title: Compensatory RNA polymerase 2 loading determines the efficacy and transcriptional selectivity of JQ1 in Myc-driven tumors.
abstract: Inhibition of bromodomain and extraterminal motif (BET) proteins such as BRD4 bears great promise for cancer treatment and its efficacy has been frequently attributed to Myc downregulation. Here, we use B-cell tumors as a model to address the mechanism of action of JQ1, a widely used BET inhibitor. Although JQ1 led to widespread eviction of BRD4 from chromatin, its effect on gene transcription was limited to a restricted set of genes. This was unlinked to Myc downregulation or its chromatin association. Yet, JQ1-sensitive genes were enriched for Myc and E2F targets, were expressed at high levels, and showed high promoter occupancy by RNAPol2, BRD4, Myc and E2F. Their marked decrease in transcriptional elongation upon JQ1 treatment, indicated that BRD4-dependent promoter clearance was rate limiting for transcription. At JQ1-insensitive genes the drop in transcriptional elongation still occurred, but was compensated by enhanced RNAPol2 recruitment. Similar results were obtained with other inhibitors of transcriptional elongation. Thus, the selective transcriptional effects following JQ1 treatment are linked to the inability of JQ1-sensitive genes to sustain compensatory RNAPol2 recruitment to promoters. These observations highlight the role of BET proteins in supporting transcriptional elongation and rationalize how a general suppression of elongation may selectively affects transcription.
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Donato
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Croci
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sabò
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: H
authors.initials: H
authors.lastname: Muller
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: M J
authors.initials: MJ
authors.lastname: Morelli
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pelizzola
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: S
authors.identifier: 0000-0003-4547-6849
authors.initials: S
authors.lastname: Campaner
mesh_terms: D001381:Azepines / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D050684:E2F Transcription Factors / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014230:Triazoles / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D002843:Chromatin; D042863:Cyclin-Dependent Kinase 9; D050684:E2F Transcription Factors; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D012319:RNA Polymerase II; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins