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The Bromodomain Protein 4 Contributes to the Regulation of Alternative Splicing. 2019

Sheetal Uppal, and Anne Gegonne, and Qingrong Chen, and Petria S Thompson, and Dan Cheng, and Jie Mu, and Daoud Meerzaman, and Hari S Misra, and Dinah S Singer
Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.

The bromodomain protein 4 (BRD4) is an atypical kinase and histone acetyl transferase (HAT) that binds to acetylated histones and contributes to chromatin remodeling and early transcriptional elongation. During transcription, BRD4 travels with the elongation complex. Since most alternative splicing events take place co-transcriptionally, we asked if BRD4 plays a role in regulating alternative splicing. We report that distinct patterns of alternative splicing are associated with a conditional deletion of BRD4 during thymocyte differentiation in vivo. Similarly, the depletion of BRD4 in T cell acute lymphoblastic leukemia (T-ALL) cells alters patterns of splicing. Most alternatively spliced events affected by BRD4 are exon skipping. Importantly, BRD4 interacts with components of the splicing machinery, as assessed by both immunoprecipitation (IP) and proximity ligation assays (PLAs), and co-localizes on chromatin with the splicing regulator, FUS. We propose that BRD4 contributes to patterns of alternative splicing through its interaction with the splicing machinery during transcription elongation.

UI MeSH Term Description Entries
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D005091 Exons The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA. Mini-Exon,Exon,Mini Exon,Mini-Exons
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D014157 Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Transcription Factor,Factor, Transcription,Factors, Transcription
D017398 Alternative Splicing A process whereby multiple RNA transcripts are generated from a single gene. Alternative splicing involves the splicing together of other possible sets of EXONS during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form a mature RNA. The alternative forms of mature MESSENGER RNA produce PROTEIN ISOFORMS in which one part of the isoforms is common while the other parts are different. RNA Splicing, Alternative,Splicing, Alternative,Alternate Splicing,Nested Transcripts,Alternate Splicings,Alternative RNA Splicing,Alternative RNA Splicings,Alternative Splicings,Nested Transcript,RNA Splicings, Alternative,Splicing, Alternate,Splicing, Alternative RNA,Splicings, Alternate,Splicings, Alternative,Splicings, Alternative RNA,Transcript, Nested,Transcripts, Nested
D047468 Immunoprecipitation The aggregation of soluble ANTIGENS with ANTIBODIES, alone or with antibody binding factors such as ANTI-ANTIBODIES or STAPHYLOCOCCAL PROTEIN A, into complexes large enough to fall out of solution. Co-Immunoprecipitation,Immune Precipitation,Co Immunoprecipitation,Co-Immunoprecipitations,Immune Precipitations,Precipitation, Immune,Precipitations, Immune
D054198 Precursor Cell Lymphoblastic Leukemia-Lymphoma A neoplasm characterized by abnormalities of the lymphoid cell precursors leading to excessive lymphoblasts in the marrow and other organs. It is the most common cancer in children and accounts for the vast majority of all childhood leukemias. Leukemia, Lymphoblastic,Leukemia, Lymphoid, Acute,Lymphoblastic Leukemia,Lymphoblastic Lymphoma,Lymphocytic Leukemia, Acute,Lymphoma, Lymphoblastic,ALL, Childhood,Acute Lymphoid Leukemia,Leukemia, Acute Lymphoblastic,Leukemia, Lymphoblastic, Acute,Leukemia, Lymphoblastic, Acute, L1,Leukemia, Lymphoblastic, Acute, L2,Leukemia, Lymphoblastic, Acute, Philadelphia-Positive,Leukemia, Lymphocytic, Acute,Leukemia, Lymphocytic, Acute, L1,Leukemia, Lymphocytic, Acute, L2,Lymphoblastic Leukemia, Acute,Lymphoblastic Leukemia, Acute, Adult,Lymphoblastic Leukemia, Acute, Childhood,Lymphoblastic Leukemia, Acute, L1,Lymphoblastic Leukemia, Acute, L2,Lymphocytic Leukemia, L1,Lymphocytic Leukemia, L2,Acute Lymphoblastic Leukemia,Acute Lymphocytic Leukemia,Childhood ALL,L1 Lymphocytic Leukemia,L2 Lymphocytic Leukemia,Leukemia, Acute Lymphocytic,Leukemia, Acute Lymphoid,Leukemia, L1 Lymphocytic,Leukemia, L2 Lymphocytic,Lymphoid Leukemia, Acute,Precursor Cell Lymphoblastic Leukemia Lymphoma
D060168 Thymocytes HEMATOPOIETIC PROGENITOR CELLS that have migrated to the THYMUS where they differentiate into T-LYMPHOCYTES. Thymocytes are classified into maturational stages based on the expression of CELL SURFACE ANTIGENS. Thymocyte
D018797 Cell Cycle Proteins Proteins that control the CELL DIVISION CYCLE. This family of proteins includes a wide variety of classes, including CYCLIN-DEPENDENT KINASES, mitogen-activated kinases, CYCLINS, and PHOSPHOPROTEIN PHOSPHATASES as well as their putative substrates such as chromatin-associated proteins, CYTOSKELETAL PROTEINS, and TRANSCRIPTION FACTORS. Cell Division Cycle Proteins,Cell-Cycle Regulatory Proteins,cdc Proteins,Cell Cycle Regulatory Proteins

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