Pro-inflammatory lymphocytes are key cells in the immune system that are specialized in combating bacterial, viral, and fungal infections. While critical to immunity, their dysregulated function has been implicated in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Understanding the gene regulatory networks that distinguish healthy versus pathogenic immune responses will inform novel approaches for therapeutic interventions in disease. To this end, we integrate global regulatory information from genetic mouse models and primary human samples to identify and characterize the regulators that govern the development, plasticity, and pathogenicity of inflammatory immune responses.
Regulation of functional plasticity in inflammation
Pro-inflammatory lymphocytes have tremendous plasticity and can undergo functional conversion into either pathogenic or regulatory/anti-inflammatory effector subclasses. Harnessing this attribute holds enormous potential to control the trajectory of inflammatory disease. Using a combination of genetic fate-mapping approaches in mice to track cellular transitions, and integrative regulatory network analyses, we have begun to identify the regulators that mediate such plastic switches (Carr T, et al, Nature Communications, 2017; Zuberbuehler MK et al, Nature Immunology, 2019). Funding provided by NIH/NIGMS.
Contribution of non-coding variation to autoimmune disease
Genome wide association (GWA) studies have identified numerous single nucleotide polymorphisms (SNP) in the non-coding genome that are associated with enhanced risk of disease. Major challenges include identifying the causal SNP in disease, its bone fide gene target, and the mechanism of dysregulation. We are addressing these challenges using a combination of global chromatin confirmation capture (Hi-C, Hi-ChIP), enhancer landscape profiling (ATAC-seq, ChIP-seq), and expression profiling of pathogenic T cells in patients with multiple sclerosis. Funding provided by the National Multiple Sclerosis Society.
Contribution of non-coding variation to schizophrenia
Similar to the autoimmune disease (see above) and other common disorders, GWA and whole exome sequencing studies for schizophrenia points to noncoding variation as contributing to disease risk. We have performed extensive chromatin accessibility mapping using ATAC-seq on 100's on postmortem brain samples from schizophrenia cases and controls (Bryois et al., Nature Neuroscience, 2018). While we do not detect chromatin accessibility differences between cases and controls, we do find that heritability enrichment for the disorder is much higher in the regulatory elements we have identified. To followup these studies, we are performing high-throughput STARR-seq reporter and high-throughput CRISPR genome editing screens to narrow down causal risk elements and variants. Funding provided by the National Institute of Mental Health, and Open Philanthropy.
Contribution of non-coding variation to rare recessive disorders
The majority of rare recessive disorders are due to pathogenic coding variants. However, there are many patients that display a clear phenotypic and biochemical diagnosis, but the genetic testing is inconclusive where only one pathogenic variant is detected on one allele. We have identified a number of patients with these types of inconclusive genetic testing, and will search for novel splicing, structural, and noncoding pathogenic variants. Funding provided by the National Human Genome Research Institute.