MicroRNA-29b/Tet1 regulatory axis epigenetically modulates mesendoderm differentiation in mouse embryonic stem cells

Abstract

Ten eleven translocation (Tet) family-mediated DNA oxidation on 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) represents a novel epigenetic modification that regulates dynamic gene expression during embryonic stem cells (ESCs) differentiation. Through the role of Tet on 5hmC regulation in stem cell development is relatively defined, how the Tet family is regulated and impacts on ESCs lineage development remains elusive. In this study, we show non-coding RNA regulation on Tet family may contribute to epigenetic regulation during ESCs differentiation, which is suggested by microRNA-29b (miR-29b) binding sites on the Tet1 3′ untranslated region (3′ UTR). We demonstrate miR-29b increases sharply after embyoid body (EB) formation, which causes Tet1 repression and reduction of cellular 5hmC level during ESCs differentiation. Importantly, we show this miR-29b/Tet1 regulatory axis promotes the mesendoderm lineage formation both in vitro and in vivo by inducing the Nodal signaling pathway and repressing the key target of the active demethylation pathway, Tdg. Taken together, our findings underscore the contribution of small non-coding RNA mediated regulation on DNA demethylation dynamics and the differential expressions of key mesendoderm regulators during ESCs lineage specification. MiR-29b could potentially be applied to enrich production of mesoderm and endoderm derivatives and be further differentiated into desired organ-specific cells.

Decrease in Lymphoid Specific Helicase and 5-hydroxymethylcytosine Is Associated with Metastasis and Genome Instability

“…A combined approach involving assessment of miR expression (using microarrays) and bioinformatic prediction of miR targets has revealed that distinct miR signatures fine-tune each step of malignancies; in turn, miRs that target critical suppressors could act as powerful proto-oncogenes. Several miRs, including miR-22, miR-29b and miR-26a, exert control by negatively regulating TET protein levels in mouse and human 45 - 47 . In this study, we demonstrated that both miR-26b-5p and miR-29c-5p silenced TET2 expression, whereas LSH was not recruited to the promoters of TET2 and TET3, providing a novel finding that LSH upregulated TET2 expression by silencing the expression levels of miRs.…”

Long‐term high altitude hypoxia during gestation suppresses large conductance Ca2+‐activated K+ channel function in uterine arteries: a causal role for microRNA‐210

“…; Tu et al . ). The reciprocal changes of miR‐210 and TET1 in uterine arteries of hypoxic animals suggest that miR‐210 may negatively regulate TET1 expression.…”

MiR-29b/TET1/ZEB2 signaling axis regulates metastatic properties and epithelial-mesenchymal transition in breast cancer cells

“…There have been many studies on miR-29b/TET1 being clearly associated with cell development [ 47 ]. In one study, Tu et al found that miR-29b regulation of TET1 contributed to epigenetic regulation during ESC differentiation [ 48 ]. In another study, Morita et al reported that miR-29b directly inhibited TET1 to repress the activity of DNA demethylases [ 49 ].…”