The value of junk DNA

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.