DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells

Mutations in the epigenetic modifiers DNMT3A and TET2 non-randomly co-occur in lymphoma and leukemia despite their epistasis in the methylation-hydroxymethylation pathway. Using Dnmt3a and Tet2 double knock-out (DKO) mice in which malignancy development is accelerated, we show that the DKO methylome...

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Autores principales: Zhang, Xiaotian, Su, Jianzhong, Jeong, Mira, Ko, Myunggon, Huang, Yun, Park, Hyun Jung, Guzman, Anna, Lei, Yong, Huang, Yung-Hsin, Rao, Anjana, Li, Wei, Goodell, Margaret A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957136/
https://www.ncbi.nlm.nih.gov/pubmed/27428748
http://dx.doi.org/10.1038/ng.3610
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author Zhang, Xiaotian
Su, Jianzhong
Jeong, Mira
Ko, Myunggon
Huang, Yun
Park, Hyun Jung
Guzman, Anna
Lei, Yong
Huang, Yung-Hsin
Rao, Anjana
Li, Wei
Goodell, Margaret A.
author_facet Zhang, Xiaotian
Su, Jianzhong
Jeong, Mira
Ko, Myunggon
Huang, Yun
Park, Hyun Jung
Guzman, Anna
Lei, Yong
Huang, Yung-Hsin
Rao, Anjana
Li, Wei
Goodell, Margaret A.
author_sort Zhang, Xiaotian
collection PubMed
description Mutations in the epigenetic modifiers DNMT3A and TET2 non-randomly co-occur in lymphoma and leukemia despite their epistasis in the methylation-hydroxymethylation pathway. Using Dnmt3a and Tet2 double knock-out (DKO) mice in which malignancy development is accelerated, we show that the DKO methylome reflects regions of independent, competitive and cooperative activity. Expression of lineage-specific transcription factors, including the erythroid regulator Klf1 is upregulated in DKO HSCs. DNMT3A and TET2 both repress Klf1 suggesting a model of cooperative inhibition by the epigenetic modifiers. These data demonstrate a dual role for TET2 in promoting and inhibiting HSC differentiation, loss of which, along with DNMT3A, obstructs differentiation leading to transformation.
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spelling pubmed-49571362017-01-18 DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells Zhang, Xiaotian Su, Jianzhong Jeong, Mira Ko, Myunggon Huang, Yun Park, Hyun Jung Guzman, Anna Lei, Yong Huang, Yung-Hsin Rao, Anjana Li, Wei Goodell, Margaret A. Nat Genet Article Mutations in the epigenetic modifiers DNMT3A and TET2 non-randomly co-occur in lymphoma and leukemia despite their epistasis in the methylation-hydroxymethylation pathway. Using Dnmt3a and Tet2 double knock-out (DKO) mice in which malignancy development is accelerated, we show that the DKO methylome reflects regions of independent, competitive and cooperative activity. Expression of lineage-specific transcription factors, including the erythroid regulator Klf1 is upregulated in DKO HSCs. DNMT3A and TET2 both repress Klf1 suggesting a model of cooperative inhibition by the epigenetic modifiers. These data demonstrate a dual role for TET2 in promoting and inhibiting HSC differentiation, loss of which, along with DNMT3A, obstructs differentiation leading to transformation. 2016-07-18 2016-09 /pmc/articles/PMC4957136/ /pubmed/27428748 http://dx.doi.org/10.1038/ng.3610 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Zhang, Xiaotian
Su, Jianzhong
Jeong, Mira
Ko, Myunggon
Huang, Yun
Park, Hyun Jung
Guzman, Anna
Lei, Yong
Huang, Yung-Hsin
Rao, Anjana
Li, Wei
Goodell, Margaret A.
DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells
title DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells
title_full DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells
title_fullStr DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells
title_full_unstemmed DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells
title_short DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells
title_sort dnmt3a and tet2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957136/
https://www.ncbi.nlm.nih.gov/pubmed/27428748
http://dx.doi.org/10.1038/ng.3610
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