title: Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome.
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.
authors: Department of Biochemistry, University of Oxford, Oxford OX1 2JD, UK.
authors: Anne-Valerie
authors: AV
authors: Gendrel
authors: Anwyn
authors: A
authors: Apedaile
authors: Heather
authors: H
authors: Coker
authors: Ausma
authors: A
authors: Termanis
authors: Ilona
authors: I
authors: Zvetkova
authors: Jonathan
authors: J
authors: Godwin
authors: Y Amy
authors: YA
authors: Tang
authors: Derek
authors: D
authors: Huntley
authors: Giovanni
authors: G
authors: Montana
authors: Steven
authors: S
authors: Taylor
authors: Eleni
authors: E
authors: Giannoulatou
authors: Edith
authors: E
authors: Heard
authors: Irina
authors: I
authors: Stancheva
authors: Neil
authors: N
authors: Brockdorff
mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D049951:X Chromosome Inactivation
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D020033:Protein Isoforms; C529024:SmcHD1 protein, mouse