MicroRNA Let-7adf in Tet regulation

In our recent work [1], we examined let-7adf to understand pathways that a cell uses to respond to inflammatory signaling. We know myeloid cells are critical to Tet2-mediated IL-6 inhibition. The action of Tet2 is in myeloid cells because a conditional KO and a global KO of Tet2 have similar effects. Our work adds to the previous work [2], which revealed that myeloid cell-specific Tet2-deficient mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis and displayed a more severe inflammatory phenotype than WT mice, with exacerbated colon inflammation including higher production of IL-6. In this work, we discovered a novel regulatory control of Tet2 by let-7adf. Although functional roles of Tet2 in macrophages have been extensively studied, the knowledge of how Tet2 is precisely regulated has been limited. The questions regarding the complicated network of regulation of Tet2 through interaction with the let-7 miR remain open and will be an area of significant interest. The posttranscriptional effectors engaged in the regulation of gene expression, including RNA-binding proteins and other non-coding RNAs, can affect miR-mediated gene regulation. For instance, Lin28 RNA binding protein blocks biogenesis of let-7 miRs [3] and the H19 long non-coding RNA acts as a molecular sponge for the let-7 family of miRs [3]. We would speculate that either Lin28 or H19 might control Tet2 through regulating behavior of let-7 in activated macrophages.