Long non-coding RNAs in tumor development
Pseudogene-mediated epigenetic regulation of the tumor suppressor gene PTEN.
Tumor cells undergo both genetic and epigenetic changes during cancer progression. While genetic alterations, such as mutations and deletions, result in changes in the DNA sequence and lost or altered protein function, epigenetic changes dysregulate genes while leaving the DNA sequence intact.
We are currently analyzing the role of long non-coding RNAs (lncRNAs) in epigenetic regulation and their possible involvement in cancer development. Tumor cells often show signs of general hypomethylation. In contrast, certain genes, such as tumor suppressor genes, are specifically enriched for inactive chromatin states with methylated DNA and histones. These genes are thus functionally inactivated as a consequence of their low level of expression. Our overall aim is to investigate whether lncRNAs are involved in directing these epigenetic changes and why certain genes undergo epigenetic inactivation, while others do not.
Our group, in collaboration with the Kevin Morris group at the Scripps Research Institute, recently characterized a novel antisense RNA (asRNA) to the PTEN gene (Johnsson et al., 2013). Antisense transcripts, which are RNAs that share some degree of complementarity to other RNAs, represent a specific subset of ncRNAs. While most asRNAs described to date act in trans, we found a cis-acting asRNA emanating from the PTEN pseudogene (PTENpg1, Figure 1). The PTENpg1 locus on chromosome 9 shares high sequence homology with the PTEN protein-coding counterpart on chromosome 10. While PTENpg1 lacks protein-coding capacity it is still transcribed into RNA in both sense and antisense direction. We investigated the functional properties of the PTENpg1 asRNA and found that this asRNA directs chromatin-remodeling complexes, such as EZH2 and DNMT3a, to the PTEN promoter. Moreover, we found that by targeting this asRNA-protein complex, PTEN expression can be re-activated and tumor cells sensitized to chemotherapeutic treatment.
By understanding the general molecular mechanisms of ncRNA-mediated epigenetic regulation, we hope to be able to revert the inactivation of critical tumor suppressor genes, such as PTEN.
A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells.
Nat. Struct. Mol. Biol. 2013 Apr;20(4):440-6