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Principal Investigator: Jorge Henao-Mejia
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $645,276
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Group 1, 2, and 3 innate lymphoid cells (ILC1, ILC2, and ILC3) are immune effector cells that contribute to tissue
homeostasis and host defense against nearly all classes of pathogens, but their dysregulation also play key roles
in prevalent diseases such as cancer, obesity, asthma, and colitis. The transcription factor (TF) networks that
control the development and functions of the different groups of ILC have recently been identified. Yet how the
chromatin accessibility landscape and the 3-dimensional (3D) genome architecture determine the development,
homeostasis, and effector functions of ILC is largely unknown. Thus, the overarching goal of this proposal is
to uncover how the 3D genomic and epigenetic architecture regulate the development of each ILC subset
and to the development of allergic airway inflammation. It is now well-stablished that the transcriptional
repressor Id2 determines the commitment and identity of the ILC lineage. As such, Id2 expression is now
considered a hallmark of all ILC subsets in mice and humans. Our preliminary data indicates that Id2 expression
is controlled in ILC1, but not ILC2 or ILC3, by specific long-range DNA interacting loops between specific distal
cis-regulatory elements (cis-RE) and the Id2 promoter. Moreover, we showed that ablation of these promoter-
cis-RE interactions in mice leads to a dramatic reduction in ILC1 in multiple tissues, while the development and
functions of ILC2 and ILC3 were unaltered. Thus, our findings indicate for the first time that Id2 expression is
regulated by long-range DNA interacting loops between the Id2 promoter and distal cis-RE in an ILC-subset
specific manner. Moreover, it indicates that ablating these cis-RE is a powerful strategy to generate genetic tools
to study the roles of each ILC subset in the context of an otherwise intact immune system. Yet how the chromatin
accessibility landscape and the 3D genomic architecture determines Id2 expression specifically in ILC2 and ILC3
remains unknown. Thus, in aims 1 and 2 of this project, we will use novel genetic tools that we generated, single
cell sequencing technologies, and HiC to elucidate how chromatin folding and accessibility determine the
development and functions of ILC2 and ILC3 through the regulation of Id2 expression. In aim 3, we will exploit
the specificity of these regulatory mechanisms to study the functions of ILC2 during allergic airway inflammation
in the context of an otherwise intact immune system. Collectively, these studies will answer the long-standing
question of how Id2 expression is controlled to drive the ILC fate. Moreover, it will generate an atlas of the 3D
genomic landscape of each ILC subset, which
that
will allow us to identify unknown non-coding regulatory regions
are critical for the function and development ILC1, ILC2, and ILC3.Importantly, through the identification of
specific regulatory mechanisms in each ILC subset, we have created novel mouse genetic tools to study the
functions of each group of ILC in the context of an otherwise intact immune system, which might unveil novel
therapeutic approaches to target ILC during inflammatory disorders.
Terms: <3-D><3-Dimensional><3C-based approach><3C-based assay><3C-based method><3C-based strategy><3C-based technique><3C-based technology><3D><Ablation><Address><Allergens><Allergic><Allergic inflammation><Architecture><Asthma><Atlases><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Binding><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Bronchial Asthma><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cancers><Cell Growth and Maintenance><Cell Lineage><Cell Maintenance><Chromatin><Colitis><DNA><Data><Data Set><Defect><Deoxyribonucleic Acid><Development><Disease><Disorder><Distal><Effector Cell><Engineering / Architecture><Enhancers><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Fetal Liver><Functional RNA><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic><Genetic Transcription><Genome><Genomic Segment><Genomics><Goals><Homeostasis><Host Defense><Human><Immune><Immune response><Immune system><Immunes><Immunological response><Inflammatory><Innate Immune System><Lung><Lung Respiratory System><Lymphoid Cell><Malignant Neoplasms><Malignant Tumor><Metabolic><Mice><Mice Mammals><Modern Man><Molecular Interaction><Mouse Strains><Murine><Mus><Names><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleic Acid Regulator Regions><Nucleic Acid Regulatory Sequences><Obesity><Pathology><Physiological Homeostasis><Play><Population><Process><Progenitor Cells><RNA Expression><Regulation><Regulatory Element><Regulatory Regions><Role><Single cell seq><Specificity><T4 Cells><T4 Lymphocytes><Technology><Testing><Time><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription Repressor><Transcription factor genes><Transcriptional Repressor><Untranslated RNA><adiposity><allergen response><allergic airway epithelium inflammation><allergic airway inflammation><allergic response><allergy response><chromatin conformation capture><chromosome capture><chromosome conformation capture><corpulence><developmental><epigenetically><genetic regulatory element><genetic repressor><genome segment><genomic region><histone modification><host response><immune system response><immunoresponse><malignancy><mouse genetics><mouse model><murine model><name><named><naming><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><noncoding><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathogen><promoter><promotor><pulmonary><scATAC sequencing><scATAC-seq><scRNA-seq><single cell ATAC-seq><single cell ATAC-sequencing><single cell Assay for Transposase Accessible Chromatin sequencing><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell next generation sequencing><single cell sequencing><single cell sequencing assay for transposase accessible chromatin><single cell transcriptomic profiling><single-cell Assay for Transposase-Accessible Chromatin with sequencing><single-cell RNA sequencing><single-cell assay for transposase-accessible chromatin using sequencing><single-cell assay for transposase-accessible chromatin-seq><social role><stem cells><three dimensional><tissue repair><tool><transcription factor>