RPA Interacts with HIRA and Regulates H3.3 Deposition at Gene Regulatory Elements in Mammalian Cells

Honglian Zhang; Haiyun Gan; Zhiquan Wang; Jeong-Heon Lee; Hui Zhou; Tamas Ordog; Marc S Wold; Mats Ljungman; Zhiguo Zhang

doi:10.1016/j.molcel.2016.11.030

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RPA Interacts with HIRA and Regulates H3.3 Deposition at Gene Regulatory Elements in Mammalian Cells

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RPA Interacts with HIRA and Regulates H3.3 Deposition at Gene Regulatory Elements in Mammalian Cells

Honglian Zhang, Haiyun Gan, Zhiquan Wang, Jeong-Heon Lee, Hui Zhou, Tamas Ordog, Marc S Wold, Mats Ljungman and Zhiguo Zhang

Molecular cell, Vol.65(2), pp.272-284

01/19/2017

DOI: 10.1016/j.molcel.2016.11.030

PMCID: PMC5460635

PMID: 28107649

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Abstract

The histone chaperone HIRA is involved in depositing histone variant H3.3 into distinct genic regions, including promoters, enhancers, and gene bodies. However, how HIRA deposits H3.3 to these regions remains elusive. Through a short hairpin RNA (shRNA) screening, we identified single-stranded DNA binding protein replication protein A (RPA) as a regulator of the deposition of newly synthesized H3.3 into chromatin. We show that RPA physically interacts with HIRA to form RPA-HIRA-H3.3 complexes, and it co-localizes with HIRA and H3.3 at gene promoters and enhancers. Depletion of RPA1, the largest subunit of the RPA complex, dramatically reduces both HIRA association with chromatin and the deposition of newly synthesized H3.3 at promoters and enhancers and leads to altered transcription at gene promoters. These results support a model whereby RPA, best known for its role in DNA replication and repair, recruits HIRA to promoters and enhancers and regulates deposition of newly synthesized H3.3 to these regulatory elements for gene regulation. [Display omitted] •RPA regulates the deposition of newly synthesized H3.3 independent of the cell cycle•RPA interacts with HIRA directly and forms a RPA-HIRA-H3.3 complex•RPA co-localizes with HIRA and H3.3 at gene regulatory elements•RPA and HIRA regulate transcriptional directionality at promoters RPA is a DNA binding protein involved in DNA replication and repair. Zhang et al. show that RPA is also involved in nucleosome assembly of histone H3 variant H3.3. RPA recruits histone chaperone HIRA, which deposits newly synthesized H3.3 into gene regulatory elements.

HIRA

RPA

enhancer

R-loop

H3.3 deposition

nucleosome assembly

promoter

histone chaperone

Details

Title: Subtitle: RPA Interacts with HIRA and Regulates H3.3 Deposition at Gene Regulatory Elements in Mammalian Cells
Creators: Honglian Zhang - Departments of Pediatrics and Genetics and Development, Institute for Cancer Genetics, Irving Cancer Research Center, College of Surgeons and Physicians, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA
Haiyun Gan - Departments of Pediatrics and Genetics and Development, Institute for Cancer Genetics, Irving Cancer Research Center, College of Surgeons and Physicians, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA
Zhiquan Wang - Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Jeong-Heon Lee - Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Hui Zhou - Departments of Pediatrics and Genetics and Development, Institute for Cancer Genetics, Irving Cancer Research Center, College of Surgeons and Physicians, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA
Tamas Ordog - Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Marc S Wold - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Mats Ljungman - Departments of Radiation Oncology and Environmental Health Sciences, Translational Oncology Program and Center for RNA Biomedicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Zhiguo Zhang - Departments of Pediatrics and Genetics and Development, Institute for Cancer Genetics, Irving Cancer Research Center, College of Surgeons and Physicians, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA
Resource Type: Journal article
Publication Details: Molecular cell, Vol.65(2), pp.272-284
Publisher: Elsevier Inc
DOI: 10.1016/j.molcel.2016.11.030
PMID: 28107649
PMCID: PMC5460635
ISSN: 1097-2765
eISSN: 1097-4164
Grant note: DOI: 10.13039/100000002, name: NIH, award: GM118015, CA157489, HG006786, CA086862; name: Epigenomics Program of the Mayo Clinic Center for Individualized Medicine
Language: English
Date published: 01/19/2017
Academic Unit: Radiation Oncology; Biochemistry and Molecular Biology
Record Identifier: 9984024527902771

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