Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive x chromosome |
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Authors: | Anne-Valerie Gendrel Anwyn Apedaile Heather Coker Ausma Termanis Ilona Zvetkova Jonathan Godwin Y Amy Tang Derek Huntley Giovanni Montana Steven Taylor Eleni Giannoulatou Edith Heard Irina Stancheva Neil Brockdorff |
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Affiliation: | Department of Biochemistry, University of Oxford, Oxford OX1 2JD, UK; Genetics and Developmental Biology Unit, Institut Curie, CNRS UMR3215, INSERM U934, 75005 Paris, France. |
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Abstract: | X chromosome inactivation involves multiple levels of chromatin modification, established progressively and in a stepwise manner during early development. The chromosomal protein Smchd1 was recently shown to play an important role in DNA methylation of CpG islands (CGIs), a late step in the X inactivation?pathway that is required for long-term maintenance of gene silencing. Here we show that inactive X chromosome (Xi) CGI methylation can occur via either Smchd1-dependent or -independent pathways. Smchd1-dependent CGI methylation, the primary pathway, is acquired gradually over an extended period, whereas Smchd1-independent CGI methylation occurs rapidly after the onset of X inactivation. The de novo methyltransferase Dnmt3b is required for methylation of both classes of CGI, whereas Dnmt3a and Dnmt3L are dispensable. Xi CGIs methylated by these distinct pathways differ with respect to their sequence characteristics and immediate chromosomal environment. We discuss the implications of these results for understanding CGI methylation during development. |
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