Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of CpG Island Methylation on the Inactive X Chromosome

Summary

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.

Abstract

Graphical Abstract

Highlights

► Xi CGIs exhibit either fast or slow DNA methylation kinetics ► Xi CGI methylation requires Dnmt3b but not Dnmt3a or Dnmt3L ► Recruitment of the chromosomal protein Smchd1 is a late step in X inactivation ► Slow, but not fast, Xi CGI methylation requires the chromosomal protein Smchd1

Abstract

What mechanisms contribute to developmental gene regulation and long-term silencing? Gendrel et al. uncover on the inactive X chromosome parallel pathways of slow and fast CpG-island methylation kinetics associated with different chromosomal contexts. Only slow methylation needs the chromosomal protein Smchd1, but both pathways require the de novo methyltransferase Dnmt3b.