Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM090278-05
Application #
8630307
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
2010-03-01
Project End
2018-07-31
Budget Start
2014-09-18
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$455,875
Indirect Cost
$192,845
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Sarma, Kavitha; Cifuentes-Rojas, Catherine; Ergun, Ayla et al. (2014) ATRX directs binding of PRC2 to Xist RNA and Polycomb targets. Cell 159:869-83
Yang, Lin; Froberg, John E; Lee, Jeannie T (2014) Long noncoding RNAs: fresh perspectives into the RNA world. Trends Biochem Sci 39:35-43
Cifuentes-Rojas, Catherine; Hernandez, Alfredo J; Sarma, Kavitha et al. (2014) Regulatory interactions between RNA and polycomb repressive complex 2. Mol Cell 55:171-85
Kung, Johnny T Y; Lee, Jeannie T (2013) RNA in the loop. Dev Cell 24:565-7
Kung, Johnny T Y; Colognori, David; Lee, Jeannie T (2013) Long noncoding RNAs: past, present, and future. Genetics 193:651-69
Sadreyev, Ruslan I; Yildirim, Eda; Pinter, Stefan F et al. (2013) Bimodal quantitative relationships between histone modifications for X-linked and autosomal loci. Proc Natl Acad Sci U S A 110:6949-54
Simon, Matthew D; Pinter, Stefan F; Fang, Rui et al. (2013) High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. Nature 504:465-9
Froberg, John E; Yang, Lin; Lee, Jeannie T (2013) Guided by RNAs: X-inactivation as a model for lncRNA function. J Mol Biol 425:3698-706
Yildirim, Eda; Sadreyev, Ruslan I; Pinter, Stefan F et al. (2012) X-chromosome hyperactivation in mammals via nonlinear relationships between chromatin states and transcription. Nat Struct Mol Biol 19:56-61
Jeon, Yesu; Sarma, Kavitha; Lee, Jeannie T (2012) New and Xisting regulatory mechanisms of X chromosome inactivation. Curr Opin Genet Dev 22:62-71

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