DNA methylation and late replication probably aid cell memory, and type I DNA reeling could aid chromosome folding and enhancer function

Abstract

DNA methylation in mammals is reviewed, and it is concluded that one role of methylation is to aid cell memory, which is defined as the ability of mitotically derived progeny cells to remember and re-establish their proper cellular identity. Methylation of X-linked CpG-rich islands probably stabilizes X-chromosome inactivation, but other mechanisms appear to be involved. Late replication is discussed as a key ancestral mechanism for X inactivation, and it is emphasized that early and late replication domains may each be self perpetuating. Therefore, early-late replication timing becomes another strong candidate mechanism for cell memory. A chromosome-loop folding enigma is discussed, and it is concluded that special mechanisms are needed to explain the formation and maintenance of specific looped domains. DNA reeling, such as done by type I restriction-modification enzymes, is proposed to provide this special mechanism for folding. DNA reeling mechanisms can help to explain the cis-spreading of X-chromosome inactivation as well as long-range action by enhancers.

In vivo footprint and methylation analysis by PCR-aided genomic sequencing: comparison of active and inactive X chromosomal DNA at the CpG island and promoter of human PGK-1.

“…lian development (Riggs 1989}. There is rather convincing evidence that DNA methylation is important for the maintenance of X chromosome inactivation (for review, see Monk 1986; Grant and Chapman 1988;Lyon 1988;Riggs 1990).…”

“…There is rather convincing evidence that DNA methylation is important for the maintenance of X chromosome inactivation (for review, see Monk 1986; Grant and Chapman 1988;Lyon 1988;Riggs 1990). Some of the critical methylation sites involved in the maintenance of X chromosome inactivation may be found in CpG islands, because sex-specific island methylation is correlated with stability of the inactive state (Kaslow and Migeon 1987;Migeon et al 1989).…”

Chromatin differences between active and inactive X chromosomes revealed by genomic footprinting of permeabilized cells using DNase I and ligation-mediated PCR.

“…Perhaps the higher-order chromatin structure that we have begun to analyze on the Xi can only form in the second half of S phase and, once formed, is stable until the next late S phase. This idea leads to an experimentally testable model for cell memory (Riggs 1990a).…”

“…The stable, somatically heritable maintenance of differentiated states is of central importance for vertebrate development. However, little is known about the required cell memory mechanisms (see Riggs 1989Riggs , 1990a, although methylated CpG sites are somatically heritable entities (Pfeifer et al 1990b) and a strong case can be made for DNA cytosine methylation being involved as an important component of X chromosome inactivation. The transcription start sites for PGK-1 are located near the center of what appears to be a typical CpG-rich island.…”

DNA repair in sea star asterias rubens: genomic aspects

“…DNA methylation: In mammals, DNA methylation is associated with the regulation of gene expression and the maintenance of the differential state in cell lineages [1]. It is also present in other phylogenetic groups such as some invertebrates: sponges, some insects, sea urchins.…”