Linker Histone H1.2 Directs Genome-wide Chromatin Association of the Retinoblastoma Tumor Suppressor Protein and Facilitates Its Function
Shonagh Munro,
Edward S. Hookway,
Melanie Floderer,
Simon M. Carr,
Rebecca Konietzny,
Benedikt M. Kessler,
Udo Oppermann,
Nicholas B. La Thangue
Affiliations
Shonagh Munro
Laboratory of Cancer Biology, Medical Sciences Division, Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, Oxford OX3 7DQ, UK
Edward S. Hookway
Nuffield Orthopaedic Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, Oxford OX3 7HE, UK
Melanie Floderer
Laboratory of Cancer Biology, Medical Sciences Division, Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, Oxford OX3 7DQ, UK
Simon M. Carr
Laboratory of Cancer Biology, Medical Sciences Division, Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, Oxford OX3 7DQ, UK
Rebecca Konietzny
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK
Benedikt M. Kessler
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK
Udo Oppermann
Nuffield Orthopaedic Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, Oxford OX3 7HE, UK
Nicholas B. La Thangue
Laboratory of Cancer Biology, Medical Sciences Division, Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, Oxford OX3 7DQ, UK
The retinoblastoma tumor suppressor protein pRb is a master regulator of cellular proliferation, principally through interaction with E2F and regulation of E2F target genes. Here, we describe the H1.2 linker histone as a major pRb interaction partner. We establish that H1.2 and pRb are found in a chromatin-bound complex on diverse E2F target genes. Interrogating the global influence of H1.2 on the genome-wide distribution of pRb indicated that the E2F target genes affected by H1.2 are functionally linked to cell-cycle control, consistent with the ability of H1.2 to hinder cell proliferation and the elevated levels of chromatin-bound H1-pRb complex, which occur in growth-arrested cells. Our results define a network of E2F target genes as susceptible to the regulatory influence of H1.2, where H1.2 augments global association of pRb with chromatin, enhances transcriptional repression by pRb, and facilitates pRb-dependent cell-cycle arrest.
