Hominoid-Specific Transposable Elements and KZFPs Facilitate Human Embryonic Genome Activation and Control Transcription in Naive Human ESCs

Cell Stem Cell. 2019 May 2;24(5):724-735.e5. doi: 10.1016/j.stem.2019.03.012. Epub 2019 Apr 18.


Expansion of transposable elements (TEs) coincides with evolutionary shifts in gene expression. TEs frequently harbor binding sites for transcriptional regulators, thus enabling coordinated genome-wide activation of species- and context-specific gene expression programs, but such regulation must be balanced against their genotoxic potential. Here, we show that Krüppel-associated box (KRAB)-containing zinc finger proteins (KZFPs) control the timely and pleiotropic activation of TE-derived transcriptional cis regulators during early embryogenesis. Evolutionarily recent SVA, HERVK, and HERVH TE subgroups contribute significantly to chromatin opening during human embryonic genome activation and are KLF-stimulated enhancers in naive human embryonic stem cells (hESCs). KZFPs of corresponding evolutionary ages are simultaneously induced and repress the transcriptional activity of these TEs. Finally, the same KZFP-controlled TE-based enhancers later serve as developmental and tissue-specific enhancers. Thus, by controlling the transcriptional impact of TEs during embryogenesis, KZFPs facilitate their genome-wide incorporation into transcriptional networks, thereby contributing to human genome regulation.

Keywords: HERVH; HERVK; KRAB-zinc finger proteins; Krüppel-like factors; SVA; Transposable elements; cis-regulatory elements; embryonic genome activation; human genome evolution; morula.

Publication types

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

MeSH terms

  • Animals
  • Biological Evolution
  • Chromatin / genetics
  • Chromatin / microbiology*
  • DNA Transposable Elements / genetics*
  • Embryonic Stem Cells / physiology*
  • Evolution, Molecular
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Genetic Speciation
  • Hominidae
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism
  • Phylogeny
  • Sequence Alignment
  • Species Specificity


  • Chromatin
  • DNA Transposable Elements
  • Kruppel-Like Transcription Factors