Transcription factor MITF and remodeller BRG1 define chromatin organisation at regulatory elements in melanoma cells
Patrick Laurette,
Thomas Strub,
Dana Koludrovic,
Céline Keime,
Stéphanie Le Gras,
Hannah Seberg,
Eric Van Otterloo,
Hana Imrichova,
Robert Siddaway,
Stein Aerts,
Robert A Cornell,
Gabrielle Mengus,
Irwin Davidson
Affiliations
Patrick Laurette
Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France
Thomas Strub
Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
Dana Koludrovic
Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France
Céline Keime
Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France
Stéphanie Le Gras
Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France
Hannah Seberg
University of Iowa College of Medicine, Iowa City, United States
Eric Van Otterloo
University of Iowa College of Medicine, Iowa City, United States
Hana Imrichova
Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, Leuven, Belgium
Robert Siddaway
Arthur and Sonia Labatt Brain Tumor Research Centre, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Canada
Stein Aerts
Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, Leuven, Belgium
Robert A Cornell
University of Iowa College of Medicine, Iowa City, United States
Gabrielle Mengus
Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France
Irwin Davidson
Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France
Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. To understand how MITF regulates transcription, we used tandem affinity purification and mass spectrometry to define a comprehensive MITF interactome identifying novel cofactors involved in transcription, DNA replication and repair, and chromatin organisation. We show that MITF interacts with a PBAF chromatin remodelling complex comprising BRG1 and CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF-associated regulatory elements (MAREs) at active enhancers. Combinations of MITF, SOX10, TFAP2A, and YY1 bind between two BRG1-occupied nucleosomes thus defining both a signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of the regulatory elements they occupy. BRG1 also regulates the dynamics of MITF genomic occupancy. MITF-BRG1 interplay thus plays an essential role in transcription regulation in melanoma.
