TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells

Kasper D. Rasmussen, Ivan Berest, Sandra Keβler, Koutarou Nishimura, Lucía Simón-Carrasco, George S. Vassiliou, Marianne T. Pedersen, Jesper Christensen, Judith B. Zaugg, Kristian Helin

Research output: Contribution to journalArticle

10 Downloads (Pure)

Abstract

The epigenetic regulator TET2 is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development and lead to altered DNA methylation landscapes and an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type–specific enhancers. We find that deletion of Tet2 in native hematopoiesis as well as fully transformed acute myeloid leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we provide evidence that loss of TET2 leads to attenuation of chromatin binding of members of the basic helix–loop–helix (bHLH) TF family. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provides an example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.

Original languageEnglish
Pages (from-to)564-575
Number of pages12
JournalGenome Research
Volume29
Issue number4
Early online date22 Feb 2019
DOIs
Publication statusPublished - Apr 2019

Fingerprint

Chromatin
Transcription Factors
Epigenomics
Hematologic Diseases
Chromosome Mapping
Hematopoiesis
Hematologic Neoplasms
DNA Methylation
Hematopoietic Stem Cells
Acute Myeloid Leukemia
Binding Sites
Gene Expression
Mutation

Cite this

Rasmussen, K. D., Berest, I., Keβler, S., Nishimura, K., Simón-Carrasco, L., Vassiliou, G. S., ... Helin, K. (2019). TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells. Genome Research, 29(4), 564-575. https://doi.org/10.1101/gr.239277.118
Rasmussen, Kasper D. ; Berest, Ivan ; Keβler, Sandra ; Nishimura, Koutarou ; Simón-Carrasco, Lucía ; Vassiliou, George S. ; Pedersen, Marianne T. ; Christensen, Jesper ; Zaugg, Judith B. ; Helin, Kristian. / TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells. In: Genome Research. 2019 ; Vol. 29, No. 4. pp. 564-575.
@article{59dec166c2ab4dcfa8fbf270bd978923,
title = "TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells",
abstract = "The epigenetic regulator TET2 is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development and lead to altered DNA methylation landscapes and an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type–specific enhancers. We find that deletion of Tet2 in native hematopoiesis as well as fully transformed acute myeloid leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we provide evidence that loss of TET2 leads to attenuation of chromatin binding of members of the basic helix–loop–helix (bHLH) TF family. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provides an example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.",
author = "Rasmussen, {Kasper D.} and Ivan Berest and Sandra Keβler and Koutarou Nishimura and Luc{\'i}a Sim{\'o}n-Carrasco and Vassiliou, {George S.} and Pedersen, {Marianne T.} and Jesper Christensen and Zaugg, {Judith B.} and Kristian Helin",
year = "2019",
month = "4",
doi = "10.1101/gr.239277.118",
language = "English",
volume = "29",
pages = "564--575",
journal = "Genome Research",
issn = "1088-9051",
publisher = "Cold Spring Harbor Laboratory Press",
number = "4",

}

Rasmussen, KD, Berest, I, Keβler, S, Nishimura, K, Simón-Carrasco, L, Vassiliou, GS, Pedersen, MT, Christensen, J, Zaugg, JB & Helin, K 2019, 'TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells' Genome Research, vol. 29, no. 4, pp. 564-575. https://doi.org/10.1101/gr.239277.118

TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells. / Rasmussen, Kasper D.; Berest, Ivan; Keβler, Sandra; Nishimura, Koutarou; Simón-Carrasco, Lucía; Vassiliou, George S.; Pedersen, Marianne T.; Christensen, Jesper; Zaugg, Judith B.; Helin, Kristian.

In: Genome Research, Vol. 29, No. 4, 04.2019, p. 564-575.

Research output: Contribution to journalArticle

TY - JOUR

T1 - TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells

AU - Rasmussen, Kasper D.

AU - Berest, Ivan

AU - Keβler, Sandra

AU - Nishimura, Koutarou

AU - Simón-Carrasco, Lucía

AU - Vassiliou, George S.

AU - Pedersen, Marianne T.

AU - Christensen, Jesper

AU - Zaugg, Judith B.

AU - Helin, Kristian

PY - 2019/4

Y1 - 2019/4

N2 - The epigenetic regulator TET2 is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development and lead to altered DNA methylation landscapes and an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type–specific enhancers. We find that deletion of Tet2 in native hematopoiesis as well as fully transformed acute myeloid leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we provide evidence that loss of TET2 leads to attenuation of chromatin binding of members of the basic helix–loop–helix (bHLH) TF family. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provides an example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.

AB - The epigenetic regulator TET2 is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development and lead to altered DNA methylation landscapes and an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type–specific enhancers. We find that deletion of Tet2 in native hematopoiesis as well as fully transformed acute myeloid leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we provide evidence that loss of TET2 leads to attenuation of chromatin binding of members of the basic helix–loop–helix (bHLH) TF family. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provides an example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.

UR - http://www.scopus.com/inward/record.url?scp=85063984040&partnerID=8YFLogxK

U2 - 10.1101/gr.239277.118

DO - 10.1101/gr.239277.118

M3 - Article

VL - 29

SP - 564

EP - 575

JO - Genome Research

JF - Genome Research

SN - 1088-9051

IS - 4

ER -