Abstract
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.
Highlights
Female puberty is subject to Polycomb Group (PcG)-dependent transcriptional repression
Pulsatile gonadotropin hormone releasing hormone (GnRH) secretion is a mode of neurosecretion characterized by the periodic release of discrete amounts of GnRH into the portal circulation connecting the hypothalamus to the pituitary gland[54,55]
Increased GnRH pulse frequency is crucial for female reproductive function as it is required for both pubertal maturation and the follicular and preovulatory phases of the menstrual cycle in a dults[56,57]
Summary
Female puberty is subject to Polycomb Group (PcG)-dependent transcriptional repression. By repressing Kdm6b expression, EED increases H3K27me[3] abundance at these gene promoters, reducing gene expression throughout a gene network controlling puberty activation. At the end of the juvenile period, increased GnRH pulse frequency is achieved due to diminished inhibitory control as well as increased excitatory trans-synaptic inputs provided by glutamatergic[1,13] neurons and a family of peptides, known as k isspeptins[14,15,16,17], that robustly stimulate the GnRH network. It is proposed that this cellular feedback loop of activation followed by inhibition in KNDy neurons is the main component of a controlling cellular system termed the GnRH “pulse generator”[24,25] that plays a central role in the initiation of puberty. These proteins are encoded by the Yy1 gene[31]
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