TY - JOUR

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

AU - Rasmussen, Kasper D

AU - Berest, Ivan

AU - Kessler, Sandra

AU - Nishimura, Koutarou

AU - Simon-Carrasco, Lucia

AU - Vassiliou, George S

AU - Pedersen, Marianne Terndrup

AU - Christensen, Jesper

AU - Zaugg, Judith

AU - Helin, Kristian

N1 - Published by Cold Spring Harbor Laboratory Press.

PY - 2019

Y1 - 2019

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, lead to altered DNA methylation landscapes and to 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 provide a compelling 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, lead to altered DNA methylation landscapes and to 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 provide a compelling example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.

U2 - 10.1101/gr.239277.118

DO - 10.1101/gr.239277.118

M3 - Journal article

C2 - 30796038

VL - 29

SP - 564

EP - 575

JO - Genome Research

JF - Genome Research

SN - 1088-9051

IS - 4

ER -