Wednesday, January 15, 2025
1/15/2025
SUMMARY Gout is prevalent in the US (3.9% of the adult population) and not only directly impacts peoples’ lives but is also co-morbid with cardiometabolic disease. Gout consists of unpredictable episodes of acute inflammation or flares resulting from monocyte NLRP3 inflammasome activation by monosodium urate (MSU) crystals in people with hyperuricemia, the subsequent production of IL-1, and recruitment of large numbers of inflammatory cells into the affected joint. Epigenetic reprogramming and altered gene transcription in response to elevated levels of soluble urate are mechanisms of this enhanced cellular reactivity to the secondary stimuli, known as innate trained immunity. To better understand the factors controlling the progression from hyperuricemia to gout we have completed a very large genome-wide association study (GWAS) in gout, identifying several hundred gout-associated loci. Loci include long-noncoding RNAs (lncRNAs) that have diverse functions including regulation of gene expression, deposition of epigenetic modifications and organization of chromosome architecture. Some are immune gene-priming lncRNAs (IPLs) that direct transcriptional machinery over multiple promoters. From these loci we have identified one key causal pathway (clonal hematopoiesis of indeterminate potential (CHIP)) for which we will study the molecular genetic processes controlling its activation. The CHIP pathway is involved in control of the epigenome - DNA methylation, histone modification and metabolism of substrates. It may make people more susceptible to gout by causing the innate immune system to be hyper-responsive to MSU crystals. We hypothesize that the genetic loci identified from the gout GWAS control activity of this pathway by regulation of gene expression, including through regulation of the epigenome. In testing this hypothesis, in three Aims, we will understand the molecular control of the pathway and provide a basis for future studies in targeting this pathway for improved management of gout. In Aim 1 we will use experimental systems, including a zebrafish model of gout, to understand where regulatory regions are expressed and how the gout-associated loci influence NLRP3- inflamasome activation. Zebrafish are translucent, allowing development of innovative models, and there is 82% conservation of genes with humans and functionally equivalent macrophages and neutrophils. In Aim 2 we will compare the transcriptome and epigenome in MSU crystal-stimulated monocytes of individuals with high and low burdens of gout risk alleles in order to gain further insights into the molecular regulation of the pathways, and to identify downstream pathways. Individual genes will be knocked down in a cell line. In Aim 3 we will use our established pipeline to understand how lncRNAs (i.e. IPLs) connect transcriptional machinery to the promoters of innate immune genes at specific loci in the molecular control of activation of the gout flare. Our studies will deepen our knowledge of the mechanisms of gout flares and its genetic basis, and ultimately point to areas of research that may allow for novel treatments in gout.
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