Control of T cell development and function by Protein Arginine Methyltransferase 5

Abstract

Abstract Temporally and spatially regulated gene expression is essential for the development of thymocytes and functional T cells. Gene transcription is controlled, in part, by reversible post-translational modifications (PTM) of histones by epigenetic regulators. In turn, histone PTMs are bound by reader proteins, which mediate transcriptional activation and repression. Together, PTMs and readers enhance or suppress the accessibility of DNA to sequence-specific DNA-binding proteins. Epigenetic mechanisms are often dysregulated in human diseases and are promising targets for cancer treatments and immunotherapy. One such candidate is Protein Arginine Methyltransferase 5 (PRMT5), a type II arginine methyltransferase. PRMT5 catalyzes symmetric dimethylation (Rme2s) of arginines on histones H2A, H3, and H4. Rme2s strongly correlates with transcriptional repression. However, the roles of PRMT5-dependent histone arginine methylation in thymocyte development and T cell activation are poorly understood. Dynamic expression of Prmt5 transcripts suggests that the methyltransferase modulates transcription at select stages in T lymphopoiesis. Previous studies employing hematopoietic system-wide depletion of Prmt5 detected reduced cellularity of T cell progenitor populations, but effects on thymocyte transcriptomes were not determined. Here, we describe consequences of the loss of PRMT5 on T cell progenitor stage-specific transcription. PRMT5 suppresses activities of key transcription factors by regulating DNA accessibility, which in turn prevents inappropriate transcription in thymocytes in vitro and in vivo. Together, our data support a role of PRMT5 as an essential ‘gatekeeper’ of T cell development and function.