4.7 Article

The epigenetic role of HTR1A antagonist in facilitating GnRH expression for pubertal initiation control

期刊

MOLECULAR THERAPY-NUCLEIC ACIDS
卷 25, 期 -, 页码 198-206

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CELL PRESS
DOI: 10.1016/j.omtn.2021.05.014

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资金

  1. National Natural Science Foundation of China [81871131]
  2. Interdisciplinary Program of Shanghai Jiao Tong University [YG2021ZD25]
  3. Hospital Level Project of Shanghai Children's Hospital [2018YQN002]
  4. Cultivation Plan for Excellent Young Talents of Shanghai Children's Hospital [2017YYQ05]
  5. Shanghai Sailing Program [20YF1440700]

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In this study, HTR1A antagonists were found to enhance GnRH transcription by promoting PRC1 degradation and H2AK119ub loss through reduced CBX4 expression via suppression of the PI3K/Akt and MAPK/ERK pathways in GT1-7 cells, potentially providing an epigenetic mechanism of action of HTR1A on GnRH gene expression for mammalian puberty onset.
Serotonin (5-hydroxytryptamine [5-HT]), a metabolite of tryptophan, acts on the components of the hypothalamus-hypophysis-gonad axis and induces puberty delay in mammals via 5-HT receptor 1A (HTR1A). However, the roles of HTR1A in the hypothalamus in pubertal regulation of gene expression are not fully understood. In the current study, the upregulated gonadotropin-releasing hormone (GnRH) expression in GT17 GnRH neuronal cells induced by the HTR1A antagonist WAY-100635 maleate was observed in vitro. Furthermore, RNA sequencing (RNA-seq) showed decreased expression of chromobox 4 (CBX4), a member of the polycomb-repressive complex 1 (PRC1), and the loss of RING2 and YY1 interaction with CBX4, suggesting the degradation of the PRC1 in GT1-7 cells treated with maleate. Chromatin immunoprecipitation sequencing (ChIP-seq) showed that the genome-wide occupancy of CBX4 and histone H2A lysine-119 ubiquitination (H2AK119ub) was compromised, especially on the promoter of GnRH. Finally, we determined that inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) contributed to CBX4 downregulation. Taken together, we concluded that HTR1A antagonists could enhance GnRH transcription via PRC1 degradation and H2AK119ub loss driven by reduced CBX4 expression through PI3K/Akt and MAPK/ERK pathway suppression in GT1-7 cells and provided a potential epigenetic mechanism of action of HTR1A on GnRH gene expression for mammalian puberty onset.

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