A recent discovery by researchers at the National Cancer Institute has shed light on the illusive mechanism whereby the addition of DNA modifications is regulated during development. Control over the addition of methyl groups is an actively pursued research topic because aberrations in DNA methylation been implicated in the process of aging and the development of various diseases, including cancer.
Published in Genes & Development, Dr. Kathrin Muegge and colleagues have discovered that a protein called Lsh, a member of the SNF2 chromatin remodeling protein family, is required for normal genome-wide methylation during development.
As Lsh is similar to proteins that are known to alter chromatin, or compact DNA structure, the determination that Lsh is necessary for genome-wide methylation suggests that chromatin structure affects DNA methylation. Previously, only the reverse was thought to be true.
DNA methylation is the process by which a carbon bound to three hydrogens (a methyl group) is transferred to a DNA nucleotide via a DNA methyltransferase enzyme. In vertebrates both specific single copy sequences, like specific protein-coding genes, and repetitive sequences, like non-coding satellite sequences, are methylated.
In general, DNA methylation is associated with genes that are not being expressed. Thus the hypothesis has arisen that DNA methylation silences genes, and aberrant methylation can alter normal gene expression patterns, causing developmental defects and disease.
Dr. Muegge and colleagues began studying the Lsh gene because it shares some sequence identity with another SNF2 family member that modulates genome-wide methylation in plants. In order to determine the effect of Lsh on methylation patterns in mammals, Dr. Muegge and colleagues made knock-out mice deficient in Lsh.
These Lsh mutant mice survived embryogenesis, but had substantially less DNA methylation at both single copy and repetitive sequences. Because the DNA methylation machienery, like the DNA methyltransferases enzymes, appeared to be intact in these Lsh mutant mice, it is proposed that the effect of Lsh on chromatin structure has implications in the establishment and/or the maintenance of global genome methylation patterns.
This discovery presents the first evidence that chromatin structure may affect global DNA methylation in mammals, and will certainly spearhead new research efforts into the regulation of DNA methylation in the context of chromatin structure.
Journal
Genes & Development