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

Genes Dev. 2021 Apr 1;35(7-8):489-494. doi: 10.1101/gad.345397.120. Epub 2021 Mar 18.

Abstract

While changes in MeCP2 dosage cause Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), its transcriptional regulation is poorly understood. Here, we identified six putative noncoding regulatory elements of Mecp2, 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 Mecp2/MECP2 and highlights genomic sites that could serve as diagnostic and therapeutic targets in RTT or MDS.

Keywords: MeCP2; cis-regulatory elements; neurological disorders; noncoding.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Conserved Sequence / genetics
  • Gene Deletion
  • Gene Expression Regulation / genetics*
  • Humans
  • Male
  • Mental Retardation, X-Linked / genetics*
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / pathology*
  • Regulatory Elements, Transcriptional / genetics*
  • Rett Syndrome / genetics*

Substances

  • Methyl-CpG-Binding Protein 2

Supplementary concepts

  • Lubs X-linked mental retardation syndrome