Dosage compensation in the mammal occurs by transcriptional silencing of one X-chromosome in the female sex. Known as ?X-chromosome inactivation? (XCI), this process exemplifies the large number of regulatory mechanisms used in epigenomic regulation, particularly those involving interactions between long noncoding RNAs (lncRNAs) and chromatin modifiers. The X-inactivation center (Xic) ? the X-linked region that controls the initiation, spread, and maintenance of silencing ? harbors a large number of genes encoding functional lncRNAs, including Xist, RepA, Tsix, and Jpx, each of which plays a distinct role during XCI. The crucial Xist RNA initiates formation of heterochromatin as the RNA spreads along the X-chromosome. During the last funding period (2010-2014), our work has helped define mechanisms by which Xist RNA recruits Polycomb complexes to the X. Major achievements include: (i) discovering a ?nucleation center? required for loading of Xist-Polycomb complexes before they are propagated in cis; (ii) defining YY1 as an essential factor that tethers Xist RNA to the nucleation center; (iii) identifying a hierarchy of binding sites for spreading of Polycomb complexes along the inactive X; and (iv) uncovering a genomewide transcriptome of >9,000 transcripts that associate with PRC2. Together, these findings lead to two over-arching conclusions. First, targeting of Polycomb complexes is genetically and biochemically separable from loading. Second, both steps require RNA. Third, RNA-mediated targeting of Polycomb complexes is likely to be a general theme in epigenomic regulation. Over the next five years, we will use XCI as a model and extend understanding of RNA-guided chromatin change by addressing: (1) How nucleation of the Xist-Polycomb complex is regulated; (2) How spreading of XCI occurs via a hierarchy of Polycomb stations; and (3) How lncRNAs target and load Polycomb complexes throughout the genome. Because many lncRNAs are misexpressed in human disease and Polycomb complexes are often aberrantly targeted in cancers, answers to these questions will help develop novel methodologies to treat diseases in which Polycomb complexes and lncRNAs are implicated.
The proposed research to study long noncoding RNA (lncRNA), Polycomb proteins, and YY1 is of significant public health relevance due to the growing awareness of their involvement in development of congenital diseases and cancer. As evidence, technologies and lncRNA targets that emerged from the last funding cycle have already been licensed to RaNA Therapeutics, a company that seeks to harness the potential of Polycomb lncRNAs to treat diseases of the brain, imprinting, and cancer. Knowledge gained from follow-up studies proposed herein will further enhance understanding of normal development, define steps towards disease, and identify additional therapeutic strategies.
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