Identification and characterization of conserved noncoding <i>cis</i>-regulatory elements that impact <i>Mecp2</i> expression and neurological functions

Abstract

While changes in MeCP2 dosage cause Rett syndrome (RTT) and <i>MECP2</i> duplication syndrome (MDS), its transcriptional regulation is poorly understood. Here, we identified six putative noncoding regulatory elements of <i>Mecp2</i>, two of which are conserved in humans. Upon deletion in mice and human iPSC-derived neurons, these elements altered RNA and protein levels in opposite directions and resulted in a subset of RTT- and MDS-like behavioral deficits in mice. Our discovery provides insight into transcriptional regulation of <i>Mecp2/MECP2</i> and highlights genomic sites that could serve as diagnostic and therapeutic targets in RTT or MDS.