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Published June 6, 2017 | Published + Supplemental Material
Journal Article Open

Histone-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 regulatory role in the transcriptional program that drives myeloid differentiation.

Additional Information

© 2017 National Academy of Sciences. Edited by Douglas C. Rees, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, and approved April 26, 2017 (received for review January 6, 2017) We thank Alina Patke for critical reading of the manuscript; David King for mass spectrometry analysis; and Jens Kaiser and the scientific staff of Stanford Synchrotron Radiation Lightsource (SSRL) Beamline 12-2 for their support with X-ray diffraction measurements. The operations at SSRL are supported by the Department of Energy and the National Institutes of Health. We acknowledge the Gordon and Betty Moore Foundation, the Beckman Institute, and the Sanofi-Aventis Bioengineering Research Program for their support of the Molecular Observatory at the California Institute of Technology and the Beckmann Institute Laser Resource Center for access to their Circular Dichroism Spectrometer. The DPF2 interaction analysis was carried out at the Taplin Mass Spectrometry Facility at Harvard Medical School. F.M.H. was supported by a PhD fellowship of the Boehringer Ingelheim Fonds. A.M.D. was supported by a National Institutes of Health Research Service Award 5 T32 GM07616. S.D.N. was supported by National Institutes of Health, National Cancer Institute Grant R01 CA166835. A.H. is a Faculty Scholar of the Howard Hughes Medical Institute, an Investigator of the Heritage Medical Research Institute, and was supported by the Albert Wyrick V Scholar Award of the V Foundation for Cancer Research, a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research, and a Teacher-Scholar Award of the Camille and Henry Dreyfus Foundation. F.M.H., S.M.G., and A.M.D. contributed equally to this work. Author contributions: S.D.N. and A.H. conceived of the project; F.M.H., S.M.G., A.M.D., S.D.N., and A.H. designed research; F.M.H., S.M.G., A.M.D., C.M., Y.X., and L.P.V. performed research; F.M.H., S.M.G., A.M.D., S.D.N., and A.H. analyzed data; and F.M.H., S.M.G., A.M.D., S.D.N., and A.H. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 5VDC). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1700328114/-/DCSupplemental.

Attached Files

Published - PNAS-2017-Huber-6016-21.pdf

Supplemental Material - pnas.201700328SI.pdf


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