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Histone-binding of DPF2 mediates its repressive role in myeloid differentiation

Significance Double plant homeodomain finger 2 (DPF2) is a regulator of myeloid differentiation and implicated in a range of human cancers, including acute myelogenous leukemia. Recruitment of DPF2 to chromatin has been shown to alter the expression of target genes and inhibit myeloid differentiation. Here, we present the crystal structure of the human DPF2 tandem plant homeodomain finger domain and comprehensive structure-guided biochemical and in vivo analyses. Combined, our data delineate the determinants of DPF2’s chromatin recruitment and establish its regulatory role in human hematopoietic stem/progenitor cell differentiation. 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.