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

By T. Nesterova, Guifeng Wei, Heather Coker, G. Pintacuda, Joseph S. Bowness, Tianyi Zhang, Mafalda Almeida, B. Bloechl, Benoit Moindrot, E. Carter and 5 more. 2018

127 citations recorded by the source corpus.

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. Xist RNA is the master regulator of X chromosome inactivation. Here the authors describe a systematic analysis of Xist-mediated allelic silencing in mouse ESC models and define the contribution of different pathways that regulate gene silencing.

Subfields: Molecular Biology

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In Molecular Biology

1. Edith Heard
2. Lothar Schermelleh
3. Kathrin Plath
4. N. Brockdorff
5. M. Guttman
6. T. Nesterova

Citations in the corpus

• Time-resolved structured illumination microscopy reveals key principles of Xist RNA spreading (2020, methodology): “S10B), consistent with prior studies (26, 27).”
• Xist nucleates local protein gradients to propagate silencing across the X chromosome (2021, background): “However, a subset of X-linked genes also requires other Xist-interactors for silencing, including non-canonical PRC1-type Polycomb group protein complexes and the architectural protein structural-maintenance of chromosomes hinge domain containing 1 (SMCHD1) (Almeida et al., 2017; Blewitt et al., 200”