Independent Mechanisms Target SMCHD1 to Trimethylated Histone H3 Lysine 9-Modified Chromatin and the Inactive X Chromosome

Mol Cell Biol. 2015 Dec;35(23):4053-68. doi: 10.1128/MCB.00432-15. Epub 2015 Sep 21.


The chromosomal protein SMCHD1 plays an important role in epigenetic silencing at diverse loci, including the inactive X chromosome, imprinted genes, and the facioscapulohumeral muscular dystrophy locus. Although homology with canonical SMC family proteins suggests a role in chromosome organization, the mechanisms underlying SMCHD1 function and target site selection remain poorly understood. Here we show that SMCHD1 forms an active GHKL-ATPase homodimer, contrasting with canonical SMC complexes, which exist as tripartite ring structures. Electron microscopy analysis demonstrates that SMCHD1 homodimers structurally resemble prokaryotic condensins. We further show that the principal mechanism for chromatin loading of SMCHD1 involves an LRIF1-mediated interaction with HP1γ at trimethylated histone H3 lysine 9 (H3K9me3)-modified chromatin sites on the chromosome arms. A parallel pathway accounts for chromatin loading at a minority of sites, notably the inactive X chromosome. Together, our results provide key insights into SMCHD1 function and target site selection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / metabolism
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Chromatin / chemistry
  • Chromatin / metabolism*
  • Chromobox Protein Homolog 5
  • Chromosomal Proteins, Non-Histone / chemistry
  • Chromosomal Proteins, Non-Histone / metabolism*
  • HEK293 Cells
  • Histones / chemistry
  • Histones / metabolism*
  • Humans
  • Lysine / analysis
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Interaction Maps
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Sequence Alignment
  • X Chromosome / metabolism*


  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Histones
  • SMCHD1 protein, human
  • SmcHD1 protein, mouse
  • Chromobox Protein Homolog 5
  • Adenosine Triphosphatases
  • Lysine

Associated data

  • PDB/1GXL
  • PDB/3NA3