6mA regulation mechanism
1. the mechanism of the enhancer-promoter (EP) interaction
（1）Core Promoter Targeting within TADs
TADs can restrict or direct enhancer function during transcriptional regulation, but enhancer–core-promoter communication within TADs is not restricted to specific positions.
Disruptions of TADs boundaries lead to gene deregulation, like hypermethylation of CTCF binding sites can impair boundary function and have been implicated in cancer.
（2）Promoters selection
promoter-proximal tethering element (PTE) near promoters and promoter-targeting sequences near enhancers. Such enhancer–core-promoter tethering would be compatible with the observation of looping and stable enhancer–polymerase contacts as observed during development
enhancer will skip the proximal promoter with transcriptional inactivity due to promoter inaccessibility
the respective core-promoter sequences are important determinants of enhancer targeting
The distinctive distribution of TF motifs and the differential binding of the corresponding TFs suggest that the core-promoter specificity is encoded in enhancer sequences and is mediated by trans-activating factors
Different transcription factors (TFs) and cofactors (COFs) can differentially activate house- keeping core promoters (hkCPs) over developmental core promoters (dCPs)
Different core promoters that are activated by the same TF are differentially affected by depletion of different cofactors, suggesting that they rely on different trans factors
- Transcriptional Activation Mediated via Activating Microenvironments
2. Biological roles of 6mA
1）Restriction–modification systems: Whereas eukaryotes have evolved complex immune systems, prokaryotes use DNA methylation as a marking system to distinguish self DNA from foreign DNA.
2) Effects on transcription: These species- and tissue- dependent effects could be due to two potentially opposing consequences of DNA methylation: physical relaxing of the DNA structure, which is conducive to increased gene expression; and the recruitment of 6mA- specific binding proteins (occurs in clusters around the transcriptional start sites), which could either activate or repress gene transcription.
3) Nucleosome positioning: In Tetrahymena thermophila, C. reinhardtii and O. trifallax 6mA is preferentially localized in linker regions between nucleosomes, raising the possibility that this modification could help to direct nucleosome positioning
4) DNA damage control: mutants that lack DNA adenine methyltransferase function have higher mutation rates and are more sensitive to DNA- damaging agents, suggesting that 6mA could protect against DNA damage or affect the DNA repair process
5) Cell cycle regulation:
3. 6mA interact with enhancer and promoter
SATB1, a well-known SIDD-regulating protein, is mainly expressed in developing T cells16, epidermis17, and trophoblast stem cells (TSCs). SATB1 binds to SIDD and then stabilizes the DNA double helix, thereby establishing and maintaining large-scale euchromatin and heterochromatin domains. For example, SATB1 binds directly to key enhancers in pro- and pre-T cells, thereby activating gene expression in these cells while repressing the mature T cell fate.
In a nature papers, they have shown how N6-mA helps to regulate chromatin structure by antagonizing SATB1 at SIDD during early development.(following picture) N6-mA accumulates at the boundaries between euchromatin and heterochromatin and restricts euchromatin regions from spreading, thereby preventing ES cells from adopting a TSC fate.[2]
References
[1] Li Z, Zhao S, Nelakanti RV, et al. N6-methyladenine in DNA antagonizes SATB1 in early development. Nature. 2020;583(7817):625-630. doi:10.1038/s41586-020-2500-9
[2] Kitagawa, Y. et al. Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat. Immunol. 18, 173–183 (2017).
