Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation

Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):E3535-44. doi: 10.1073/pnas.1504232112. Epub 2015 Jun 19.


Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is an epigenetic repressor with described roles in X inactivation and genomic imprinting, but Smchd1 is also critically involved in the pathogenesis of facioscapulohumeral dystrophy. The underlying molecular mechanism by which Smchd1 functions in these instances remains unknown. Our genome-wide transcriptional and epigenetic analyses show that Smchd1 binds cis-regulatory elements, many of which coincide with CCCTC-binding factor (Ctcf) binding sites, for example, the clustered protocadherin (Pcdh) genes, where we show Smchd1 and Ctcf act in opposing ways. We provide biochemical and biophysical evidence that Smchd1-chromatin interactions are established through the homodimeric hinge domain of Smchd1 and, intriguingly, that the hinge domain also has the capacity to bind DNA and RNA. Our results suggest Smchd1 imparts epigenetic regulation via physical association with chromatin, which may antagonize Ctcf-facilitated chromatin interactions, resulting in coordinated transcriptional control.

Keywords: Ctcf; Smchd1; clustered protocadherins; epigenetic control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Blotting, Western
  • Brain / cytology
  • Brain / embryology
  • Brain / metabolism
  • CCCTC-Binding Factor
  • Cells, Cultured
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Developmental
  • Genome*
  • Genomic Imprinting
  • Histones / metabolism
  • Male
  • Methylation
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Stem Cells / metabolism
  • Protein Binding
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcriptome / genetics


  • CCCTC-Binding Factor
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Ctcf protein, mouse
  • Histones
  • Repressor Proteins
  • SmcHD1 protein, mouse

Associated data

  • GEO/GSE65749