The epigenetic role of HTR1A antagonist in facilitating GnRH expression for pubertal initiation control
Shasha Zhou, Yihang Shen, Shaolian Zang, Xiaoqin Yin, Pin Li
Abstract
. 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.