2025 Theses Doctoral

Long noncoding RNAs reveal hidden genetic circuitry that drives complex inflammatory disease susceptibility

Yang-Fischer, Ruxiao

The immune system plays a central role in protecting the body against pathogen invasion, guiding development, and maintaining physiological homeostasis. When dysregulated, however, it can contribute to a wide range of common diseases, including cancer, neurodegeneration, allergies, hypersensitivity, and autoimmunity. Most of these are complex diseases, in which environmental insults interact with multiple genetic factors to produce a quantitative distribution of phenotypes across the population.

Over the past few decades, genome-wide association studies (GWAS) have provided significant insights into the intricate architecture of polygenic risk variants underlying susceptibility to complex diseases. Notably, more than 90% of these variants lie within the noncoding genome, and their mechanisms of disease causation remain largely undefined. The prevailing model assumes that noncoding variants act primarily by modulating DNA regulatory elements, which in turn regulate the nearest protein-coding genes. However, this framework largely overlooks RNA-level mechanisms.

Although only ~2% of the genome encodes proteins, at least 60% of it is transcriptionally active. Among the resulting transcripts is a recently characterized class of noncoding RNAs—long noncoding RNAs (lncRNAs)—which are pervasively expressed across the genome. Despite their abundance, the physiological roles of most lncRNAs remain unknown.

In this thesis, I employed a bioinformatic screening strategy pioneered in Dr. Sankar Ghosh’s laboratory to identify novel lncRNA genetic risk factors for autoimmune diseases—a group of incurable disorders with largely unknown etiologies. Using an integrated approach combining human samples, molecular biology, and mouse models, we identified and characterized several novel, physiologically relevant lncRNA genetic risk factors for complex diseases, in detail. These studies not only uncover new pathways of immune regulation but also reveal several regulatory logics by which noncoding SNPs cause disease, challenging the prevailing protein- and DNA-centric paradigms of genetic disease causation.