The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer
| Autor: | Shinpei Kawaoka, Eric Wang, Justin B. Kinney, Christopher R. Vakoc, Anand S. Bhagwat, Anja F. Hohmann, Yali Xu, Junwei Shi, Yutaka Suzuki, Jae Seok Roe |
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| Rok vydání: | 2015 |
| Předmět: |
Cellular differentiation
Apoptosis Trim33 Mice Gene Regulatory Networks Biology (General) RNA Small Interfering B-Lymphocytes B cell Bcl-2-Like Protein 11 Gene Expression Regulation Leukemic General Neuroscience leukemia General Medicine 3. Good health Leukemia medicine.anatomical_structure Enhancer Elements Genetic Genes and Chromosomes Medicine Protein Binding Signal Transduction QH301-705.5 Cell Survival Science Short Report Mice Transgenic Biology General Biochemistry Genetics and Molecular Biology Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Proto-Oncogene Proteins medicine Animals Humans Cell Lineage Bim human Enhancer Transcription factor mouse Binding Sites General Immunology and Microbiology PU.1 Membrane Proteins medicine.disease TRIM33 B-cell leukemia Cancer research Trans-Activators enhancer CD5 Apoptosis Regulatory Proteins Transcription Factors |
| Zdroj: | eLife eLife, Vol 4 (2015) |
| ISSN: | 2050-084X |
| Popis: | Most mammalian transcription factors (TFs) and cofactors occupy thousands of genomic sites and modulate the expression of large gene networks to implement their biological functions. In this study, we describe an exception to this paradigm. TRIM33 is identified here as a lineage dependency in B cell neoplasms and is shown to perform this essential function by associating with a single cis element. ChIP-seq analysis of TRIM33 in murine B cell leukemia revealed a preferential association with two lineage-specific enhancers that harbor an exceptional density of motifs recognized by the PU.1 TF. TRIM33 is recruited to these elements by PU.1, yet acts to antagonize PU.1 function. One of the PU.1/TRIM33 co-occupied enhancers is upstream of the pro-apoptotic gene Bim, and deleting this enhancer renders TRIM33 dispensable for leukemia cell survival. These findings reveal an essential role for TRIM33 in preventing apoptosis in B lymphoblastic leukemia by interfering with enhancer-mediated Bim activation. DOI: http://dx.doi.org/10.7554/eLife.06377.001 eLife digest The DNA inside every cell in a human body is the same, and yet the activities that occur within different types of cells can vary greatly. White blood cells, for example, are different from skin cells or liver cells because different genes are active in each type of cell. Molecules called transcription factors and transcriptional cofactors associate with specific DNA sequences to control the activity of nearby genes. It is common for a single transcription factor or cofactor to bind to thousands of sites across the DNA of any cell. In humans, our immune systems protect us against infectious diseases and from malfunctioning cells that could become cancerous. White blood cells called B cells provide part of this immune defense. These cells help to identify invading bacteria and viruses, and can also develop into memory cells that help the immune system to rapidly recognize, respond to and eliminate a disease if it is re-encountered. Immature B cells—also known as B lymphoblasts—mature within bone marrow. If any problem occurs in a cell as it matures, that cell is usually programmed to self-destruct in a process called apoptosis. If these cells are not destroyed, they can accumulate in the bone marrow and prevent the production of other immune cells. This leads to a type of cancer called acute lymphoblastic leukemia. Wang et al. now reveal that TRIM33—a protein that B-lymphoid leukemia cells need to survive—is a transcriptional cofactor that prevents apoptosis. Furthermore, unlike other known transcription factors and cofactors in mammals, TRIM33 binds to an exceedingly small number of sites across the DNA of B cells. In fact, the cancer cell's dependency on the protein is due to TRIM33 associating with just a single binding site. The role of TRIM33 in B cell leukemia also has potential therapeutic implications. Although it is found in cells throughout the body, Wang et al. found that inhibiting TRIM33 in mice resulted in lower numbers of B cells being produced, but did not affect other tissues. Developing drugs that prevent TRIM33 from working could therefore provide new options for treating leukemia. DOI: http://dx.doi.org/10.7554/eLife.06377.002 |
| Databáze: | OpenAIRE |
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