Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-20040-3
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Funding
- NIH [R01-HG004361, RM1-HG007735]
- King Abdulaziz University
- Damon Runyon-Sohn Foundation Pediatric Cancer Fellowship Award [DRSG-14-15]
- Stanford Jump Start Award of Excellence in Postdoctoral Research
- Pathway to Independence Award from NHGRI [1R00HG009662]
- USC Norris Comprehensive Cancer Center [P30CA014089]
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Long noncoding RNAs are thought to regulate gene expression by organizing protein complexes through unclear mechanisms. XIST controls the inactivation of an entire X chromosome in female placental mammals. Here we develop and integrate several orthogonal structure-interaction methods to demonstrate that XIST RNA-protein complex folds into an evolutionarily conserved modular architecture. Chimeric RNAs and clustered protein binding in fRIP and eCLIP experiments align with long-range RNA secondary structure, revealing discrete XIST domains that interact with distinct sets of effector proteins. CRISPR-Cas9-mediated permutation of the Xist A-repeat location shows that A-repeat serves as a nucleation center for multiple Xist-associated proteins and m(6)A modification. Thus modular architecture plays an essential role, in addition to sequence motifs, in determining the specificity of RBP binding and m(6)A modification. Together, this work builds a comprehensive structure-function model for the XIST RNA-protein complex, and suggests a general strategy for mechanistic studies of large ribonucleoprotein assemblies. The long noncoding RNA XIST plays a central role in sex-specific gene expression in humans by silencing one of two X chromosomes in female cells. Here the authors show that higher order secondary structure creates the modular domain structure of XIST ribonucleoprotein complex and spatial separation of functions.
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