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

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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

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Rasmussen, K. D., Berest, I., Keβler, S., Nishimura, K., Simón-Carrasco, L., Vassiliou, G. S., Pedersen, M. T., Christensen, J., Zaugg, J. B., & 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