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Principal Investigator: Ye Zheng
Organization: SALK INSTITUTE FOR BIOLOGICAL STUDIES
Fiscal Year: 2024
Award: $237,500
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Regulatory T cells (Treg) play a crucial role in keeping the immune system in balance and preventing
autoimmune disease. Defective Treg function leads to autoimmune diseases, while intra-tumor Tregs can block
effective anti-tumor immune responses. Tregs can undergo further specialization in adaptation to their tissue
microenvironment. Recent studies showed that a unique RORgt (retinoic acid–related orphan receptor gamma
t) expressing Treg cell population could be induced in the colon lamina propria. These RORgt+ Tregs play an
important role in the suppression of colon inflammation. In Treg cells, REV-ERBa is highly expressed in RORgt+
colonic Tregs, but not in RORgt- colonic Tregs or spleen Tregs. Mice with Treg-specific deletion of REV-ERB
were more susceptible to TNBS-induced colitis with decreased RORgt+ Treg cells and increased Th1/Th17 cell-
mediated inflammation in the colon. RNA-sequencing experiment showed that the expression of a set of genes
related to Treg function, including CTLA-4, IL-10, and c-Maf, were reduced in REV-ERB deficient colonic Tregs
compared to WT controls. To study the mechanism of gene regulation by REV-ERB in Tregs, Dr. Zheng’s lab
performed Cut & Run assays with WT RORgt+ iTregs using Foxp3, REV-ERBa, and RORgt antibodies to map
their binding peaks genome-wide. The results showed a significant overlap of the binding peaks of these 3
transcription factors, suggesting coordination in gene regulation among Foxp3, REV-ERB, and RORgt in Treg
cells. The overall objective of the proposed study is to define the role of REV-ERB in Treg function. This goal will
be accomplished by dissecting the molecular mechanism of REV-ERB function in RORgt+ Treg cells (Aim 1),
and characterizing the role of REV-ERB in Treg in mouse models of IBD (Aim 2). The outcomes of the proposed
study are expected to reveal the functional and mechanistic role of REV-ERB in RORgt+ Tregs. Such results are
expected to further advance our understanding of how the identity and function of RORgt+ Tregs are established
and maintained. Additionally, this study will provide key insights into how transcriptional repressor such as REV-
ERB serves as key regulator and tune the function of transcriptional activators in Treg cells. Finally, the outcomes
of this study could provide evidence supporting the development of therapeutics targeting REV-ERB for IBD
treatment.
Terms: <ATRA><Agonist><Antibodies><Assay><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Binding><Bioassay><Biological Assay><Body Tissues><Brittle Diabetes Mellitus><CD152><CD152 Antigen><CD152 Gene><CSIF><CSIF-10><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><CUT&RUN><Cell Body><Cell Function><Cell Lineage><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Colon><Colonic inflammation><Cytokine Synthesis Inhibitory Factor><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Data><Development><Disseminated Sclerosis><E2A Immunoglobulin Enhancer Binding Factor E12><E2A Immunoglobulin Enhancer Binding Factor E47><Equilibrium><FOXP3><FOXP3 gene><Family><Forkhead Box P3><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Goals><Homeostasis><Human><IDDM><IL-10><IL10><IL10A><Immune system><Immunoglobulin Transcription Factor 1><Immunosuppressants><Immunosuppressive Agents><Immunosuppressive drug><Immunosuppressive treatment><Inflammation><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Insulin-Dependent Diabetes Mellitus><Interleukin 10 Precursor><Interleukin-10><JM2><Juvenile-Onset Diabetes Mellitus><KO mice><Kappa-E2-Binding Factor><Ketosis-Prone Diabetes Mellitus><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Lamina Propria><Lead><Link><Lymphoproliferative Disorders><Maintenance><Maps><Mediating><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Multiple Sclerosis><Murine><Mus><NGS Method><NGS system><Nuclear Hormone Receptor Superfamily><Nuclear Hormone Receptors><Nuclear Receptors><Null Mouse><Orphan><Outcome><Outcome Study><Pb element><Physiological Homeostasis><Play><Population><Predisposition><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Receptor Inhibition><Receptor Protein><Regulatory T-Lymphocyte><Repression><Research><Retinoic Acid><Role><SCURFIN><Side><Spleen><Spleen Reticuloendothelial System><Subcellular Process><Sudden-Onset Diabetes Mellitus><Susceptibility><T-Cells><T-Lymphocyte><T1 DM><T1 diabetes><T1D><T1DM><TNBS colitis><TNBS mice><TNBS model><TNBS mouse model><TNBS-induced colitis><Testing><Tissues><Trans Vitamin A Acid><Transcription><Transcription Activator><Transcription Coactivator><Transcription Factor 3><Transcription Factor Coactivator><Transcription Factor E2-Alpha><Transcription Factor Proto-Oncogene><Transcription Repressor><Transcription factor genes><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Transcriptional Repressor><Treg><Tretinoin><Tretinoinum><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Vitamin A Acid><Work><all-trans-Retinoic Acid><all-trans-Vitamin A acid><anti-tumor immune response><autoimmune condition><autoimmune disorder><autoimmunity disease><balance><balance function><colitis mouse model><colitis murine model><conditional knock-out><conditional knockout><cytotoxic T-lymphocyte antigen 4><developmental><experiment><experimental research><experimental study><experiments><genetic repressor><genome scale><genome-wide><genomewide><heavy metal Pb><heavy metal lead><immune suppressive agent><immune suppressor><immunopathology><immunosuppressive substance><immunosuppressor><in vivo><in vivo Model><inflamed colon><inflammatory disease of the intestine><inflammatory disorder of the intestine><insight><insular sclerosis><insulin dependent diabetes><insulin dependent type 1><intestinal autoinflammation><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><loss of function mutation><lymphoproliferative disease><member><mouse colitis><mouse model><murine colitis><murine model><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><next gen sequencing><next generation sequencing><nextgen sequencing><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><prevent><preventing><protective effect><receptor><receptor function><regulatory T-cells><social role><therapeutic agent development><therapeutic development><therapeutic target><thymus derived lymphocyte><trans-Retinoic Acid><transcription co-activator><transcription factor><transcriptional co-activator><transcriptome sequencing><transcriptomic sequencing><trinitrobenzene sulfonic acid colitis><trinitrobenzene sulfonic acid induced colitis><trinitrobenzene sulfonic acid induced mouse model><trinitrobenzene sulfonic acid model><trinitrobenzene sulfonic acid mouse model><type I diabetes><type one diabetes>