Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells

Nat Genet. 2019 Sep;51(9):1380-1388. doi: 10.1038/s41588-019-0479-7. Epub 2019 Aug 19.

Abstract

Chromatin architecture has been implicated in cell type-specific gene regulatory programs, yet how chromatin remodels during development remains to be fully elucidated. Here, by interrogating chromatin reorganization during human pluripotent stem cell (hPSC) differentiation, we discover a role for the primate-specific endogenous retrotransposon human endogenous retrovirus subfamily H (HERV-H) in creating topologically associating domains (TADs) in hPSCs. Deleting these HERV-H elements eliminates their corresponding TAD boundaries and reduces the transcription of upstream genes, while de novo insertion of HERV-H elements can introduce new TAD boundaries. The ability of HERV-H to create TAD boundaries depends on high transcription, as transcriptional repression of HERV-H elements prevents the formation of boundaries. This ability is not limited to hPSCs, as these actively transcribed HERV-H elements and their corresponding TAD boundaries also appear in pluripotent stem cells from other hominids but not in more distantly related species lacking HERV-H elements. Overall, our results provide direct evidence for retrotransposons in actively shaping cell type- and species-specific chromatin architecture.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation
  • Chromatin / genetics*
  • Endogenous Retroviruses / genetics*
  • Gene Expression Regulation*
  • Humans
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / physiology
  • Primates
  • Response Elements*
  • Retroelements / genetics*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic*

Substances

  • Chromatin
  • Retroelements
  • Transcription Factors