RNA and Genomic Junk in Fundamental Chromosome Architecture and Regulation

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. This project has potential to illuminate a very large but poorly understood component of the human genome, as we seek to find meaningful information in non-coding, repeat-rich sequence, the bulk of our genomes. Emerging evidence shows that much of the non-coding genome is expressed, but often at low levels. A few clearly functional long non-coding RNAs (lncRNAs) are known, yet it remains unclear whether thousands of other low-level, mostly nuclear, lncRNAs are functionally relevant. Based on much progress in the current cycle, we are primed to further advance a broad, impactful hypothesis for how “junk RNAs” may collectively contribute to genome regulation. Our recent work suggests that many long repeat rich (Cot-1) RNAs (including lncRNAs and introns/pre-mRNAs), are not just “products”, but serve essentially as dynamic components of open euchromatin structure. This current MIRA grant represents the convergence of two previously separate projects, one which focused on the long non-coding XIST RNA which transforms an active X-chromosome to a condense heterochromatic Barr Body, and the other focused on nuclear organization of active genes. However, our insights increasingly indicated there was a telling dichotomy between the two, unified by the hypothesis that XIST RNA is not a special example of RNA that impacts chromosome architecture, but exemplifies a much broader aspect of genome/chromosome biology. Rather than XIST RNA simply tethered to chromatin to modify histones, our findings support that XIST RNA also functions to directly modify components of an “RNP-scaffold” that influences the heterochromatin versus euchromatic state. Other recent evidence suggests the RNP-scaffold may be disrupted in certain disease states. As we investigate RNA involvement in chromosome structure at the sequence level, we will seek to connect that to an overall vision of how chromosomes are organized at a much larger scale, and coordinately regulated through development. These ambitious goals will be bolstered by a strong collaborative team, with Dr. Zhiping Weng and Dr. Daryl Bosco.