Functionally Distinct Roles for TET-oxidized 5-methylcytosine Bases in Somatic Reprogramming to Pluripotency

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2020 Dec 22

PMID 33352108

Citations 21

Authors

Blake A Caldwell

Monica Yun Liu

Rexxi D Prasasya

Tong Wang

Jamie E DeNizio

N Adrian Leu

Nana Yaa A Amoh

Christopher Krapp

Yemin Lan

Emily J Shields

Roberto Bonasio

Christopher J Lengner

Rahul M Kohli

Marisa S Bartolomei

Affiliations

Soon will be listed here.

Abstract

Active DNA demethylation via ten-eleven translocation (TET) family enzymes is essential for epigenetic reprogramming in cell state transitions. TET enzymes catalyze up to three successive oxidations of 5-methylcytosine (5mC), generating 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), or 5-carboxycytosine (5caC). Although these bases are known to contribute to distinct demethylation pathways, the lack of tools to uncouple these sequential oxidative events has constrained our mechanistic understanding of the role of TETs in chromatin reprogramming. Here, we describe the first application of biochemically engineered TET mutants that unlink 5mC oxidation steps, examining their effects on somatic cell reprogramming. We show that only TET enzymes proficient for oxidation to 5fC/5caC can rescue the reprogramming potential of Tet2-deficient mouse embryonic fibroblasts. This effect correlated with rapid DNA demethylation at reprogramming enhancers and increased chromatin accessibility later in reprogramming. These experiments demonstrate that DNA demethylation through 5fC/5caC has roles distinct from 5hmC in somatic reprogramming to pluripotency.

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