Tet2 facilitates the derepression of myeloid target genes during CEBPα-induced transdifferentiation of pre-B cells

TY - JOUR

T1 - Tet2 facilitates the derepression of myeloid target genes during CEBPα-induced transdifferentiation of pre-B cells

AU - Kallin, Eric M

AU - Rodríguez-Ubreva, Javier

AU - Christensen, Jesper Aagaard

AU - Cimmino, Luisa

AU - Aifantis, Iannis

AU - Helin, Kristian

AU - Ballestar, Esteban

AU - Graf, Thomas

N1 - Copyright © 2012 Elsevier Inc. All rights reserved.

PY - 2012/10/26

Y1 - 2012/10/26

N2 - The methylcytosine hydroxylase Tet2 has been implicated in hematopoietic differentiation and the formation of myeloid malignancies when mutated. An ideal system to study the role of Tet2 in myelopoeisis is CEBPα-induced transdifferentiation of pre-B cells into macrophages. Here we found that CEBPα binds to upstream regions of Tet2 and that the gene becomes activated. Tet2 knockdowns impaired the upregulation of macrophage markers as well as phagocytic capacity, suggesting that the enzyme is required for both early and late stage myeloid differentiation. A slightly weaker effect was seen in primary cells with a Tet2 ablation. Expression arrays of transdifferentiating cells with Tet2 knockdowns permitted the identification of a small subset of myeloid genes whose upregulation was blunted. Activation of these target genes was accompanied by rapid increases of promoter hydroxy-methylation. Our observations indicate that Tet2 helps CEBPα rapidly derepress myeloid genes during the conversion of pre-B cells into macrophages.

AB - The methylcytosine hydroxylase Tet2 has been implicated in hematopoietic differentiation and the formation of myeloid malignancies when mutated. An ideal system to study the role of Tet2 in myelopoeisis is CEBPα-induced transdifferentiation of pre-B cells into macrophages. Here we found that CEBPα binds to upstream regions of Tet2 and that the gene becomes activated. Tet2 knockdowns impaired the upregulation of macrophage markers as well as phagocytic capacity, suggesting that the enzyme is required for both early and late stage myeloid differentiation. A slightly weaker effect was seen in primary cells with a Tet2 ablation. Expression arrays of transdifferentiating cells with Tet2 knockdowns permitted the identification of a small subset of myeloid genes whose upregulation was blunted. Activation of these target genes was accompanied by rapid increases of promoter hydroxy-methylation. Our observations indicate that Tet2 helps CEBPα rapidly derepress myeloid genes during the conversion of pre-B cells into macrophages.

KW - Azacitidine

KW - CCAAT-Enhancer-Binding Proteins

KW - Cell Differentiation

KW - Cell Line

KW - Cell Transdifferentiation

KW - DNA-Binding Proteins

KW - Gene Expression Regulation, Developmental

KW - Gene Knockdown Techniques

KW - Hematopoietic Stem Cells

KW - Humans

KW - Macrophages

KW - Myeloid Cells

KW - Myelopoiesis

KW - Precursor Cells, B-Lymphoid

KW - Proto-Oncogene Proteins

U2 - 10.1016/j.molcel.2012.08.007

DO - 10.1016/j.molcel.2012.08.007

M3 - Journal article

C2 - 22981865

SN - 1097-2765

VL - 48

SP - 266

EP - 276

JO - Molecular Cell

JF - Molecular Cell

IS - 2

ER -