A protein assembly mediates Xist localization and gene silencing.

Nature. 2020 Nov;587(7832):145-151. Epub 2020 Sep 09

Amy Pandya-Jones ¹ , Yolanda Markaki ² , Jacques Serizay ³ , Tsotne Chitiashvili ² , Walter R Mancia Leon ⁴ ,

Amy Pandya-Jones ¹ , Yolanda Markaki ² , Jacques Serizay ³ , Tsotne Chitiashvili ² , Walter R Mancia Leon ⁴ , Andrey Damianov ⁵ , Constantinos Chronis ⁶ , Bernadett Papp ⁷ , Chun-Kan Chen ⁸ , Robin McKee ¹ , Xiao-Jun Wang ⁵ , Anthony Chau ¹ , Shan Sabri ¹ , Heinrich Leonhardt ² , Sika Zheng ⁹ , Mitchell Guttman ¹⁰ , Douglas L Black ¹¹ , Kathrin Plath ¹²

+ et al

Author information

¹ Department of Biological Chemistry at the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
² Department of Biology and Center for Integrated Protein Science, LMU Munich, Munich, Germany.
³ The Gurdon Institute and Department of Genetics, University of Cambridge, Cambridge, UK.
⁴ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA.
⁶ Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.
⁷ Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA.
⁸ Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
⁹ Division of Biomedical Science, University of California Riverside, Riverside, CA, USA.
¹⁰ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
¹¹ Graduate Program in the Biosciences, University of California Los Angeles, Los Angeles, CA, USA. dougb@microbio.ucla.edu.
¹² Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. kplath@mednet.ucla.edu.

摘要

Nuclear compartments have diverse roles in regulating gene expression, yet the molecular forces and components that drive compartment formation remain largely unclear¹. The long non-coding RNA Xist establishes an intra-chromosomal compartment by localizing at a high concentration in a territory spatially close to its transcription locus² and binding diverse proteins^3-5 to achieve X-chromosome inactivation (XCI)^6,7. The XCI process therefore serves as a paradigm for understanding how RNA-mediated recruitment of various proteins induces a functional compartment. The properties of the inactive X (Xi)-compartment are known to change over time, because after initial Xist spreading and transcriptional shutoff a state is reached in which gene silencing remains stable even if Xist is turned off⁸. Here we show that the Xist RNA-binding proteins PTBP1⁹, MATR3¹⁰, TDP-43¹¹ and CELF1¹² assemble on the multivalent E-repeat element of Xist⁷ and, via self-aggregation and heterotypic protein-protein interactions, form a condensate¹ in the Xi. This condensate is required for gene silencing and for the anchoring of Xist to the Xi territory, and can be sustained in the absence of Xist. Notably, these E-repeat-binding proteins become essential coincident with transition to the Xist-independent XCI phase⁸, indicating that the condensate seeded by the E-repeat underlies the developmental switch from Xist-dependence to Xist-independence. Taken together, our data show that Xist forms the Xi compartment by seeding a heteromeric condensate that consists of ubiquitous RNA-binding proteins, revealing an unanticipated mechanism for heritable gene silencing.

原始数据

保存测序数据

Sample name	Organism	Experiment title	Sample type	Library instrument	Attributes
Sample name	Organism	Experiment title	Sample type	Library instrument