DECODER · DECiphering the role of long non COding Rna in cancer
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2011-11-01 → 2014-10-31
- Финансиране от ЕС
- 236 442 €
- Участници
- 1
- Схема
- MC-IOF
Линиите свързват координатора с партньорите.
Накратко на български
Дългите некодиращи РНК се анализират чрез модел на остър промиелоцитен левкемия, за да се разбере ролята им при развитието на рака. Това помага да се разбере как определени генетични програми контролират узряването на кръвните клетки и спират растежа на левкемичните клетки.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
DECiphering the role of long non COding Rna in cancer
Coding Genes represent less than 2% of our genome. However about 80% of our genome is biochemically functional and 70% is actively transcribed, with long non coding RNAs (lncRNAs) and pseudogenes largely outnumbering the amount of coding genes. In this project we started to analyze the biological significance of lncRNAs in cancer using Acute Promyelocytic Leukemia (APL) as a model system. APL accounts for more than 10% of all acute myeloid leukemias and is characterized by reciprocal translocations involving the retinoic acid alpha-receptor (RARA) and the promyelocytic gene (PML). PML-RARA is a potent epigenetic modifier able to bind specific genetic loci and to consequently arrest the differentiation program at the promyelocitic stage of myeloid maturation. Treatment with pharmacological doses of Retinoic Acid can result in APL differentiation, by modulating the expression of thousands of genetic loci including many lncRNAs. Here we investigated the biogenesis of lncRNA candidates and identified regulatory regions involved in their transcription. Interestingly, we observed that these regions are conserved and bound by transcriptional factors involved in normal myeloid commitment and differentiation. Indeed, although lncRNAs are poorly conserved, DNA motifs and transcriptional factors involved in their regulation are generally conserved across evolution. We identified a lncRNAs family, including members which are significantly upregulated upon Retinoic Acid treatment of APL cells and during normal myelopoiesis. Thus these lncRNAs are likely to be an integral part of the genetic program activated during myeloid differentiation. Overexpressing one of the family members had a citostatic effect on leukemic cells. The same family member was upregulated in primary AML samples following ATRA treatment. Thus this lncRNA may represent a valuable biomarker to evaluate response to therapy in leukemia. Deconstructing the complexity of the non-coding genome and studying the relationship between the coding and non-coding component of DNA may represent the basis to identify novel relevant pathways and to ultimately develop new therapeutic strategies in cancer.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Increasing evidence indicates that non coding RNAs play a major role in the regulation of gene expression. A significant fraction of the non-coding transcriptome is represented by large intervening non coding RNA (lincRNAs), which seem to be involved with the epigenetic control of gene expression through binding with several members of the Polycomb Repressive Complexes (PRCs). Recently, dysregulation of lincRNAs has been associated to cancer. The HOTAIR lincRNA triggers the invasive program of breast epithelial cells by promoting epigenetic remodelling (Gupta et al., 2010). Although this report suggests an impact of lincRNAs in the transition to the metastatic phenotype, the role of lincRNAs in transformation remains largely unexplored. In this project I want to define the role of lincRNAs in the pathogenesis of cancer, using acute promyelocytic leukaemia (APL) as a model system. APL accounts for more than 10% of all Acute Myeloid Leukemias and is characterized by reciprocal translocations involving the retinoic acid α-receptor (RARα). APL blasts respond to all-trans retinoic acid (ATRA) treatment with differentiation, which involves epigenetic remodelling. The availability of new sequencing technologies coupled to tiling arrays and to the power of new computational biology programs, makes it now possible to study the whole non–coding RNA transcriptome. Determining the pattern of expression of lincRNAs during ATRA-induced APL differentiation, defining their functional significance, and deciphering the network of interactions between lincRNAs, the PML-RARα chimeric protein and the PRCs, will contribute to a better understanding of the nature of epigenetic deregulation in cancer and ultimately represent the basis to develop new anti-cancer strategies.""
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITA DEGLI STUDI DI TORINO · TorinoКоординаторИталия
Връзки
Данни: CORDIS, © Европейски съюз