Nuclear matrix attachment regions antagonize methylation-dependent repression of long-range enhancer–promoter interactions


Cold Spring Harbor Laboratory Press


The immunoglobulin intragenic μ enhancer region acts as a locus control region that mediates transcriptional activation over large distances in germ line transformation assays. In transgenic mice, but not in transfected tissue culture cells, the activation of a variable region (VH) promoter by the μ enhancer is dependent on flanking nuclear matrix attachment regions (MARs). Here, we examine the effects of DNA methylation, which occurs in early mouse development, on the function of the μ enhancer and the MARs. We find that methylation of rearranged μ genes in vitro, before transfection, represses the ability of the μ enhancer to activate the VH promoter over the distance of 1.2 kb. However, methylation does not affect enhancer-mediated promoter activation over a distance of 150 bp. In methylated DNA templates, the μ enhancer alone induces only local chromatin remodeling, whereas in combination with MARs, the μ enhancer generates an extended domain of histone acetylation. These observations provide evidence that DNA methylation impairs the distance independence of enhancer function and thereby imposes a requirement for additional regulatory elements, such as MARs, which facilitate long-range chromatin remodeling.

Documentos Relacionados