Discrete Roles for Histone Acetylation in Human T Helper 1 Cell-specific Gene Expression

Abstract

To better understand the control of T helper (T H ) 1-expressed genes, we compared and contrasted acetylation and expression for three key genes, IFNG, TBET, and IL18RAP and found them to be distinctly regulated. The TBET and the IFNG genes, but not the IL18RAP gene, showed preferential acetylation of histones H3 and H4 during T H 1 differentiation. Analysis of acetylation of specific histone residues revealed that H3(Lys-9), H4(Lys-8), and H4(Lys-12) were preferentially modified in T H 1 cells, suggesting a possible contribution of acetylation of these residues for induction of these genes. On the other hand, the acetylation of IL18RAP gene occurred both in T H 1 and T H 2 cells with the similar kinetics and on the same residues, demonstrating that selective histone acetylation was not universally the case for all T H 1-expressed genes. Histone H3 acetylation of IFNG and TBET genes occurred with different kinetics, however, and was distinctively regulated by cytokines. Interleukin (IL)-12 and IL-18 enhanced the histone acetylation of the IFNG gene. By contrast, histone acetylation of the TBET gene was markedly suppressed by IL-4, whereas IL-12 and IL-18 had only modest effects suggesting that histone acetylation during T H 1 differentiation is a process that is regulated by various factors at multiple levels. By treating Th2 cells with a histone deacetylase inhibitor, we restored histone acetylation of the IFNG and TBET genes, but it did not fully restore their expression in T H 2 cells, again suggesting that histone acetylation explains one but not all the aspects of T H 1-specific gene expression.

Acetylation of Retinal Histones in Diabetes Increases Inflammatory Proteins

“…Chung and colleagues found that the acetylation of histone H3K9 recruited NF-B inducing kinase to promoters of proinflammatory genes such as IL-6, IL-8, and COX-2 (41, 42). Morinobu et al showed that acetylation of histone H3K9, H3K8, and H4K12 contributes to the preferential induction of IFN-␥ and T-bet genes in T helper cells (43). These results support the hypothesis that acetylation of histones participates in the regulation of inflammatory responses.…”

Histone deacetylases and the immunological network: implications in cancer and inflammation

“…Interestingly, when Th2 cells are treated with HDI, the acetylation status of both genes is recovered even though their gene expression is not restored, suggesting a more complex mechanism involved in Th1/Th2 differentiation (Morinobu et al, 2004). A similar mechanism regulates the IL-4 gene locus in T-cell differentiation.…”

cAMP-responsive Element Modulator (CREM)α Protein Induces Interleukin 17A Expression and Mediates Epigenetic Alterations at the Interleukin-17A Gene Locus in Patients with Systemic Lupus Erythematosus

“…Subsequently, cells were expanded in a new flask for another 3 days with replenished IL-12 (Th1), IL-4 (Th2), and IL-21/TGF␤ (Th17) without any antibodies (30,31). Differentiation experiments were performed individually with naïve T cells from single blood donors.…”

“…Because our findings suggest a role for CREM␣ in transcriptional control of the IL17A gene, we analyzed CREM␣ involvement in T helper (Th) cell differentiation by addition of specific cytokines and antibodies priming toward a Th1 (IL-12 and anti-IL-4), Th2 (IL-4 and anti-IFN␥), and Th17 (TGF␤ and IL-21) cell fate decision (29,30). Compared with Th1 and Th2 conditions, CREM␣ binding to CRE site (Ϫ111/Ϫ104) was significantly increased in Th17 differentiated cells (Fig.…”