Journal
NATURE
Volume 604, Issue 7904, Pages 160-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04537-z
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Funding
- Merck MINt Award
- US National Institutes of Health [R01-HD097665]
- Howard Hughes Medical Institute
- Pew Charitable Trust Latin American Fellows Program
- MGH Fund for Medical Discovery
- MITACS fellowship
- NSERC PGS-D fellowship
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More and more diseases are now being attributed to non-coding RNA, which could be systematically targeted by drug-like compounds to disrupt RNA structure and epigenetic function.
Although more than 98% of the human genome is non-coding(1), nearly all of the drugs on the market target one of about 700 disease-related proteins. The historical reluctance to invest in non-coding RNA stems partly from requirements for drug targets to adopt a single stable conformation(2). Most RNAs can adopt several conformations of similar stabilities. RNA structures also remain challenging to determine(3). Nonetheless, an increasing number of diseases are now being attributed to non-coding RNA(4) and the ability to target them would vastly expand the chemical space for drug development. Here we devise a screening strategy and identify small molecules that bind the non-coding RNA prototype Xist(5). The X1 compound has drug-like properties and binds specifically the RepA motif(6) of Xist in vitro and in vivo. Small-angle X-ray scattering analysis reveals that RepA can adopt multiple conformations but favours one structure in solution. X1 binding reduces the conformational space of RepA, displaces cognate interacting protein factors (PRC2 and SPEN), suppresses histone H3K27 trimethylation, and blocks initiation of X-chromosome inactivation. X1 inhibits cell differentiation and growth in a female-specific manner. Thus, RNA can be systematically targeted by drug-like compounds that disrupt RNA structure and epigenetic function.
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