X-chromosome inactivation (XCI) is a biological process used by mammals like us to ensure that boys (XY) and girls (XX) have equal sex chromosome dosage despite having a different number of X-chromosomes. XCI happens very early during uterine development and leads to inactivation of one of the female embryo’s 2 X-chromosomes. For XCI to occur, every embryo “counts” chromosomes. In embryos with 2 Xs, one of the Xs makes a “choice” to undergo inactivation. For this to happen properly, each X has to know what the other X intends to do. We believe that the Xs communicate this choice through a “pairing” process in which they make contact briefly at two noncoding loci — Tsix/Xite and the telomere. The chosen X chromosome then initiates “silencing” within a specific region — called the “X-inactivation center” — and silencing is “spread” throughout the large sex chromosome. During the silencing process, the X chromosome is folded like origami into a unique shape that helps to suppress gene activity. Thus, XCI involves a series of highly orchestrated steps. It is particularly interesting, because the major decision-makers (molecular regulators) appear to be non-coding in nature. Non-coding RNA plays a key role in every step of the XCI process, from counting to pairing to silencing and to 3D chromosome-folding. Our lab’s goal is to understand how RNA interfaces with protein at each step of the XCI process.
We also aim to translate the knowledge gained from basic studies to treat human disorders — particularly neuro-developmental disorders and X-linked intellectual disabilities (XLID). Three disease areas of current interest are Rett Syndrome, the Fragile X Syndrome, and CDKL5 Syndrome. In each case, the girls and boys who suffer from the disorder harbor a perfectly good copy of the necessary gene, but the good copy is locked up by a silencing mechanism: MECP2 in the case of Rett Syndrome, FMR1 for Fragile X, and CDKL5 for CDKL5 Syndrome. Our goal is to use our understanding of XCI to unlock the silent copy of each gene for therapeutic benefit.
Wang CY, Jegu T, Chu HP, Oh HJ, Lee JT. SMCHD1 merges chromosome compartments and assists formation of Super-structures on the inactive X. Cell. 2018;174(2):406-421.
Carrette LG, Wang CY, Press W, Ma W, Kelleher RJ, Lee JT. Xi-reactivation:A mixed modality approach to MECP2 restoration for Rett Syndrome and other X-linked disorders. Proc Natl Acad Sci. USA 2017 ;115(4):E668-E675.
Del Rosario BC, Del Rosario AM, Anselmo A, Wang PI, Sadreyev RI, Lee JT. Genetic intersection of Tsix and Hedgehog signaling during the initiation of X chromosome inactivation. Dev Cell. 2017; 43, 359-371.
Rosenberg M, Blum R, Kesner B, Maier VK, Szanto A, Lee JT. Denaturing CLIP, dCLIP, pipeline identifies discrete RNA footprints on chromatin-associated proteins and reveals that CBX7 targets 3’ UTRs to regulate mRNA expression. Cell Syst. 2017; 5, 368-385.
Chu HP, Froberg JE, Kesner B, Oh HJ, Ji F, Sadreyev R, Pinter SF, Lee JT. PAR-TERRA directs homologous sex chromosome pairing. Nat Struct Mol Biol. 2017; 24,620-631.
Chu HP, Cifuentes-Rojas C, Kesner B, Aeby E, Lee HG, Wei C, Oh HJ, Boukhali M, Haas W, Lee JT. TERRA RNA antagonizes ATRX and protects telomeres. Cell. 2017; 170:86-101.
Zovoilis A, Cifuentes-Rojas C, Chu HP, Nernandez AJ, Lee JT. Destabilization of B2 RNA by EZH2 activates the stress response. Cell. 2017; 167, 1788-1802.