Event
BIOE Seminar: Inference of immune regulatory mechanisms from scRNA-seq and scATAC-seq
Friday, April 4, 2025
9:00 a.m.-10:00 a.m.
A. James Clark Hall, Room #2121
Alex Xu
alexmxu@umd.edu
Emily Miraldi
Associate Professor, Cincinnati Children’s Hospital
Inference of immune regulatory mechanisms from scRNA-seq and scATAC-seq
Abstract
Inflammatory Bowel Disease (IBD) is a chronic and often debilitating autoinflammatory condition, with an increasing incidence in children. Standard-of-care therapies lead to sustained transmural healing and clinical remission in fewer than one-third of patients. For children, TNF inhibition remains the only FDA-approved biologic therapy, providing an even greater urgency to understanding mechanisms of response. Genome-wide association studies (GWAS) have identified 420 independent genetic risk loci contributing to IBD, yet the majority are noncoding and their mechanisms of action are difficult to decipher. If causal, they likely alter transcription factor (TF) binding and downstream gene expression in particular cell types and contexts. To bridge this knowledge gap, we built a novel resource: multiome-seq (tandem single-nuclei (sn)RNA-seq and chromatin accessibility (snATAC)-seq) of intestinal tissue from pediatric IBD patients, where anti-TNF response was defined by endoscopic healing. From the snATAC-seq data, we generated a first-time atlas of chromatin accessibility (putative regulatory elements) for diverse intestinal cell types in the context of IBD. For cell types/contexts mediating genetic risk, we reasoned that accessible chromatin will co-localize with genetic disease risk loci. The accessible chromatin maps of intestinal immune populations were significantly enriched for CD, UC and IBD variants, with macrophage and CD4+ T cell maps exhibiting the strongest enrichments. Taking advantage of our single-cell data, we resolved heterogeneous macrophage and CD4+ T cells into subpopulations, to further pinpoint cell type mediators of IBD genetic risk and associations with anti-TNF response. Here, we elucidate the gene regulatory networks impacted by the genetic risk variants and their downstream impacts on intercellular communication networks and tissue homeostasis.
Speaker Bio
Dr. Miraldi is a computational and systems immunologist. Situated at Cincinnati Children’s Hospital, Dr. Miraldi and her lab are dedicated to the design of computational methods and systems-immunology studies that will ultimately improve the health of children. Her studies leverage new biotechnologies (e.g., chromatin accessibility, single-cell genomics measurements) and often require development of new computational methods. Modeling approaches span mechanistic (e.g., dynamic gene regulatory networks) to deep learning (e.g., prediction of cellular epigenomes from DNA sequence). Through close collaboration with physician and experimental colleagues, her team-science initiatives enable iterative experimental testing of computational predictions and model refinement, leading to novel insights into immune-cell function and new therapeutic strategies in the context of immune-mediated diseases.
