Large DNA Methylation Nadirs Anchor Chromatin Loops Maintaining Hematopoietic Stem Cell Identity

Mol Cell. 2020 May 7;78(3):506-521.e6. doi: 10.1016/j.molcel.2020.04.018.


Higher-order chromatin structure and DNA methylation are implicated in multiple developmental processes, but their relationship to cell state is unknown. Here, we find that large (>7.3 kb) DNA methylation nadirs (termed "grand canyons") can form long loops connecting anchor loci that may be dozens of megabases (Mb) apart, as well as inter-chromosomal links. The interacting loci cover a total of ∼3.5 Mb of the human genome. The strongest interactions are associated with repressive marks made by the Polycomb complex and are diminished upon EZH2 inhibitor treatment. The data are suggestive of the formation of these loops by interactions between repressive elements in the loci, forming a genomic subcompartment, rather than by cohesion/CTCF-mediated extrusion. Interestingly, unlike previously characterized subcompartments, these interactions are present only in particular cell types, such as stem and progenitor cells. Our work reveals that H3K27me3-marked large DNA methylation grand canyons represent a set of very-long-range loops associated with cellular identity.

Keywords: 3D genomics; CpG; DNA methylation; DNA methylation canyon; Polycomb; chromosomal looping; hematopoietic; self-renewal; stem cells.

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

  • CCCTC-Binding Factor / genetics
  • CCCTC-Binding Factor / metabolism
  • Cell Differentiation
  • Chromatin / chemistry*
  • Chromatin / genetics*
  • Chromatin / metabolism
  • DNA Methylation*
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / physiology*
  • Histones / genetics
  • Histones / metabolism
  • Homeodomain Proteins / genetics
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lysine / genetics
  • Lysine / metabolism
  • Nuclear Proteins / genetics
  • SOXB1 Transcription Factors / genetics
  • Short Stature Homeobox Protein / genetics
  • Transcription Factors / genetics


  • CCCTC-Binding Factor
  • CTCF protein, human
  • Chromatin
  • Histones
  • Homeodomain Proteins
  • Nuclear Proteins
  • SHOX protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Short Stature Homeobox Protein
  • Transcription Factors
  • ZIC2 protein, human
  • HoxA protein
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Lysine