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Cxxc finger protein 1 maintains homeostasis and function of
Abstract:
Abstract:
Aging is accompanied by homeostatic and functional dysregulation of multiple immune cell subsets. Group 3 innate lymphoid cells (ILC3s) constitute a heterogeneous cell population that plays pivotal roles in intestinal immunity. In this study, we found that ILC3s in aged mice exhibited dysregulated homeostasis and function, leading to bacterial and fungal infection susceptibility. Moreover, our data revealed that the enrichment of the H3K4me3 modification in effector genes of aged gut CCR6+ ILC3s was specifically decreased compared to young mice counterparts. Disruption of Cxxc finger protein 1 (Cxxc1) activity, a key subunit of H3K4 methyltransferase, in ILC3s led to similar aging-related phenotypes. An integrated analysis revealed Kruppel-like factor 4 (Klf4) as a potential Cxxc1 target. Klf4 overexpression partially restored the differentiation and functional defects seen in both aged and Cxxc1-deficient intestinal CCR6+ ILC3s. Therefore, these data suggest that targeting intestinal ILC3s may provide strategies to protect against age-related infections.
Aging is accompanied by homeostatic and functional dysregulation of multiple immune cell subsets. Group 3 innate lymphoid cells (ILC3s) constitute a heterogeneous cell population that plays pivotal roles in intestinal immunity. In this study, we found that ILC3s in aged mice exhibited dysregulated homeostasis and function, leading to bacterial and fungal infection susceptibility. Moreover, our data revealed that the enrichment of the H3K4me3 modification in effector genes of aged gut CCR6+ ILC3s was specifically decreased compared to young mice counterparts. Disruption of Cxxc finger protein 1 (Cxxc1) activity, a key subunit of H3K4 methyltransferase, in ILC3s led to similar aging-related phenotypes. An integrated analysis revealed Kruppel-like factor 4 (Klf4) as a potential Cxxc1 target. Klf4 overexpression partially restored the differentiation and functional defects seen in both aged and Cxxc1-deficient intestinal CCR6+ ILC3s. Therefore, these data suggest that targeting intestinal ILC3s may provide strategies to protect against age-related infections.
The big questions
The big questions
Which immune cell population(s) contributes significantly to intestinal homeostasis that is dysregulated during aging?
What are the key regulatory factors maintaining such population(s)?
Major discoveries
Major discoveries
Aged mice exhibited a diminished CCR6+ ILC3 population, leading to increased susceptibility to bacterial and fungal infection, due to attenuated ability to secrete IL-22 and IL-17A
Cxxc1 promotes CCR6+ ILC3s by maintaining H3K4me3 on their effector genes, including a direct target, Klf4.
My contributions
My contributions
Leading in formal integrative analysis of single-cell RNA-seq data and ChIP-seq data
Contributed to manuscript writing
Future directions
Future directions
Exploring potential interacting partners with CCR6+ ILC3s in the intestines that may collectively form an aging-dependent homeostasis-maintaining microenvironment
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