Identify transcriptional regulators of Mc4r in the hypothalamus [ATAC-Seq]

Human MC4R mutations can increase or decrease obesity risk. Other than intracellular signaling, MC4R function is also influenced by its levels. However, the genetic programs that govern MC4R transcription in the brain remain largely unknown. Moreover, it is unclear whether human genetic variants exist that affect Mc4r expression and obesity risk. Here, we identify the homeodomain transcription factor Otp as one regulator of Mc4r expression in a specific subset of hypothalamic neurons. Selective loss of Otp in these neurons during development or adulthood results in reduced Mc4r expression and excessive body weight gain. Moreover, OTP interacts with upstream regulatory sequences of Mc4r to modulate its transcription. Overall design: To pinpoint the promoter region of Mc4r in PVH cells, we conducted an ATAC-Seq (transposase-accessible chromatin with sequencing) experiment in 12-week-old mice. To further validate the effect of Otp on Mc4r, we hypothesized that the absence of Otp could diminish transcriptional activity, resulting in less accessible chromatin near its transcriptional targets. To test this hypothesis, we analyzed ATAC peaks in the PVH of OtpPVH KO mice following the adult deletion of Otp.