Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia
| Autor: | Ana Rio-Machin, Özgen Deniz, Miguel R. Branco, Mark A. Dawson, Christopher D. Todd, Mamataz Ahmed |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Tumour heterogeneity Science Transcriptional regulatory elements General Physics and Astronomy Endogenous retrovirus Biology General Biochemistry Genetics and Molecular Biology Article Acute myeloid leukaemia Cell Line Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Animals Humans Gene Regulatory Networks Epigenetics lcsh:Science Enhancer Gene Transcription factor 030304 developmental biology Epigenomics Regulation of gene expression 0303 health sciences Multidisciplinary Genome Human Endogenous Retroviruses Myeloid leukemia Interspersed repetitive sequences General Chemistry Pediatric cancer Chromatin 3. Good health Cell biology Leukemia Myeloid Acute 030104 developmental biology 030220 oncology & carcinogenesis DNA Transposable Elements lcsh:Q |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) |
| ISSN: | 2041-1723 |
| Popis: | Acute myeloid leukemia (AML) is characterised by a series of genetic and epigenetic alterations that result in deregulation of transcriptional networks. One understudied source of transcriptional regulators are transposable elements (TEs), whose aberrant usage could contribute to oncogenic transcriptional circuits. However, the regulatory influence of TEs and their links to AML pathogenesis remain unexplored. Here we identify six endogenous retrovirus (ERV) families with AML-associated enhancer chromatin signatures that are enriched in binding of key regulators of hematopoiesis and AML pathogenesis. Using both locus-specific genetic editing and simultaneous epigenetic silencing of multiple ERVs, we demonstrate that ERV deregulation directly alters the expression of adjacent genes in AML. Strikingly, deletion or epigenetic silencing of an ERV-derived enhancer suppresses cell growth by inducing apoptosis in leukemia cell lines. This work reveals that ERVs are a previously unappreciated source of AML enhancers that may be exploited by cancer cells to help drive tumour heterogeneity and evolution. Transposable elements are a potential source of transcriptional regulators, but how these sequences contribute to oncogenesis remains poorly understood. Here, the authors identify endogenous retroviruses (ERVs) with acute myeloid leukemia (AML)-associated enhancer chromatin signatures, and provide evidence that ERV activation provides an additional layer of gene regulation in AML. |
| Databáze: | OpenAIRE |
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