TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells
- Kasper D. Rasmussen1,2,7,8,
- Ivan Berest3,7,
- Sandra Keβler1,2,9,
- Koutarou Nishimura1,4,
- Lucía Simón-Carrasco1,2,
- George S. Vassiliou5,6,
- Marianne T. Pedersen1,2,
- Jesper Christensen1,2,
- Judith B. Zaugg3 and
- Kristian Helin1,2,4
- 1Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;
- 2The Novo Nordisk Foundation Center for Stem Cell Biology (Danstem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;
- 3European Molecular Biology Institute, Structural and Computational Unit, 69115 Heidelberg, Germany;
- 4Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
- 5Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB2 0XY, United Kingdom;
- 6Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0PT, United Kingdom
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↵7 These authors contributed equally to this work.
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.239277.118.
- Received May 7, 2018.
- Accepted February 19, 2019.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
