Systematic allelic analysis defines the interplay of key pathways in X chromosome inactivation

Tatyana B. Nesterova, Guifeng Wei, Heather Coker, Greta Pintacuda, Joseph S. Bowness, Tianyi Zhang, Mafalda Almeida, Bianca Bloechl, Benoit Moindrot, Emma J. Carter, Ines Alvarez Rodrigo, Qi Pan, Ying Bi, Chun-Xiao Song and Neil Brockdorff ()
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Tatyana B. Nesterova: University of Oxford
Guifeng Wei: University of Oxford
Heather Coker: University of Oxford
Greta Pintacuda: University of Oxford
Joseph S. Bowness: University of Oxford
Tianyi Zhang: University of Oxford
Mafalda Almeida: University of Oxford
Bianca Bloechl: University of Oxford
Benoit Moindrot: University of Oxford
Emma J. Carter: University of Oxford
Ines Alvarez Rodrigo: University of Oxford
Qi Pan: University of Oxford
Ying Bi: University of Oxford
Chun-Xiao Song: University of Oxford
Neil Brockdorff: University of Oxford

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Xist RNA, the master regulator of X chromosome inactivation, acts in cis to induce chromosome-wide silencing. Whilst recent studies have defined candidate silencing factors, their relative contribution to repressing different genes, and their relationship with one another is poorly understood. Here we describe a systematic analysis of Xist-mediated allelic silencing in mouse embryonic stem cell-based models. Using a machine learning approach we identify distance to the Xist locus and prior gene expression levels as key determinants of silencing efficiency. We go on to show that Spen, recruited through the Xist A-repeat, plays a central role, being critical for silencing of all except a subset of weakly expressed genes. Polycomb, recruited through the Xist B/C-repeat, also plays a key role, favouring silencing of genes with pre-existing H3K27me3 chromatin. LBR and the Rbm15/m6A-methyltransferase complex make only minor contributions to gene silencing. Together our results provide a comprehensive model for Xist-mediated chromosome silencing.

Date: 2019
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DOI: 10.1038/s41467-019-11171-3

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