Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125.
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136.
Proc Natl Acad Sci U S A. 2017 Jun 6;114(23):6016-6021. doi: 10.1073/pnas.1700328114. Epub 2017 May 22.
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.
双植物同源域蛋白 2（DPF2）是 d4 蛋白家族中高度进化保守的成员，在人类组织中广泛表达，最近研究表明其可抑制造血干细胞/祖细胞和急性髓系白血病细胞的髓系分化。在此，我们呈现了人 DPF2 串联植物同源域蛋白结构域的晶体结构，分辨率为 1.6Å。我们发现 DPF2 通过 DPF2 表面的二分结合口袋与组蛋白 3 和 4 的乙酰化尾部相互作用。通过靶向 DPF2 的突变破坏这些相互作用，可阻止其募集到靶染色质区域，以及其在体内防止髓系分化的能力。我们的研究结果表明，DPF2 与组蛋白的结合在驱动髓系分化的转录程序中发挥重要的调控作用。
