Dual Functions of TET1 in Germ Layer Lineage Bifurcation Distinguished by Genomic Context and Dependence on 5-Methylcytosine Oxidation

Authors

Bernard K van der Veer
Lehua Chen
Colin Custers
Paraskevi Athanasouli
Mariana Schroiff
Riet Cornelis
Jonathan Sai-Hong Chui
Richard H Finnell
Frederic Lluis
Kian Peng Koh

Publication Date

6-23-2023

Journal

Nucleic Acids Research

DOI

10.1093/nar/gkad231

PMID

37021585

PMCID

PMC10287924

PubMedCentral® Posted Date

4-6-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Mice, 5-Methylcytosine, beta Catenin, DNA-Binding Proteins, Germ Layers, Genomics, Cell Differentiation, Proto-Oncogene Proteins

Abstract

Gastrulation begins when the epiblast forms the primitive streak or becomes definitive ectoderm. During this lineage bifurcation, the DNA dioxygenase TET1 has bipartite functions in transcriptional activation and repression, but the mechanisms remain unclear. By converting mouse embryonic stem cells (ESCs) into neuroprogenitors, we defined how Tet1-/- cells switch from neuroectoderm fate to form mesoderm and endoderm. We identified the Wnt repressor Tcf7l1 as a TET1 target that suppresses Wnt/β-catenin and Nodal signalling. ESCs expressing catalytic dead TET1 retain neural potential but activate Nodal and subsequently Wnt/β-catenin pathways to generate also mesoderm and endoderm. At CpG-poor distal enhancers, TET1 maintains accessible chromatin at neuroectodermal loci independently of DNA demethylation. At CpG-rich promoters, DNA demethylation by TET1 affects the expression of bivalent genes. In ESCs, a non-catalytic TET1 cooperation with Polycomb represses primitive streak genes; post-lineage priming, the interaction becomes antagonistic at neuronal genes, when TET1's catalytic activity is further involved by repressing Wnt signalling. The convergence of repressive DNA and histone methylation does not inhibit neural induction in Tet1-deficient cells, but some DNA hypermethylated loci persist at genes with brain-specific functions. Our results reveal versatile switching of non-catalytic and catalytic TET1 activities based on genomic context, lineage and developmental stage.

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