Specific or not specific recruitment of DNMTs for DNA methylation, an epigenetic dilemma

Abstract

Our current view of DNA methylation processes is strongly moving: First, even if it was generally admitted that DNMT3A and DNMT3B are associated with de novo methylation and DNMT1 is associated with inheritance DNA methylation, these distinctions are now not so clear. Secondly, since one decade, many partners of DNMTs have been involved in both the regulation of DNA methylation activity and DNMT recruitment on DNA. The high diversity of interactions and the combination of these interactions let us to subclass the different DNMT-including complexes. For example, the DNMT3L/DNMT3A complex is mainly related to de novo DNA methylation in embryonic states, whereas the DNMT1/PCNA/UHRF1 complex is required for maintaining global DNA methylation following DNA replication. On the opposite to these unspecific DNA methylation machineries (no preferential DNA sequence), some recently identified DNMT-including complexes are recruited on specific DNA sequences. The coexistence of both types of DNA methylation (un/specific) suggests a close cooperation and an orchestration between these systems to maintain genome and epigenome integrities. Deregulation of these systems can lead to pathologic disorders.

Keywords: DNA methylation; DNMT-including complexes; DNMT1; DNMT3A; DNMT3B; DNMT3L; Epigenetics.

Fig. 1

Representative structure of DNMTs. Adapted from [–8]

Fig. 2

Schema of the main kinds of DNMT-including complexes. Maintaining (mainly catalyzed by DNMT1: dark blue curve) or de novo (mainly catalyzed by DNMT3A and DNMT3B: light blue curve) DNA methylation can be processed by numerous DNMT-including complexes which are either not specific (green curve) or specific (yellow curve) of particular DNA sequences. Specific complexes included polycomb proteins or transcriptional factor (TF), whereas unspecific complexes included heterochromatin readers or replication associated proteins

Fig. 3

Examples of cooperation between DNA methylation machineries and proteins regulating post-translational modifications of histones. Left: Silencing of a DNA region following DNA replication. Addition of the repressive H3K9me3 mark, removal of H3 acetylation (Ac) and methylation of the new DNA strand is catalyzed by the DNMT1/UHRF1/PCNA/G9a/HDAC1 complex. Right: de novo methylation of a DNA region of heterochromatin (e.g., major satellites). The addition of the H3K9me3 repressive mark by SUV39H1 is read by HP1 and that further induces the recruitment of DNMT3A and/or DNMT3B for de novo methylation of both strands of DNA. Black circles: 5mC; white circles: C. Parental strand: blue; new synthetized strand: orange

Fig. 4

Illustration of the role different DNMT-including complexes in the maintaining DNA methylation. Left: The canonical unspecific DNMT1/UHRF1/PCNA complex processed the maintaining of DNA methylation of most of the CpGs. A cooperation with specific DNMT-including complexes, as illustrated by the SP1/DNMT1 interaction catalyzed the methylation of CpGs on particular loci (e.g., SP1 response elements) which were not methylated by the DNMT1/UHRF1/PCNA complex [40]. Up right: DNA deamination is repaired by a cooperation between the DNA repair machinery (MMR) and DNMT1 [119]. Bottom right: in absence of MIZ, cMYC binds to its response element and activate the expression of the p21 gene. In presence of MIZ, the ternary complex MIZ/cMYC/DNMT3A repressed the p21 gene in a DNA methylation manner [155, 156]

Fig. 5

Putative TF/DNMT interactions. In vitro experiments with transcriptional factors arrays and recombinant DNMT1, DNMT3A, DNMT3B or DNMT3L revealed that some TFs can potentially interact with several or only one DNMT. White: TFs interacting only with DNMT3L; red: TFs interacting only with DNMT1; yellow: TFs interacting only with DNMT3A; blue: TFs interacting only with DNMT3B; green (blue+yellow): TFs interacting with both DNMT3A and DNMT3B; orange (red + yellow): TFs interacting with both DNMT3A and DNMT1; purple (red + blue): TFs interacting with both DNMT3B and DNMT1; light red: TFs interacting with both DNMT1 and DNMT3L; brown (red + blue + yellow): TFs interacting with DNMT1, DNMT3A and DNMT3B; light yellow (yellow + white): TFs interacting with both DNMT3A and DNMT3L; light blue (blue + white): TFs interacting with both DNMT3B and DNMT3L; light green (green + white): TFs interacting with DNMT3A, DNMT3B and DNMT3L; light orange (orange + white): TFs interacting with DNMT1, DNMT3A and DNMT3L; light purple (purple + white): TFs interacting with DNMT1, DNMT3BDNMT3L; light brown (brown + white): TFs interacting with all DNMTs. Adapted from [140, 156, 163]

Fig. 6

TF: a balance between activator and repressor. The switch between the activator role or the repressor role of a TF, as that is found in DNMT-including complexes to specificallly methylate some DNA sequences could be explained by different hypothesis: (i) a modulation of the TF/DNMT versus free TF ratio [157, 161], (ii) the stabilization of the TF/DNMT interaction by another co-repressor (e.g., HMTs, HDACs) [–152], and (iii) post-translation modifications of TF in favor of DNMT/TF interaction; a genetic (fusion protein) or 3D structure modification of the TF in favor of DNMT/TF interaction [, –147]