H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis

Elife. 2019 Oct 1;8:e49278. doi: 10.7554/eLife.49278.


Cell-type-specific 3D organization of the genome is unrecognizable during mitosis. It remains unclear how essential positional information is transmitted through cell division such that a daughter cell recapitulates the spatial genome organization of the parent. Lamina-associated domains (LADs) are regions of repressive heterochromatin positioned at the nuclear periphery that vary by cell type and contribute to cell-specific gene expression and identity. Here we show that histone 3 lysine 9 dimethylation (H3K9me2) is an evolutionarily conserved, specific mark of nuclear peripheral heterochromatin and that it is retained through mitosis. During mitosis, phosphorylation of histone 3 serine 10 temporarily shields the H3K9me2 mark allowing for dissociation of chromatin from the nuclear lamina. Using high-resolution 3D immuno-oligoFISH, we demonstrate that H3K9me2-enriched genomic regions, which are positioned at the nuclear lamina in interphase cells prior to mitosis, re-associate with the forming nuclear lamina before mitotic exit. The H3K9me2 modification of peripheral heterochromatin ensures that positional information is safeguarded through cell division such that individual LADs are re-established at the nuclear periphery in daughter nuclei. Thus, H3K9me2 acts as a 3D architectural mitotic guidepost. Our data establish a mechanism for epigenetic memory and inheritance of spatial organization of the genome.

Keywords: C. elegans; H3K9me2; cell biology; chromosomes; gene expression; genome organization; mitosis; mouse; nuclear architecture; nuclear lamina; peripheral heterochromatin.

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
  • Cell Line
  • Heterochromatin / metabolism*
  • Histones / metabolism*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Methylation
  • Mitosis*
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • Wills*


  • Heterochromatin
  • Histones