Dual functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation

Author:

van der Veer Bernard K1ORCID,Chen Lehua1ORCID,Custers Colin1ORCID,Athanasouli Paraskevi2ORCID,Schroiff Mariana1ORCID,Cornelis Riet1ORCID,Chui Jonathan Sai-Hong2ORCID,Finnell Richard H34ORCID,Lluis Frederic2ORCID,Koh Kian Peng13ORCID

Affiliation:

1. KU Leuven, Department of Development and Regeneration, Laboratory of Stem Cell and Developmental Epigenetics , B-3000 Leuven, Belgium

2. KU Leuven, Department of Development and Regeneration, Laboratory of Stem Cell Signaling , B-3000 Leuven, Belgium

3. Baylor College of Medicine, Department of Molecular and Cellular Biology, Center for Precision Environmental Health , Houston , TX 77030 , USA

4. Baylor College of Medicine, Department of Molecular and Human Genetics, Department of Medicine , Houston , TX 77030 , USA

Abstract

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.

Funder

Belgium Research Foundation – Flanders (FWO) Research Projects

KU Leuven Internal Funds

FWO

China Scholarship Council

Flemish Government

Publisher

Oxford University Press (OUP)

Subject

Genetics

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