Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Helmin, K. A.; Morales-Nebreda, L.; Torres Acosta, M. A.; Anekalla, K. R.; Chen, S.-Y.; Abdala-Valencia, H.; Politanska, Y.; Cheresh, P.; Akbarpour, M.; Steinert, E. M.; Weinberg, S. E.; Singer, B. D.

doi:10.1101/2020.02.03.926949

bioRxiv · 10.1101/2020.02.03.926949

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Helmin, K. A.·Morales-Nebreda, L.·Torres Acosta, M. A.·Anekalla, K. R.·Chen, S.-Y.·Abdala-Valencia, H.·Politanska, Y.·Cheresh, P.·Akbarpour, M.·Steinert, E. M.·Weinberg, S. E.·Singer, B. D.

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Abstract

Regulatory T (Treg) cells require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Treg cells persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg cell lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator Uhrf1 is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3+ cells resulted in global yet non-uniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg cell lineage, spontaneous inflammation, and enhanced tumor immunity. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg cell genome for both lineage establishment and stability of identity and suppressive function.

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Helmin, K. A., Morales-Nebreda, L., Torres Acosta, M. A., Anekalla, K. R., Chen, S.-Y., Abdala-Valencia, H., Politanska, Y., Cheresh, P., Akbarpour, M., Steinert, E. M., Weinberg, S. E., Singer, B. D.. 2020-02-04. Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function. https://doi.org/10.1101/2020.02.03.926949

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