The Histone Methyltransferase SETDB1 Controls T Helper Cell Lineage Integrity by Repressing Endogenous Retroviruses.

Upon activation, naive CD4+ T cells differentiate into distinct T cell subsets via processes reliant on epigenetically regulated, lineage-specific developmental programs. Here, we examined the function of the histone methyltransferase SETDB1 in T helper (Th) cell differentiation. Setdb1-/- naive CD4+ T cells exhibited exacerbated Th1 priming, and when exposed to a Th1-instructive signal, Setdb1-/- Th2 cells crossed lineage boundaries and acquired a Th1 phenotype. SETDB1 did not directly control Th1 gene promoter activity but relied instead on deposition of 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 suggest that these retrotransposons regulate Th1 gene cis-regulatory elements or act as Th1 gene enhancers. Thus, H3K9me3 deposition by SETDB1 ensures Th 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.

Surveillance of Retroelement Expression and Nucleic-Acid Immunity by Histone Methyltransferase SETDB1.

In human cancers, histone methyltransferase SETDB1 (SET domain, bifurcated 1) is frequently overexpressed but its significance in carcinogenesis remains elusive. A recent study shows that SETDB1 downregulation induces de-repression of retroelements and innate immunity in cancer cells. The possibility of SETDB1 functioning as a surveillant of retroelement expression is discussed in this study: the cytoplasmic presence of retroelement-derived nucleic acids (RdNAs) drives SETDB1 into the nucleus by the RNA-interference route, rendering the corresponding retroelement transcriptionally inert. These RdNAs could, therefore, be signals of genome instability sent out for SETDB1 present in the cytoplasm to maintain genome integrity.

The pleiotropic roles of EZH2 in T-cell immunity and immunotherapy.

EZH2 is a histone methyltransferase. It catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3) to control gene transcription critical for cell proliferation, differentiation, expansion, and function. For instance, EZH2 plays a central role in regulating T-cell immune responses. EZH2 restrains terminal differentiation of effector CD8 T cells, promotes formation of precursor and mature memory CD8 T cells, regulates appropriate lineage-specification and identity maintenance of helper CD4 T cells, and maintains survival of differentiated antigen-specific T cells. Most importantly, EZH2 is shown to be important for reinvigoration of exhausted chimeric antigen receptor (CAR) T cells. Dysregulated EZH2 function has been linked to many forms of cancer, including lymphomas and solid tumors. In B-cell lymphoid malignancies, EZH2 is overexpressed to drive tumorigenesis. These specific effects of EZH2, in the context of its roles in catalyzing H3K27me3 and orchestrating gene transcription programs in both normal and malignant cells, establishes EZH2 as a unique target for drug development. Here, we will discuss Ezh2 regulation of T-cell immunity, EZH2-mediated lymphomagenesis, and therapeutic benefits of EZH2 inhibitors to the treatment of lymphoma.