jumonji/genética , Kisspeptinas/genética , Complexo Repressor Polycomb 2/genética , Puberdade/genética , Animais , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Humanos , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Neurônios/metabolismo , Sistemas Neurossecretores/crescimento & desenvolvimento , Sistemas Neurossecretores/metabolismo , Proteínas do Grupo Polycomb/genética , Regiões Promotoras Genéticas/genética , Puberdade/fisiologia , Ratos , Biologia de SistemasRESUMO
Population studies elucidating the genetic architecture of reproductive ageing have been largely limited to European ancestries, restricting the generalizability of the findings and overlooking possible key genes poorly captured by common European genetic variation. Here, we report 26 loci (all P < 5 × 10-8) for reproductive ageing, i.e. puberty timing or age at menopause, in a non-European population (up to 67,029 women of Japanese ancestry). Highlighted genes for menopause include GNRH1, which supports a primary, rather than passive, role for hypothalamic-pituitary GnRH signalling in the timing of menopause. For puberty timing, we demonstrate an aetiological role for receptor-like protein tyrosine phosphatases by combining evidence across population genetics and pre- and peri-pubertal changes in hypothalamic gene expression in rodent and primate models. Furthermore, our findings demonstrate widespread differences in allele frequencies and effect estimates between Japanese and European associated variants, highlighting the benefits and challenges of large-scale trans-ethnic approaches.
Assuntos
Envelhecimento/genética , Povo Asiático/genética , Loci Gênicos/fisiologia , Menarca/genética , Menopausa/genética , Adolescente , Adulto , Fatores Etários , Animais , Criança , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Frequência do Gene/fisiologia , Variação Genética/fisiologia , Humanos , Hipotálamo/metabolismo , Japão , Macaca mulatta , Metanálise como Assunto , Pessoa de Meia-Idade , Modelos Animais , Ratos Sprague-Dawley , População Branca/genéticaRESUMO
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.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Hipotálamo/metabolismo , Proteína de Leucina Linfoide-Mieloide/genética , Puberdade/genética , Animais , Sistemas CRISPR-Cas , Cromatina , Epigênese Genética , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Kisspeptinas/genética , Macaca mulatta , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley , Taquicininas/genéticaRESUMO
In primates, puberty is unleashed by increased GnRH release from the hypothalamus following an interval of juvenile quiescence. GWAS implicates Zinc finger (ZNF) genes in timing human puberty. Here we show that hypothalamic expression of several ZNFs decreased in agonadal male monkeys in association with the pubertal reactivation of gonadotropin secretion. Expression of two of these ZNFs, GATAD1 and ZNF573, also decreases in peripubertal female monkeys. However, only GATAD1 abundance increases when gonadotropin secretion is suppressed during late infancy. Targeted delivery of GATAD1 or ZNF573 to the rat hypothalamus delays puberty by impairing the transition of a transcriptional network from an immature repressive epigenetic configuration to one of activation. GATAD1 represses transcription of two key puberty-related genes, KISS1 and TAC3, directly, and reduces the activating histone mark H3K4me2 at each promoter via recruitment of histone demethylase KDM1A. We conclude that GATAD1 epitomizes a subset of ZNFs involved in epigenetic repression of primate puberty.