Dysregulation Of Lincrnas Is A Major Driver Of Aberrant Epigenomes During Tumorigenesis

It has now been unequivocally demonstrated that the process of tumorigenesis is driven by both genetic and epigenetic alterations, but the mechanisms of epigenetic dysregulations remain to be elucidated. Work in our laboratory has demonstrated that numerous long intergenic non-coding RNAs (lincRNAs) become dysregulated in human cancers, and a significant subset of these lincRNAs are associated with histone-modifying enzymes and DNA methyltransferases in healthy, non-tumor cells. Based on these observations, we tested an exceptionally novel hypothesis that dysregulation of chromatin-associated lincRNAs is a major mechanism driving cancer-associated aberrant epigenomes. To test this novel concept, we have performed experiments to modulate the expression of specific chromatin-associated lincRNAs in cancer cells, and assessed their impact on the epigenome. Consistent with our hypothesis, modulating the expression of lincRNAs in cancer cells resulted in massive reprogramming of their epigenomes. These epigenomic changes impacted the growth of cancer cells and global gene expression. Mapping the genomic occupancy sites of lincRNAs, and intersection of those sites with altered genomic regions in tumors, further supported direct roles of lincRNAs in modulating chromatin structure. These findings demonstrate key roles of chromatin-associated lincRNAs in suppressing tumorigenesis in normal human tissues by regulating the epigenome. Citation Format: Callie R. Merry, Megan E. Forrest, Sanford Markowitz, Ahmad M. Khalil. Dysregulation of lincRNAs is a major driver of aberrant epigenomes during tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1937.