Details

Autor(en) / Beteiligte

• Adoue, Véronique
• Binet, Bénédicte
• Malbec, Agathe
• Fourquet, Joanna
• Romagnoli, Paola
• van Meerwijk, Joost P.M.
• Amigorena, Sebastian
• Joffre, Olivier P.

Titel

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

Ist Teil von

• Immunity (Cambridge, Mass.), 2019-03, Vol.50 (3), p.629-644.e8

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. [Display omitted] •Setdb1−/− naive CD4+ T cells have exacerbated Th1 priming and unstable Th2 commitment•In Th2 cells, SETDB1 deposits the repressive H3K9me3 mark at a limited set of ERVs•In Th2 cells, the ERVs marked by H3K9me3 behave as Th1 gene cis-regulatory modules•SETDB1 ensures Th2 cell stability by repressing ERVs that control the Th1 gene network Adoue et al. find that the histone methyltransferase SETDB1 ensures T helper cell lineage integrity not by directly controlling genes associated with T helper cell differentiation but rather by repressing a restricted set of endogenous retroviruses that have been co-opted for the regulation of immune genes.