Genomic regulation of immune response in neurodegeneration in mice

National Eye Institute

Investigators

Linked publications, trials & patents

Abstract

Cytokine regulation in helper T and innate lymphoid cells (ILCs) is critical to mount a proper immune response for host defense. Dysregulated cytokine secretion leads to autoimmunity. The specification of lymphocyte lineages and their cytokine production relies on dynamic regulation of cis-regulatory elements that involve multi-dimensional epigenetic mechanisms, including DNA methylation, chromatin accessibility, transcription factor binding, histone modification and DNA-DNA interactions that form chromatin loops. Our work explores the development and dynamics of regulomes that control lymphocyte effector function that contribute to immune-related disorders. Lineage-determining transcription factors (LDTFs) shape ILC regulomes during development and prime enhancers at effector genes for rapid immune responses, while signal-regulated transcription factors (SRTFs) are recognized as inducible players to activate primed, accessible enhancers. Our recent work revealed that in addition to their conventional roles, SRTFs can also function as pioneers to unwrap inaccessible chromatins to form de novo enhancers upon natural killer (NK) cell activation, both by cytokine stimulation in vitro and during Toxoplasma gondii infection in vivo (Scium et al., Immunity, 2020). De novo enhancers further recruit LDTFs independent of their motifs, contradicting the previous model that LDTFs always bind to DNA through direct sequence recognition. This study sheds light on the mechanisms that facilitate rapid gene induction in innate immune responses. These findings along with others have been summarized in our recent review article (Fernando et al., Frontiers in Immunology, 2021). ILCs play critical roles in pathogen defense and tissue homeostasis, but our knowledge in their heterogeneity is relatively poor. Recently, our collaborative work with the Scium lab (Sapienza University of Rome) revealed two markers, Granzyme A and CD160, that can delineate ILC1 subsets with distinct effector functions (Di Censo et al., Eur J Immunol. 2021). Unlike NK cells, liver-specific GzmA+CD160- ILC1s require minimal JAK/STAT signals and the transcription factor Nfil3, despite the preservation of cytotoxicity. These findings provide insights for regulation of innate responses and new targets for immunomodulation. Epigenetic modulation is also involved in a variety of biological events. For example, dynamic enhancer landscapes pave the way for neuron development via precise gene regulation. Interestingly, our recent collaborative work with the Ward lab (NINDS) and Nussenzweig lab (NCI) indicates these enhancers are also vulnerable to DNA single-strand breaks, which with defects lead to neurodevelopmental and neurodegenerative diseases (Wu et al., Nature, 2021). Epigenetic imprinting also plays an essential role during fetal development. In collaboration with the Belkaid lab (NIAID), we recently showed that the cytokine IL-6 mediated chromatin remodeling in the fetal intestinal epithelium, in which the mom was infected by a food-borne pathogen Yersinia pseudotuberculosis during pregnancy (Lim et al., Science, 2021). This finding highlights the importance of prenatal immune education. Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are recently appreciated as critical regulators in epigenetic immunomodulation. Previously we have shown a non-coding transcript, Ifng-as1 (also termed NeST) fine-tunes cytokine interferon gamma production during host defense (Petermann et al., Immunity, 2019). Using an engineered mouse model, our recent collaborative work with the OShea lab (NIAMS) revealed roles of miR-221/222 in regulating type 3 helper T (Th17) cells (Mikami et al., Immunity, 2021). Depletion of miR-221/222 up-regulates gene expression of c-Maf, a critical transcription factor for Th17, and the IL-23 receptor, which results in hyper-responsibility to a pro-inflammatory cytokine IL-23 and greater susceptibility of DSS-induced colitis. In sum, our studies in gene regulation have significantly answered important biological questions in the fields of development and immunology. This fundamental knowledge has created new avenues for better disease prevention and treatment.