TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities

• TET2 regulates mast cell differentiation, cytokine production, and proliferation
• Lack of TET2 leads to extensive changes in transcriptome and 5hmC landscape
• Cell differentiation defects can be compensated for by other TETs
• Cell proliferation depends on TET2 expression, independent of its enzymatic activity

SummaryDioxygenases of the TET family impact genome functions by converting 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC). Here, we identified TET2 as a crucial regulator of mast cell differentiation and proliferation. In the absence of TET2, mast cells showed disrupted gene expression and altered genome-wide 5hmC deposition, especially at enhancers and in the proximity of downregulated genes. Impaired differentiation of Tet2-ablated cells could be relieved or further exacerbated by modulating the activity of other TET family members, and mechanistically it could be linked to the dysregulated expression of C/EBP family transcription factors. Conversely, the marked increase in proliferation induced by the loss of TET2 could be rescued exclusively by re-expression of wild-type or catalytically inactive TET2. Our data indicate that, in the absence of TET2, mast cell differentiation is under the control of compensatory mechanisms mediated by other TET family members, while proliferation is strictly dependent on TET2 expression.

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