Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus

Figures & data

Figure 1 Upstream regulator and direct downstream target of PDX-1. The figure highlights the central role of PDX-1 in the pancreas. Extracellular factors (Fgf2 and activin) derived from the notochord and intracellular factors (transcription factors Foxa2 and Hnf6) synergistically activate the expression of PDX-1 in the primitive intestinal endoderm.

Abbreviations: Hnf6, transcription factor one cut homeobox 1; Fgf2, fibroblast growth factor 2; Pax4, paired box protein 4.

Table 1 Correlations Between DNA Methylation of the Proximal and Distal Promoters as Well as Enhancer Regions of PDX-1 and Gene Expression in Human Donors

CpG Sites of PDX-1 with Increased DNA Methylation	PDX-1 Gene Expression Decreased P value
Proximal promoter
−90	0.0046
−100	0.042
Distal promoter
−567	0.010
−746, −741	0.047
−799	0.043
−857, −852	0.048
Enhancer
−3321	0.0022
−3342	0.00034
−3373	0.00047
−3408, −3404	0.00081
−3420, −3416	0.00065
−3479	0.0026
−3496	0.00022
−3504, −3502	0.0047
−3543	0.0000029

Note: P value means T2DM compared with nondiabetic islets.

Figure 2 The cytosine methylation and demethylation system. 5methyl cytosine (5mC) is generated by the action of DNA methyltransferases (DNMTs). In specific contexts, likely driven by tissue-specific DNA-binding transcription factors, selected 5 mC residues are oxidized by TET enzymes to produce 5hmC (5-hydroxymethyl cytosine), which can be further oxidized to 5 fC (5-formyl cytosine) and 5caC (5-carboxy cytosine). Alternatively, 5fC and 5caC can be excised by thymidine DNA glycosylase (TDG) and repaired by the base excision repair mechanism to cytosine.