SETDB1 controls T helper cell lineage integrity by repressing endogenous retroviruses

Upon activation, naïve CD4 T cells differentiate into distinct helper or regulatory T cell subsets depending on environmental signals received. This process relies on complex and lineage-specific gene expression programs, whose dynamics and stability are regulated at the level of the chromatin. The epigenetic pathways involved remain, however, largely unknown. Here, we report that the histone methyltransferase SETDB1 critically controls the Th1 gene expression program. Indeed, SETDB1-deficient naïve CD4 T cells show exacerbated Th1 priming, and when exposed to a Th1-instructive signal, SETDB1-deficient Th2 cells cross lineage boundaries and transdifferentiate into Th1 cells. Surprisingly, SETDB1 does not appear to directly control Th1 gene promoter activity. Instead, it deposits the repressive H3K9me3 mark at a restricted and cell type-specific set of endogenous retroviruses (ERVs) located in the vicinity of genes involved in immune processes. Refined bioinformatic analyses indicated that these retrotransposons either repress Th1 gene cis-regulatory elements or behave themselves as Th1 gene enhancers. In conclusion, H3K9me3 deposition by SETDB1 ensures T helper cell lineage integrity by repressing a repertoire of ERVs that have been exapted into cis-regulatory modules to shape and control the Th1 gene network. Overall design: Transcriptomic and epigenetic data for WT, Setdb1-/- and Suv39h1-/- mice T lymphocytes subsets