TY - JOUR
T1 - Histone-binding of DPF2 mediates its repressive role in myeloid differentiation
AU - Huber, Ferdinand M.
AU - Greenblatt, Sarah M.
AU - Davenport, Andrew M.
AU - Martinez, Concepcion
AU - Xu, Ye
AU - Vu, Ly P.
AU - Nimer, Stephen D.
AU - Hoelz, André
PY - 2017/6/6
Y1 - 2017/6/6
N2 - Double plant homeodomain finger 2 (DPF2) is a highly evolutionarily conserved member of the d4 protein family that is ubiquitously expressed in human tissues and was recently shown to inhibit the myeloid differentiation of hematopoietic stem/progenitor and acute myelogenous leukemia cells. Here, we present the crystal structure of the tandem plant homeodomain finger domain of human DPF2 at 1.6-Å resolution. We show that DPF2 interacts with the acetylated tails of both histones 3 and 4 via bipartite binding pockets on the DPF2 surface. Blocking these interactions through targeted mutagenesis of DPF2 abolishes its recruitment to target chromatin regions as well as its ability to prevent myeloid differentiation in vivo. Our findings suggest that the histone binding of DPF2 plays an important regulatory role in the transcriptional program that drives myeloid differentiation.
AB - Double plant homeodomain finger 2 (DPF2) is a highly evolutionarily conserved member of the d4 protein family that is ubiquitously expressed in human tissues and was recently shown to inhibit the myeloid differentiation of hematopoietic stem/progenitor and acute myelogenous leukemia cells. Here, we present the crystal structure of the tandem plant homeodomain finger domain of human DPF2 at 1.6-Å resolution. We show that DPF2 interacts with the acetylated tails of both histones 3 and 4 via bipartite binding pockets on the DPF2 surface. Blocking these interactions through targeted mutagenesis of DPF2 abolishes its recruitment to target chromatin regions as well as its ability to prevent myeloid differentiation in vivo. Our findings suggest that the histone binding of DPF2 plays an important regulatory role in the transcriptional program that drives myeloid differentiation.
KW - Isothermal titration calorimetry
KW - Myeloid differentiation
KW - Protein-protein interaction
KW - Tandem PHD finger
KW - X-ray crystallography
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U2 - 10.1073/pnas.1700328114
DO - 10.1073/pnas.1700328114
M3 - Article
C2 - 28533407
AN - SCOPUS:85020402764
VL - 114
SP - 6016
EP - 6021
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 23
ER -