Targeting Xist with compounds that disrupt RNA structure and X inactivation

Rodrigo Aguilar, Kerrie B. Spencer, Barry Kesner, Noreen F. Rizvi, Maulik D. Badmalia, Tyler Mrozowich, Jonathan D. Mortison, Carlos Rivera, Graham F. Smith, Julja Burchard, Peter J. Dandliker, Trushar R. Patel, Elliott B. Nickbarg, Jeannie T. Lee

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

Resumen

Although more than 98% of the human genome is non-coding1, 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 conformation2. Most RNAs can adopt several conformations of similar stabilities. RNA structures also remain challenging to determine3. Nonetheless, an increasing number of diseases are now being attributed to non-coding RNA4 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 Xist5. The X1 compound has drug-like properties and binds specifically the RepA motif6 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.

Idioma originalInglés
Páginas (desde-hasta)160-166
Número de páginas7
PublicaciónNature
Volumen604
N.º7904
DOI
EstadoPublicada - 7 abr. 2022

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