The repeat genome in interphase chromosome structure and regulation

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DESCRIPTION (provided by applicant): Remarkably, almost half the human genome consists of interspersed repetitive elements, but in analysis of these has not been among the many impressive advances in genome science in recent years. In fact, these high copy repeats populating all human chromosomes are routinely screened out of genomic studies, as they pose technical challenges and thwart standard molecular approaches. The lack of attention to this large mass of repeats is also due to their low sequence conservation and other properties which have led to the widely held belief that they are irrelevant evolutionary "junk". Based on recent evidence from our lab and others, we propose that this dogma is changing, and that the "repeat genome" not only contains-meaningful biology, but is likely fundamental to chromosome structure and epigenetic regulation of the genome. By probing, rather than masking, RNA from repeats in situ, we discovered strong evidence that high copy repeat elements produce abundant nuclear RNAs, which are embedded in nuclear chromosome structure. Our findings suggest that these RNAs are poorly extracted by standard methods for - molecular assays. We have a strong interdisciplinary team who will address this and other challenges to the - study of repeat sequences with innovative and multi faceted approaches. This research has potential to establish a ground breaking concept: that interspersed repeats previously thought silent make RNAs that are integral to the structure and regulation of chromosomes. In contrast to the established paradigm of ncRNAs (e.g. XIST) inducing heterochromatin or gene silencing, we hypothesize that repeat RNAs can promote open euchromatin, and may compete for binding of the same structural protein. In addition to unusual strength in nuclear RNA analysis and chromosome biology, our team includes exceptional strength in RNA biochemistry and bioinformatics of repeat sequences.