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Circadian Regulation of Chromatin State Mediates Pancreatic Incretin ResponseThe circadian clock is programmed by an autoregulatory transcription feedback loop present in brain and peripheral tissues that coordinates metabolism with nutritional state and the sleep-wake cycle. Epidemiologic and genetic studies indicate circadian disruption as a risk factor in the development of diabetes. We have demonstrated that conditional ablation of the β cell clock in adult life leads to hypoinsulinemic diabetes, and through mRNA-sequencing in mouse and human islets we revealed clock control of gene networks involved in insulin secretion, nutrient sensing, and exocytosis. A remaining question is: How does the core molecular clock modulate time-of-day dependent chromatin state to regulate pancreatic islet response to glucose and insulin secretagogues? Here we report that loss of the pancreatic β cell molecular clock results in closed chromatin at cAMP-responsive gene regulatory elements and dysregulated cAMP-dependent coregulator recruitment following cAMP agonism, consistent with a role for the molecular clock in mediating cell response to environmental stimuli. Further, tandem analyses of ATAC- and ChIP-sequencing in synchronized islets revealed dynamic chromatin accessibility across the 24-hour cycle at genes regulating insulin secretion and at genomic regions enriched for signal-inducible and circadian transcription factor motifs. Our genome-wide sequencing reveals a new role for the clock in global chromatin remodeling underlying the incretin response in pancreatic β cells.

ENDO 2020

Circadian Regulation of Chromatin State Mediates Pancreatic Islet Incretin Response

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The homeodomain transcription factor SIX3 is necessary for normal reproductive processes in mice. The loss of a single allele results in haploinsufficient phenotypes that are reflective of individuals with Kallmann Syndrome, such as hypogonadism, reduced GnRH neurons, and anosmia. Six3 heterozygous mice have reproductive impairments including an increased time to first litter, increased estrous cycle lengths in females, and fewer litters in males compared to wildtype controls. Prior studies found that deleting SIX3 specifically from GnRH neurons did not recapitulate the same phenotypes produced from a global knockout of the Six3 allele and imposed no reproductive abnormalities. This suggests that the role of SIX3 in reproduction is due to SIX3 populations outside of GnRH neurons. Using qPCR and RNA-seq, we have verified that Six3 is expressed in arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) populations of kisspeptin neurons and can regulate the kisspeptin promoter in vitro. This led us to hypothesize that SIX3 in kisspeptin neurons is required for Kiss1 regulation and maximal fertility. We selectively deleted Six3 from kisspeptin neurons by crossing a Six3-floxed mouse with a Kiss1-Cre mouse to produce Six3 flox/flox; Kiss1-Cre positive mice (cKO) and Six3 flox/flox, Kiss-Cre negative littermates (controls). In female mice, we found that the loss of SIX3 from kisspeptin neurons disrupted the estrous cycle and reduced fertility. Compared to controls, cKO mice had fewer cycles in a 16-day period (0.38 vs 1.44; p=0.004; n=8-9), and spent a greater percentage of time in diestrus (80.5 vs 61.8; p=0.002; n=8-9) and a smaller percentage of time in estrus (15.6 vs 29.2; p=0.030; n=8-9). The loss of kisspeptin-specific SIX3 also resulted in reduced fecundity, with the cKO female mice having fewer pups within 90 days (15.0 vs 34.4; p=0.048; n=5-6) compared to controls. In addition to its importance in female mice, kisspeptin-specific SIX3 also plays a role in male fertility. We found that male cKO mice had reduced motile sperm (52.2% vs 72.5%; p=0.012; n=7-9) compared to controls. We also assayed levels of Kiss1 mRNA in the male arcuate nucleus and observed decreased Kiss1 levels compared to controls (0.34 vs 1.01; p=0.042; n=3-4). These results support our hypothesis that SIX3 in kisspeptin neurons is necessary for critical reproductive processes in both females and males, including progression through the estrous cycle, fecundity, and sperm motility, potentially through Kiss1 regulation.

The Expression of the Homeodomain Transcription Factor SIX3 within Kisspeptin Neurons Is Necessary for Reproduction in Mice

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https://d3smihljt9218e.cloudfront.net/transcript/30959/subtitle/01544b8449da1199509feb387977c3b8.vtt

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Circadian Regulation of Chromatin State Mediates Pancreatic Islet Incretin Response

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