Human DNA Methyltransferase 1 Is Required for Maintenance of the Histone H3 Modification Pattern

Abstract

DNA methyltransferase 1 (DNMT1) plays an essential role in murine development and is thought to be the enzyme primarily responsible for maintenance of the global methylation status of genomic DNA. However, loss of DNMT1 in human cancer cells affects only the methylation status of a limited number of pericentromeric sequences. Here we show that human cancer cells lacking DNMT1 display at least two important differences with respect to wild type cells: a profound disorganization of nuclear architecture, and an altered pattern of histone H3 modification that results in an increase in the acetylation and a decrease in the dimethylation and trimethylation of lysine 9. Additionally, this phenotype is associated with a loss of interaction of histone deacetylases (HDACs) and HP1 (heterochromatin protein 1) with histone H3 and pericentromeric repetitive sequences (satellite 2). Our data indicate that DNMT1 activity, via maintenance of the appropriate histone H3 modifications, contributes to the preservation of the correct organization of large heterochromatic regions.Methylation of CpG dinucleotides is an epigenetic phenomenon involved in regulating important intranuclear events, such as the organization of chromatin structure, transcriptional control, and replication timing (1). The process is characterized by the transfer of methyl groups to the C-5 position of cytosine and is catalyzed by members of the DNA methyltransferase (DNMT) 1 protein family. To date, five mammalian DNMTs have been identified as follows: DNMT1, DNMT3a, DNMT3b, DNMT2, and DNMT3L (1). Of these five, DNMT1, DNMT3a, and DNMT3b are known to be essential for proper development in murine knockout models (1-3). DNMT1, the most abundant DNA methyltransferase in somatic cells, has a strong preference for hemimethylated DNA and is therefore believed to be the enzyme primarily responsible for copying and maintaining methylation patterns from the parental to the daughter strand following DNA replication (1). Strikingly, significant genomic hypomethylation was only found at pericentromeric satellite 2 and 3 sequences in human cancer cells lacking DNMT1 (KO1 cells) (4). This suggests the possibility of regional specificity on the part of DNMT1 and, furthermore, that DNMT1 loss might be partially compensated by other DNMTs (4).Accumulated evidence suggests that DNA methylation status and changes in the biochemical modification of histone tails, the "histone code," can regulate the higher order organization and function of large intranuclear regions, implicating these modifications in chromosome positioning and the maintenance of specific chromatin domains within the nucleus in a wide variety of organisms (5-10). Recent data from plant cells indicate that loss of methylated CpG dinucleotides alters the methylation pattern of histone H3 (11), suggesting that DNA methylation may also function as a central signal for the regulation of chromatin structure. A reciprocal dependence may exist, because mouse embryonic stem cells lacking Suv39h histone methyltransferase...

Transcriptional Repression and Heterochromatin Formation by MBD1 and MCAF/AM Family Proteins

“…These findings suggest that methyl H3-K9 depends on DNA methylation in Arabidopsis. On the other hand, deficiencies in Suv39h, one of the major H3-K9 methyltransferases in mammals, result in strong loss of methyl H3-K9 and reduced methylation of the major satellite DNA (14), whereas Dnmt1 knockouts cause significant DNA hypomethylation and, at least in part, affect methyl H3-K9 (19,22). Although the relationships are not precisely known, these findings suggest that DNA methylation and H3-K9 methylation may be relatively independent in mammals (16).…”

Dormant hypermethylated tumour suppressor genes: questions and answers

“…This property led to the assignment of DNMT1 as the enzyme responsible for maintaining the methylation patterns following DNA replication. In fact, the somatic genetic knockout of DNMT1 in human cells shows an aberrant nuclear structure and deorganization in the distribution of the heterochromatin protein 1 (HP1) [42], demonstrating the existence of close links between the two processes. However, there is no direct evidence that DNMT1 is not also involved in certain types of de novo methylation and in fact, DNMT1 is involved in most of the de novo methylation activity in embryo lysates.…”

RFTS-deleted DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation

“…First, the RFTS domain mediates association of DNMT1 to pericentromeric heterochromatin to maintain dense methylation 47,48 and SAT2 is the most abundant repeat in the region. 49 Second, SAT2-specific hypomethylation has been found in DNMT1-null cells 50,51 and in patients with RFTS-mutated DNMT1. 38 Third, DNA hypomethylation and RNA up-regulation of SAT2 are highly associated with various cancers and contributes to genomic instability.…”