Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of atherogenic lipoproteins

Loss-of-function mutations in hepatocyte nuclear factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare, protein-coding HNF1A variant, most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found that ∼1:5 rare protein-coding HNF1A variants in the general population cause molecular gain of function (GOF), increasing the transcriptional activity of HNF1A by up to 50% and conferring protection from type 2 diabetes (odds ratio [OR] = 0.77, p = 0.007). Increased hepatic expression of HNF1A promoted a pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including ANGPTL3 and PCSK9. In summary, ∼1:300 individuals carry a GOF variant in HNF1A that protects carriers from diabetes but enhances hepatic secretion of atherogenic lipoproteins.publishedVersio

Leveraging human genetics and functional genomics to investigate insulin resistance related disorders

Insulin resistance plays a central role in the development of multiple epidemic metabolic disorders such as type 2 diabetes (T2D) and cardiovascular disease. In this dissertation, I leverage human genetics and functional genomics to unravel the molecular mechanisms underlying insulin resistance and its related disorders, as well as identify novel key effector genes for potential therapeutic applications. The work is divided into four chapters:Chapter 1 provides an overview of the recent large-scale T2D genetic studies with particular focus on the effects of sample size and ancestral diversity on genetic discovery as well as discusses recent work on the use and limitations of genetic risk scores for T2D risk prediction. Chapter 2 describes deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome- sequenced individuals which identifies gain-of-function mutations in HNF1A which exert pleiotropic effects, conferring protection against diabetes while increasing the hepatic secretion of atherogenic lipoproteins. Chapter 3 utilizes genetic determinants of circulating protein levels to perform proteome-wide Mendelian Randomization which identifies RSPO3 as a critical mediator of non-alcoholic steatohepatitis (NASH) pathogenesis. Chapter 4 presents a genome-wide association study for the serum triglyceride to HDL-cholesterol ratio and subsequent integrative genomics which systematically prioritizes novel insulin resistance effector genes with insights into tissues of action and directional effects on metabolic disease. Collectively, this dissertation demonstrates the power of integrating large-scale human genetics with functional genomics in elucidating the intricate mechanisms contributing to insulin resistance-related disorders. These findings contribute to the growing body of knowledge in the field, offering novel insights into the pathogenesis of insulin resistance and its related disorders and identifying potential candidate genes for further investigation and therapeutic targeting

Genetics of Type 2 Diabetes: Implications from Large-Scale Studies.

Purpose of reviewType 2 diabetes (T2D) is a multifactorial, heritable syndrome characterized by dysregulated glucose homeostasis that results from impaired insulin secretion and insulin resistance. Genetic association studies have successfully identified hundreds of T2D risk loci implicating many genes in disease pathogenesis. In this review, we provide an overview of the recent T2D genetic studies from the past 3 years with particular focus on the effects of sample size and ancestral diversity on genetic discovery as well as discuss recent work on the use and limitations of genetic risk scores (GRS) for T2D risk prediction.Recent findingsRecent large-scale, multi-ancestry genetic studies of T2D have identified over 500 novel risk loci. The genetic variants (i.e., single nucleotide polymorphisms (SNPs)) marking these novel loci in general have smaller effect sizes than previously discovered loci. Inclusion of samples from diverse ancestral backgrounds shows a few ancestry specific loci marked by common variants, but overall, the majority of loci discovered are common across ancestries. Inclusion of common variant GRS, even with hundreds of loci, does not substantially increase T2D risk prediction over standard clinical risk factors such as age and family history. Common variant association studies of T2D have now identified over 700 T2D risk loci, half of which have been discovered in the past 3 years. These recent studies demonstrate that inclusion of ancestrally diverse samples can enhance locus discovery and improve accuracy of GRS for T2D risk prediction. GRS based on common variants, however, only minimally enhances risk prediction over standard clinical risk factors

Glycocalyx engineering with heparan sulfate mimetics attenuates Wnt activity during adipogenesis to promote glucose uptake and metabolism

Adipose tissue plays a crucial role in maintaining metabolic homeostasis by storing lipids and glucose from circulation as intracellular fat. As peripheral tissues like adipose tissue become insulin resistant, decompensation of blood glucose levels occurs causing type 2 diabetes (T2D). Currently, modulating the glycocalyx, a layer of cell-surface glycans, is an underexplored pharmacological treatment strategy to improve glucose homeostasis in T2D patients. Here, we show a novel role for cell-surface heparan sulfate (HS) in establishing glucose uptake capacity and metabolic utilization in differentiated adipocytes. Using a combination of chemical and genetic interventions, we identified that HS modulates this metabolic phenotype by attenuating levels of Wnt signaling during adipogenesis. By engineering, the glycocalyx of pre-adipocytes with exogenous synthetic HS mimetics, we were able to enhance glucose clearance capacity after differentiation through modulation of Wnt ligand availability. These findings establish the cellular glycocalyx as a possible new target for therapeutic intervention in T2D patients by enhancing glucose clearance capacity independent of insulin secretion

A seven-transmembrane protein-TM7SF3, resides in nuclear speckles and regulates alternative splicing

The seven-transmembrane superfamily member 3 protein (TM7SF3) is a p53-regulated homeostatic factor that attenuates cellular stress and the unfolded protein response. Here we show that TM7SF3 localizes to nuclear speckles; eukaryotic nuclear bodies enriched in splicing factors. This unexpected location for a trans -membranal protein enables formation of stable complexes between TM7SF3 and pre-mRNA splicing factors including DHX15, LARP7, HNRNPU, RBM14, and HNRNPK. Indeed, TM7SF3 regulates alternative splicing of >330 genes, mainly at the 3'end of introns by directly modulating the activity of splicing factors such as HNRNPK. These effects are observed both in cell lines and primary human pancreatic islets. Accordingly, silencing of TM7SF3 results in differential expression of 1465 genes (about 7% of the human genome); with 844 and 621 genes being up- or down-regulated, respectively. Our findings implicate TM7SF3, as a resident protein of nuclear speckles and suggest a role for seven-transmembrane proteins as regulators of alternative splicing

Firefly: The Case for a Holistic Understanding of the Global Structure and Dynamics of the Sun and the Heliosphere

This white paper is on the HMCS Firefly mission concept study. Firefly focuses on the global structure and dynamics of the Sun's interior, the generation of solar magnetic fields, the deciphering of the solar cycle, the conditions leading to the explosive activity, and the structure and dynamics of the corona as it drives the heliosphere