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 T cell differentiation.
• Loss of TET proteins paradoxically upregulates certain genes in iNKT cells.
• This suggests TET proteins may regulate gene suppressors.

Purpose of the Study:

• To investigate the role of TET2 and TET3 in regulating gene expression beyond DNA demethylation.
• To explore the impact of TET2/3 loss on microRNA biogenesis in iNKT cells.
• To uncover a novel layer of TET-mediated gene regulation.

Main Methods:

• Analysis of gene expression changes upon TET2 and TET3 loss.
• Investigation of TET2/3 regulation of Drosha expression and chromatin accessibility.
• Profiling of microRNA expression in iNKT cells lacking TET2/3.

Main Results:

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

Conclusions:

• TET proteins regulate microRNA biogenesis through Drosha.
• This pathway links TET-mediated epigenetic modification to microRNA-based gene silencing.
• Reveals a novel mechanism for TET-dependent regulation of iNKT cell differentiation.