DECODER

DECiphering the role of long non COding Rna in cancer

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

It seems that the so-called non-coding DNA is not so inactive after all. EU research has uncovered the molecular basis of its involvement in some cancers.

Descrizione progetto (Article)

More than 98 % of the human genome doesn't code for proteins. Recent research however supports the conclusion that over 90 % of our DNA is actually transcribed. The so-called non-coding RNAs (ncRNAs) are the major component of these transcripts. One type, large intervening ncRNA (lincRNA) appears to be involved in the epigenetic control of gene transcription.

Dysregulation of lincRNAs has been linked to cancer. The DECODER (Deciphering the role of long non coding RNA in cancer) project researched the role of lincRNAs in cellular transformation and differentiation. They used acute promyelocyticleukemia (APL), a sub-type of acute myeloid leukaemia (AML) as a model system.

APL is characterised by a reciprocal translocation involving the retinoic acid receptor alpha (RAR-alpha) and the promyelocytic gene (PML). All-trans-retinoic-acid (ATRA) treatment is able to induce complete remission in most patients by modulating the expression of thousands of genetic loci including many lincRNAs. The treatment results in differentiation of APL blasts and epigenetic remodelling. Blast cells are the earliest and most immature cells that give rise to platelets as well as red and white blood cells. In the case of APL, there is an overproduction of abnormal promyelocytes and these are unable to develop into mature white cells.

The DECODER scientists studied the pattern of expression of lincRNAs during ATRA-induced APL differentiation. They identified a lincRNA family, including members which are significantly upregulated upon ATRA treatment of APL cells and during normal maturation of granulocytes. This indicates that these lincRNAs are likely to be an integral part of the genetic programme activated during myeloid differentiation.

The lincRNA family identified could also be a potentially valuable biomarker to evaluate response to therapy in leukaemia. Overexpression of the corresponding gene (resulting in more lincRNA) halted cell division. The researchers noted that the same lincRNAs are also upregulated during ATRA therapy in AML samples.

DECODER work should help to further clarify the mechanisms behind the epigenetic deregulation in cancer and the functional links between coding and non-coding DNA. Ultimately, this may lead to the development of novel therapies.