Structural modularity of the XIST ribonucleoprotein complex

Zhipeng Lu (), Jimmy K. Guo, Yuning Wei, Diana R. Dou, Brian Zarnegar, Qing Ma, Rui Li, Yang Zhao, Fan Liu, Hani Choudhry, Paul A. Khavari and Howard Y. Chang ()
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Zhipeng Lu: Stanford University
Jimmy K. Guo: Stanford University
Yuning Wei: Stanford University
Diana R. Dou: Stanford University
Brian Zarnegar: Stanford University School of Medicine
Qing Ma: Stanford University
Rui Li: Stanford University
Yang Zhao: Stanford University
Fan Liu: Stanford University
Hani Choudhry: Stanford University
Paul A. Khavari: Stanford University School of Medicine
Howard Y. Chang: Stanford University

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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 m6A modification. Thus modular architecture plays an essential role, in addition to sequence motifs, in determining the specificity of RBP binding and m6A 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.

Date: 2020
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DOI: 10.1038/s41467-020-20040-3

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