Indiana University-Purdue University Indianapolis (IUPUI) / The immune system provides resistance to the myriad of pathogens in the
environment, but can also respond inappropriately causing allergic inflammation and
autoimmune disease. CD4+ T cells, which play a crucial role in adaptive immune system,
can be divided into several subsets based on their effector functions. T helper 9 (Th9)
cells, derived by the IL-4/STAT6 and TGF-β signaling pathways, produce IL-9 as a
hallmark cytokine, as well as IL-10. Through IL-9 production, Th9 cells protect against
parasite infection but are also involved in allergic inflammation and autoimmune diseases.
Transcription factors that promote Th9 development include STATs, PU.1, BATF, and
IRF4. In this study, we identify ETV5 as a factor that promotes IL-9 and IL-10 production
by binding to cis-acting regulatory elements in the respective genes. At the Il9 gene, ETV5
cooperates with PU.1 in regulating gene expression. At the Il10 gene, ETV5 facilitates
binding of other transcription factors to the locus. These studies and others suggested that
there may be additional cis-acting regulatory elements in the Il9 gene. We demonstrate
that a conserved noncoding sequence (CNS) located 25 kb upstream of the Il9
transcription start site, termed Il9 CNS-25, is critical for regulating Il9 expression in Th cell
subsets. Th9 cells derived from Il9 CNS-25 mutant (Il9 ΔCNS-25) mice produce significantly
less IL-9. Il9 CNS-25 promoted chromatin modifications at the promoter and accessibility
of the locus. Il9 ΔCNS-25 mice showed attenuated airway inflammation compared to control
mice. The Il9 CNS-25 region in mice is conserved with an IL9 CNS-18 region in the human
genome. We deleted CNS-18 in primary human Th9 cells and observed diminished IL-9
production. Thus, we have identified transcription factors that regulate multiple cytokines in Th cell lineages and have demonstrated that the Il9 CNS-25/IL9 CNS-18 elements are
respectively critical for Il9/IL9 gene expression.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/16281 |
| Date | 15 December 2017 |
| Creators | Koh, Byunghee |
| Contributors | Kaplan, Mark H., Zhou, Baohua, Blum, Janice S., Harrington, Maureen A. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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