TET proteins regulate Drosha expression and impact microRNAs in iNKT cells

Area of Science:

• Immunology
• Epigenetics
• Molecular Biology

Background:

• TET2 and TET3 are DNA demethylases crucial for invariant natural killer T (iNKT) cell differentiation.
• Loss of TET2/3 paradoxically upregulates several genes in iNKT cells, suggesting regulation of gene suppressors.

Purpose of the Study:

• To investigate the mechanism behind TET2/3-mediated gene regulation in iNKT cells.
• To explore the role of TET2/3 in microRNA biogenesis and its impact on iNKT cell differentiation.

Main Methods:

• Analysis of gene expression changes upon TET2 and TET3 loss in iNKT cells.
• Chromatin immunoprecipitation and 5-hydroxymethylcytosine (5hmC) profiling to assess TET protein activity.
• Investigation of microRNA expression, including the Let-7 family, and their targets.

Main Results:

• TET2 and TET3 synergistically regulate Drosha expression via DNA demethylation and chromatin accessibility.
• Loss of TET2/3 leads to downregulation of specific microRNAs, including the Let-7 family.
• Downregulated Let-7 microRNAs normally suppress PLZF, an iNKT cell lineage specifying factor.

Conclusions:

• TET proteins regulate microRNA biogenesis through Drosha, adding a new layer to TET-mediated gene expression control.
• This pathway links TET-mediated epigenetic regulation to microRNA-based control of iNKT cell differentiation.