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Published August 16, 2013 | Supplemental Material + Accepted Version
Journal Article Open

The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome

Abstract

Many large noncoding RNAs (lncRNAs) regulate chromatin, but the mechanisms by which they localize to genomic targets remain unexplored. We investigated the localization mechanisms of the Xist lncRNA during X-chromosome inactivation (XCI), a paradigm of lncRNA-mediated chromatin regulation. During the maintenance of XCI, Xist binds broadly across the X chromosome. During initiation of XCI, Xist initially transfers to distal regions across the X chromosome that are not defined by specific sequences. Instead, Xist identifies these regions by exploiting the three-dimensional conformation of the X chromosome. Xist requires its silencing domain to spread across actively transcribed regions and thereby access the entire chromosome. These findings suggest a model in which Xist coats the X chromosome by searching in three dimensions, modifying chromosome structure, and spreading to newly accessible locations.

Additional Information

© 2013 American Association for the Advancement of Science. Received 18 March 2013; accepted 20 June 2013. Published online 4 July 2013. We thank A. Gnirke for initial discussions about the RAP method; T. Mikkelsen for assistance with oligonucleotide synthesis; M. Garber and J. Rinn for helpful discussions and ideas; A. Wutz for generously providing Xist transgenic cell lines; S. Rao, N. Cherniavsky, and E. Lieberman-Aiden for analytical help and discussions; P. Russell, M. Cabili, E. Hacisuleyman, and L. Goff for critical reading of the manuscript; L. Gaffney for assistance with figures; and S. Knemeyer for illustrations. Supported by the Fannie and John Hertz Foundation and National Defense Science and Engineering Graduate Fellowship (J.M.E.); an NIH postdoctoral fellowship (1F32GM103139-01) (A.P.-J.); NIH Director's Early Independence Award DP5OD012190 (M.G.), National Human Genome Research Institute Center for Excellence for Genomic Sciences grant P50HG006193 (M.G.); National Institute of General Medical Sciences grant P01GM099134 (K.P.); California Institute for Regenerative Medicine grants RN1-00564, RB3-05080, and RB4-06133 (K.P.); the Broad Institute of MIT and Harvard (M.G. and E.S.L.); and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA (K.P.). Sequencing data are available online from the NCBI Gene Expression Omnibus (accession no. GSE46918, www.ncbi.nlm.nih.gov/geo/) and additional data and information is available at www.lncRNA.caltech.edu/RAP/. J.M.E., E.S.L., and M.G. are inventors on a patent application from the Broad Institute that covers the selective purification of RNA-bound molecular complexes in cells.

Attached Files

Accepted Version - nihms504267.pdf

Supplemental Material - 1237973s1.xlsx

Supplemental Material - 1237973s2.xlsx

Supplemental Material - 1237973s3.xlsx

Supplemental Material - 1237973s4.xlsx

Supplemental Material - 1237973s5.xlsx

Supplemental Material - 1237973s6.xlsx

Supplemental Material - Engreitz.SM.pdf

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Created:
August 19, 2023
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