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

Autor: Nesterova TB; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Wei G; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Coker H; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Pintacuda G; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.; Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA, 02138, USA., Bowness JS; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Zhang T; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Almeida M; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Bloechl B; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Moindrot B; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.; I2BC Paris-Sud University, Gif-Sur-Yvette, France., Carter EJ; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Alvarez Rodrigo I; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.; Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK., Pan Q; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Bi Y; Ludwig Institute for Cancer Research, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK., Song CX; Ludwig Institute for Cancer Research, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK., Brockdorff N; Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK. neil.brockdorff@bioch.ox.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Jul 16; Vol. 10 (1), pp. 3129. Date of Electronic Publication: 2019 Jul 16.
DOI: 10.1038/s41467-019-11171-3
Abstrakt: 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.
Databáze: MEDLINE