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MicroRNA-26a targets ten eleven translocation enzymes and is regulated during pancreatic cell differentiation

Significance Ten eleven translocation (TET) enzymes are recently identified proteins that mediate DNA demethylation, but their regulation is still unknown. This paper indicates that a microRNA, miR-26a, is able to directly target TETs and then modulate 5-hydroxymethylcytosine levels. Furthermore, regulation of TETs by miR-26a is shown to promote pancreatic cell differentiation both in vitro and in vivo. These results highlight a link between a miRNA, DNA demethylation, and stem/progenitor cell differentiation. It also suggests a potential approach to increase the efficiency of generating pancreatic endocrine cells in vitro through modulating miR-26a. Ten eleven translocation (TET) enzymes (TET1/TET2/TET3) and thymine DNA glycosylase (TDG) play crucial roles in early embryonic and germ cell development by mediating DNA demethylation. However, the molecular mechanisms that regulate TETs/TDG expression and their role in cellular differentiation, including that of the pancreas, are not known. Here, we report that (i) TET1/2/3 and TDG can be direct targets of the microRNA miR-26a, (ii) murine TETs, especially TET2 and TDG, are down-regulated in islets during postnatal differentiation, whereas miR-26a is up-regulated, (iii) changes in 5-hydroxymethylcytosine accompany changes in TET mRNA levels, (iv) these changes in mRNA and 5-hydroxymethylcytosine are also seen in an in vitro differentiation system initiated with FACS-sorted adult ductal progenitor-like cells, and (v) overexpression of miR-26a in mice increases postnatal islet cell number in vivo and endocrine/acinar colonies in vitro. These results establish a previously unknown link between miRNAs and TET expression levels, and suggest a potential role for miR-26a and TET family proteins in pancreatic cell differentiation.