New research links the recently discovered function of a multi-faceted transcriptional complex to control of gene expression in both normal cells and cancer stem cells. Two separate studies, published by Cell Press in the January 18th issue of Molecular Cell, provide insight into novel subunits associated with an evolutionarily conserved transcriptional regulatory complex and reveal a previously undescribed chromatin function that is required for full activity of nuclear receptors in normal cells and for the MYC oncoprotein in tumor cells.
Initiation of transcription requires sophisticated coordination of many different regulatory factors. Coactivators are multi-subunit complexes that facilitate transcription initiation directly, by interacting with RNA polymerase and general transcription factors, or indirectly, by influencing chromatin. For example, histone acetyltransferase (HAT) complexes are thought to activate gene expression by modifying chromatin-associated proteins called histones which function like spools for DNA to wind around.
The yeast SAGA complex and the homologue metazoan TFTC/STAGA, also called hSAGA, are HAT-containing complexes that facilitate access of general transcriptional factors to DNA through histone acetylation. Although hSAGA is thought to be a homologue of the well-studied yeast SAGA complex, its subunit composition and functions are not as well understood. Dr. Didier Devys from the Institute de Génétique et de Biologie Moléculaire et Cellulaire in Strasbourg, France and colleagues identified three novel subunits, ATXN7L3, USP22 and ENY2, that are homologues of previously described subunits in the yeast SAGA complex.
The researchers demonstrated that the newly identified subunits work together to remove the ubiquitin moiety from monoubiquitylated histone H2B, similarly to what has been previously described in yeast, but also remove the ubiquitin moiety from monoubiquitylated histone H2A. The latter modification is not found in yeast but is more prevalent than monoubiquitylated H2B in mammals. Importantly, the deubiquitylation module of the Drosophila TFTC/STAGA complex was an enhancer of position effect variegation and counteracted heterochromatin silencing while both the Drosophila and the human deubiquitylation module were shown to be required for full transcriptional activation by the androgen receptor. This finding is clinically significant as androgen receptor activity is often deregulated in prostate cancer.
“The association of both HAT and deubiquitylation activities in the hSAGA complex provide an attractive mechanism by which the so called “cross-talk” between given histone marks is coordinated within the same regulatory complex” says Dr. Devys. “Further mechanistic studies are essential to examine the exact link between these activities and other chromatin modifying complexes to understand how these sequential events participate in chromatin remodeling and gene activation.”
Working in parallel, a second research group led by Dr. Steven B. McMahon from Thomas Jefferson University’s Kimmel Cancer Center in Philadelphia also identified USP22 as a member of hSAGA. Previous work had identified USP22 as part of an eleven gene cancer stem cell signature that accurately distinguished patients whose tumors would eventually metastasize from those whose tumors would remain localized. “Unlike the other genes in this cancer stem cell signature, no direct mechanistic link to human cancer has been ascribed to USP22,” explains Dr. McMahon. McMahon’s group demonstrated that USP22 is required for activation of target gene transcription by the MYC oncoprotein and that USP22 depletion compromises MYC functions, including transformation of mammalian cells, and leads to cell cycle arrest.
Taken together, these results significantly advance the understanding of mechanisms that permit fine-tuning of transcriptional regulation by revealing that the hSAGA histone acetyltransferase complex is also capable of histone deubiquitylation. The findings provide critical new information about the importance of the timing and sequence of chromatin modifications in the control of gene expression in normal cells and shed light on the biochemical function of cancer stem cell marker and hSAGA subunit USP22, identifying it as a potential therapeutic target.
Zhang et al.:
The researchers include Xiao-Yong Zhang,The Department of Cancer Biology, The Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, PA, USA; Maya Varthi,The Department of Cancer Biology, The Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, PA, USA; Stephen M. Sykes, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Charles Phillips, The Department of Cancer Biology, The Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, PA, USA; Claude Warzecha, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Wenting Zhu, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Anastasia Wyce, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Alan W. Thorne, University of Portsmouth, Portsmouth, UK; Shelley L. Berger, The Wistar Institute, Philadelphia, PA, USA; and Steven B. McMahon, The Department of Cancer Biology, The Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, PA, USA.
Zhao et al.:
The researchers include Yue Zhao, Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Guillaume Lang, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Universite´ Louis Pasteur de Strasbourg, Strasbourg, France; Saya Ito, Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Jacques Bonnet, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Universite´ Louis Pasteur de Strasbourg, Strasbourg, France; Eric Metzger, Universitats-Frauenklinik und Zentrum fur Klinische Forschung, Klinikum der Universitat Freiburg, Freiburg, Germany; Shun Sawatsubashi, Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Eriko Suzuki, Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Xavier Le Guezennec, Department of Molecular Biology, NCMLS, Radboud University Nijmegen, Nijmegen, The Netherlands; Hendrik G. Stunnenberg, Department of Molecular Biology, NCMLS, Radboud University Nijmegen, Nijmegen, The Netherlands; Aleksey Krasnov, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia; Sofia G. Georgieva, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia; Roland Schule, Universitats-Frauenklinik und Zentrum fur Klinische Forschung, Klinikum der Universitat Freiburg, Freiburg, Germany; Ken-Ichi Takeyama, Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Shigeaki Kato, Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Laszlo´ Tora, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Universite´ Louis Pasteur de Strasbourg, Strasbourg, France; and Didier Devys, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Universite´ Louis Pasteur de Strasbourg, Strasbourg, France.
Zhang et al.: “The Cancer Stem Cell Marker USP22 Is a Subunit of the Human SAGA Complex Required for Activated Transcription and Cell-Cycle Progression," and Zhao et al.: “A TFTC/STAGA Module Mediates Histone H2A and H2B Deubiquitination, Coactivates Nuclear Receptors, and Counteracts Heterochromatin Silencing.”