Stage-specific GATA3 induction promotes ILC2 development after lineage commitment.

Group 2 innate lymphoid cells (ILC2s) are a subset of innate lymphocytes that produce type 2 cytokines, including IL-4, IL-5, and IL-13. GATA3 is a critical transcription factor for ILC2 development at multiple stages. However, when and how GATA3 is induced to the levels required for ILC2 development remains unclear. Herein, we identify ILC2-specific GATA3-related tandem super-enhancers (G3SE) that induce high GATA3 in ILC2-committed precursors. G3SE-deficient mice exhibit ILC2 deficiency in the bone marrow, lung, liver, and small intestine with minimal impact on other ILC lineages or Th2 cells. Single-cell RNA-sequencing and subsequent flow cytometry analysis show that GATA3 induction mechanism, which is required for entering the ILC2 stage, is lost in IL-17RB+PD-1- late ILC2-committed precursor stage in G3SE-deficient mice. Cnot6l, part of the CCR4-NOT deadenylase complex, is a possible GATA3 target during ILC2 development. Our findings implicate a stage-specific regulatory mechanism for GATA3 expression during ILC2 development.

A distal enhancer of GATA3 regulates Th2 differentiation and allergic inflammation.

Asthma is a widespread airway disorder where GATA3-dependent Type-2 helper T (Th2) cells and group 2 innate lymphoid cells (ILC2s) play vital roles. Asthma-associated single nucleotide polymorphisms (SNPs) are enriched in a region located 926-970 kb downstream from GATA3 in the 10p14 (hG900). However, it is unknown how hG900 affects the pathogenesis of allergic airway inflammation. To investigate the roles of the asthma-associated GATA3 enhancer region in experimental allergic airway inflammation, we first examined the correlation between GATA3 expression and the activation of the hG900 region was analyzed by flow cytometry and ChIP-qPCR. We found that The activation of enhancers in the hG900 region was strongly correlated to the levels of GATA3 in human peripheral T cell subsets. We next generated mice lacking the mG900 region (mG900KO mice) were generated by the CRISPR-Cas9 system, and the development and function of helper T cells and ILCs in mG900KO mice were analyzed in steady-state conditions and allergic airway inflammation induced by papain or house dust mite (HDM). The deletion of the mG900 did not affect the development of lymphocytes in steady-state conditions or allergic airway inflammation induced by papain. However, mG900KO mice exhibited reduced allergic inflammation and Th2 differentiation in the HDM-induced allergic airway inflammation. The analysis of the chromatin conformation around Gata3 by circular chromosome conformation capture coupled to high-throughput sequencing (4C-seq) revealed that the mG900 region interacted with the transcription start site of Gata3 with an influencing chromatin conformation in Th2 cells. These findings indicate that the mG900 region plays a pivotal role in Th2 differentiation and thus enhances allergic airway inflammation.

Near falls predict substantial falls in older adults: A prospective cohort study.

AIM: Little is known about the relationship between near falls and substantial falls in older adults. Clarifying this relationship would be helpful to assess fall risk in greater detail. The purpose of the present study was to clarify whether near falls predict future falls. METHODS: This was designed to be a prospective cohort study. Participants were recruited from a community apartment for older adults. After a baseline physical assessment, participants were asked to record the incidence of near falls in a diary for 3 months. After the survey period, participants were followed for 6 months by telephone contact every 2 months. Cox proportional hazards regression models were used to analyze the association between near falls and falls. RESULTS: A total of 60 participants were included in the analysis. During the initial 3 months, 23 participants (38%) experienced near falls. Eight participants (13%) experienced substantial falls during the following 6 months. Cox proportional hazards regression models adjusted for age, body mass index, sex and physical frailty showed that experience of near falls (hazards regression 6.0, 95% confidence intervals 1.1-31.7; P < 0.05) was significantly associated with incidence of future falls. CONCLUSIONS: Experience of near falls among older adults is an independent predictor of substantial falls irrespective of the physical frailty status. Clinicians might need to focus on near falls to appropriately assess the fall risk in older adults. Geriatr Gerontol Int 2017; 17: 1477-1480.