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

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

Author information

1
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
2
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
3
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: didier.trono@epfl.ch.

Abstract

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

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