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Xist Repeat A coordinates an assembly of SR proteins to recruit SPEN and induce gene silencing

Trotman, J. B.; Porrello, A.; Schactler, S. A.; DeLeon, L. E.; Eberhard, Q. E.; Boyson, S. P.; Zhang, Z.; Lee, D. M.; Kirik, S. E.; Nguyen, S. N.; Beltejar, M.-C. G.; Shinn, M. K.; Ong, S.-E.; Gonzalez-Perez, M. P.; Shaffer, S. A.; Dominguez, D.; Shechner, D. M.; Calabrese, M.

2025-05-26 genetics
10.1101/2025.05.21.655143 bioRxiv
Show abstract

The lncRNA Xist silences gene expression by recruiting the protein SPEN through its 5'-proximal Repeat A domain. How Repeat A recruits SPEN, how SPEN enacts silencing, and why Repeat A is required for Xist biogenesis in addition to silencing remain unclear. We find that sequences in Repeat A critical for SPEN recruitment, silencing, and Xist biogenesis directly bind SR-rich splicing factors and not SPEN. SRSF1, one such factor, is necessary and sufficient for SPEN recruitment to Repeat A. SPEN and SR protein-binding motifs in Repeat A enable Xists association with many proteins, including those involved in m6A methylation, RNA turnover, and transcriptional elongation. Our results reveal an unexpectedly essential role for splicing factors in coordinating silencing by SPEN and suggest a unifying model for the origin of Repeat A, the function of SPEN, and their roles in Xist biogenesis and silencing.

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