Studies from the last several years have repeatedly highlighted the importance of long noncoding RNAs (lncRNA) in epigenetic regulation, development, and disease. However, the mechanisms by which RNAs control these processes remain poorly defined. Improved understanding of RNA-based mechanisms is crucial, especially given that 70-80% of the mammalian genome is transcribed and that the vast bulk of transcription is noncoding. Nowhere is the abundance of lncRNAs more evident than at the X-inactivation center (Xic), an X-linked region that controls the X-chromosome inactivation (XCI) in the female mammal. XCI serves as an excellent model to study lncRNA regulation because this process is controlled by a series of RNA-based switches. Silencing is initiated by the 17-kb Xist RNA as it recruits Polycomb proteins to the X-chromosome. Xist RNA is in turn controlled by an antisense transcript, Tsix, which antagonizes Xist by repelling the recruitment of an RNA-protein complex containing Polycomb proteins. My laboratory has also found that Xist upregulation requires the action of two additional lncRNAs, RepA which recruits Polycomb proteins to the Xic, and Jpx which is required to activate Xist transcription. The GM58839 grant has, for the past 16 years, provided crucial support for this lncRNA research. Herein, we propose to advance our understanding of RNA regulation by studying how RNAs of the Xic control the different steps and forms of XCI. Specifically, we will: (i) Investigate how lncRNAs play a role in homologous X-chromosome pairing, a process proposed to regulate counting and choosing of X-chromosomes for inactivation; (ii) Determine the mechanism by which Jpx RNA activates Xist expression; and (iii) Elucidate fundamental differences between random and imprinted XCI. The proposed work will require five years to complete and is expected to train three postdoctoral fellows for academic careers in the fields of epigenomics, RNA regulation, and stem cell biology.

Public Health Relevance

Studies from the last several years have highlighted the importance of long noncoding RNAs in human development, health, and disease. The mechanisms remain largely unknown. X-inactivation serves as a excellent model to study RNA regulation because it is controlled by RNA-based switches. We will investigate mechanisms of RNA regulation in chromosome pairing, gene silencing, and imprinting.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Carter, Anthony D
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Massachusetts General Hospital
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Kung, Johnny T; Kesner, Barry; An, Jee Young et al. (2015) Locus-specific targeting to the X chromosome revealed by the RNA interactome of CTCF. Mol Cell 57:361-75
Broering, Tyler J; Alavattam, Kris G; Sadreyev, Ruslan I et al. (2014) BRCA1 establishes DNA damage signaling and pericentric heterochromatin of the X chromosome in male meiosis. J Cell Biol 205:663-75
Yang, Lin; Froberg, John E; Lee, Jeannie T (2014) Long noncoding RNAs: fresh perspectives into the RNA world. Trends Biochem Sci 39:35-43
Payer, Bernhard; Lee, Jeannie T (2014) Coupling of X-chromosome reactivation with the pluripotent stem cell state. RNA Biol 11:798-807
Lee, Jeannie T; Bartolomei, Marisa S (2013) X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 152:1308-23
Sun, Sha; Del Rosario, Brian C; Szanto, Attila et al. (2013) Jpx RNA activates Xist by evicting CTCF. Cell 153:1537-51
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
Payer, Bernhard; Rosenberg, Michael; Yamaji, Masashi et al. (2013) Tsix RNA and the germline factor, PRDM14, link X reactivation and stem cell reprogramming. Mol Cell 52:805-18
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

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