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

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...

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Autores principales: van der Veer, Bernard K, Chen, Lehua, Custers, Colin, Athanasouli, Paraskevi, Schroiff, Mariana, Cornelis, Riet, Chui, Jonathan Sai-Hong, Finnell, Richard H, Lluis, Frederic, Koh, Kian Peng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10287924/
https://www.ncbi.nlm.nih.gov/pubmed/37021585
http://dx.doi.org/10.1093/nar/gkad231
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author van der Veer, Bernard K
Chen, Lehua
Custers, Colin
Athanasouli, Paraskevi
Schroiff, Mariana
Cornelis, Riet
Chui, Jonathan Sai-Hong
Finnell, Richard H
Lluis, Frederic
Koh, Kian Peng
author_facet van der Veer, Bernard K
Chen, Lehua
Custers, Colin
Athanasouli, Paraskevi
Schroiff, Mariana
Cornelis, Riet
Chui, Jonathan Sai-Hong
Finnell, Richard H
Lluis, Frederic
Koh, Kian Peng
author_sort van der Veer, Bernard K
collection PubMed
description 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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spelling pubmed-102879242023-06-24 Dual functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation van der Veer, Bernard K Chen, Lehua Custers, Colin Athanasouli, Paraskevi Schroiff, Mariana Cornelis, Riet Chui, Jonathan Sai-Hong Finnell, Richard H Lluis, Frederic Koh, Kian Peng Nucleic Acids Res Gene regulation, Chromatin and Epigenetics 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. Oxford University Press 2023-04-06 /pmc/articles/PMC10287924/ /pubmed/37021585 http://dx.doi.org/10.1093/nar/gkad231 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Gene regulation, Chromatin and Epigenetics
van der Veer, Bernard K
Chen, Lehua
Custers, Colin
Athanasouli, Paraskevi
Schroiff, Mariana
Cornelis, Riet
Chui, Jonathan Sai-Hong
Finnell, Richard H
Lluis, Frederic
Koh, Kian Peng
Dual functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation
title Dual functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation
title_full Dual functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation
title_fullStr Dual functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation
title_full_unstemmed Dual functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation
title_short Dual functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation
title_sort dual functions of tet1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10287924/
https://www.ncbi.nlm.nih.gov/pubmed/37021585
http://dx.doi.org/10.1093/nar/gkad231
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