Individual retrotransposon integrants are differentially controlled by KZFP/KAP1-dependent histone methylation, DNA methylation and TET-mediated hydroxymethylation in naïve embryonic stem cells.

Epigenetics & Chromatin
Andrea ColuccioDidier Trono

Abstract

The KZFP/KAP1 (KRAB zinc finger proteins/KRAB-associated protein 1) system plays a central role in repressing transposable elements (TEs) and maintaining parent-of-origin DNA methylation at imprinting control regions (ICRs) during the wave of genome-wide reprogramming that precedes implantation. In naïve murine embryonic stem cells (mESCs), the genome is maintained highly hypomethylated by a combination of TET-mediated active demethylation and lack of de novo methylation, yet KAP1 is tethered by sequence-specific KZFPs to ICRs and TEs where it recruits histone and DNA methyltransferases to impose heterochromatin formation and DNA methylation. Here, upon removing either KAP1 or the cognate KZFP, we observed rapid TET2-dependent accumulation of 5hmC at both ICRs and TEs. In the absence of the KZFP/KAP1 complex, ICRs lost heterochromatic histone marks and underwent both active and passive DNA demethylation. For KAP1-bound TEs, 5mC hydroxylation correlated with transcriptional reactivation. Using RNA-seq, we further compared the expression profiles of TEs upon Kap1 removal in wild-type, Dnmt and Tet triple knockout mESCs. While we found that KAP1 represents the main effector of TEs repression in all three settings, we could additio...Continue Reading

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Citations

Jul 11, 2019·Molecular Ecology·Zachary M LaubachKay E Holekamp
Jan 4, 2019·Genes & Development·Nozomi TakahashiDidier Trono
May 20, 2020·Nucleic Acids Research·Huifang HuJing Qu
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Mar 15, 2019·Nature Reviews. Genetics·Özgen DenizMiguel R Branco
Oct 28, 2019·Essays in Biochemistry·Natasha Jansz
Nov 17, 2019·International Journal of Molecular Sciences·Denise DrongitisAldo Donizetti
Sep 14, 2019·Annual Review of Genetics·Melania BrunoTodd S Macfarlan
Jun 27, 2020·Cell Regeneration·Jingwen WangGuang Shi
Oct 21, 2021·ELife·Kevin R CostelloDustin E Schones
Nov 18, 2021·The EMBO Journal·Elin EnervaldSara B C Buonomo

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Datasets Mentioned

BETA
GSM2051573
GSM2051574

Methods Mentioned

BETA
ChIP-seq
hMeDIP-seq
ChIP
RNA-seq
PCR
protein assay

Software Mentioned

bamtools filter
BEDTools
GraphPad Prism
MethPrimer
R package LIMMA
Bowtie2
Bioconductor
LIMMA
deeptools2
IAPEz

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