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Histone-Binding of DPF2 Mediates Its Repressive Role in Myeloid Differentiation

Huber, Ferdinand M. and Greenblatt, Sarah M. and Davenport, Andrew M. and Martinez, Concepcion and Xu, Ye and Vu, Ly P. and Nimer, Stephen D. and Hoelz, André (2017) Histone-Binding of DPF2 Mediates Its Repressive Role in Myeloid Differentiation. Proceedings of the National Academy of Sciences of the United States of America, 114 (23). pp. 6016-6021. ISSN 0027-8424. https://resolver.caltech.edu/CaltechAUTHORS:20170522-112731942

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://dx.doi.org/10.1073/pnas.1700328114DOIArticle
http://www.pnas.org/content/114/23/6016PublisherArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1700328114/-/DCSupplementalPublisherSupporting Information
ORCID:
AuthorORCID
Hoelz, André0000-0003-1726-0127
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.
Group:Heritage Medical Research Institute
Funders:
Funding AgencyGrant Number
Department of Energy (DOE)UNSPECIFIED
NIH Predoctoral Fellowship5 T32 GM07616
Gordon and Betty Moore FoundationUNSPECIFIED
Sanofi-Aventis Bioengineering Research ProgramUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Boehringer Ingelheim FondsUNSPECIFIED
NIHR01 CA166835
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
V Foundation for Cancer ResearchUNSPECIFIED
Sidney Kimmel Foundation for Cancer ResearchUNSPECIFIED
Camille and Henry Dreyfus FoundationUNSPECIFIED
Subject Keywords:X-ray crystallography; myeloid differentiation; tandem PHD finger; isothermal titration calorimetry; protein–protein interaction
Issue or Number:23
Record Number:CaltechAUTHORS:20170522-112731942
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170522-112731942
Official Citation:Ferdinand M. Huber, Sarah M. Greenblatt, Andrew M. Davenport, Concepcion Martinez, Ye Xu, Ly P. Vu, Stephen D. Nimer, and André Hoelz Histone-binding of DPF2 mediates its repressive role in myeloid differentiation PNAS 2017 114 (23) 6016-6021; published ahead of print May 22, 2017, doi:10.1073/pnas.1700328114
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:77629
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:22 May 2017 19:20
Last Modified:03 Oct 2019 17:59

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