biostudies-literatureHuber FMHHS | National Institutes of HealthCamille and Henry Dreyfus FoundationHeritage Medical Research InstituteHoward Hughes Medical InstituteHHS | NIH | National Cancer InstituteNCI NIH HHSV Foundation for Cancer ResearchBoehringer Ingelheim FondsNIGMS NIH HHSSidney Kimmel Foundation for Cancer Research6016-6021https://www.ebi.ac.uk/biostudies/studies/S-EPMC5468650biostudies-literatureUnknown114(23)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 Proceedings of the National Academy of Sciences of the United States of AmericaHistone-binding of DPF2 mediates its repressive role in myeloid differentiation.PMC5468650N/A5 T32 GM07616R01 GM117360R01 CA166835T32 GM007616Hoelz AVu LPGreenblatt SMHuber FMDavenport AMMartinez CXu YNimer SDfalseHistone-binding of DPF2 mediates its repressive role in myeloid 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 2017-01-01T00:00:00Z2017 Jun2026-04-16T13:14:51.352Z2026-04-07T14:12:53.184ZS-EPMC54686502853340710.1073/pnas.1700328114