High-throughput transcriptome analysis reveals a developmental increase in Acvr1c which mediates epigenetic repression of the gene encoding the pubertal brake, Makorin ring finger protein 3

Makorin ring finger protein 3 (MKRN3) acts as a "pubertal brake." MKRN3 loss-of-function mutations are the most common genetic cause of central precocious puberty, and its expression in the brain drops significantly towards puberty, yet the drivers responsible for this reduction remain unclear. We aimed here to identify factors responsible for repressing <i>Mkrn3</i> expression across the pubertal transition, initially through bioinformatic analysis of developmental RNA-seq datasets from rodent tissues. Genes whose expression correlated significantly with <i>Mkrn3</i>, and are linked to puberty and signaling, were identified. Notably, these included <i>Acvr1c</i>, whose knockout was shown previously to delay puberty in mice. Experimentally, we show that <i>Acvr1c</i> activation suppresses <i>Mkrn3</i> via Smad2/3 signaling, involving recruitment of Kap1 and repressive histone modifications. These findings provide mechanistic explanation for the reduction in Mkrn3 required for pubertal onset, while underscoring the value of integrating high-throughput gene expression analyses with experimental validation to uncover novel regulatory pathways.