This work isolated adipocytes from subjects with and without insulin resistance and subjected them to transcriptional and epigenomic profiling, allowing it to identify genes, cis-regulatory elements, and pathways that associate with insulin resistance in this critical cell type.
Abstract
Insulin resistance is a key feature of type 2 diabetes (T2D) and is also associated with a wide variety of other disease states. We isolated adipocytes from subjects with and without insulin resistance and subjected them to transcriptional and epigenomic profiling, allowing us to identify genes, cis-regulatory elements, and pathways that associate with insulin resistance in this critical cell type. We focused on several differentially enriched regions near the IRS1 gene that were close to, but distinct from, single-nucleotide polymorphisms associated with T2D and insulin resistance. CRISPR interference (CRISPRi)-mediated repression of these elements identified two major enhancer regions that regulate IRS1 expression in a cell-state-dependent manner. Finally, we identified specific transcription factors that act through these sites to enhance IRS1 gene expression. These studies help to define the molecular events that characterize, and potentially determine, human insulin sensitivity and resistance.
Insulin-driven gene regulation is central to adipocyte function, but the roles of many of these genes in lipid metabolism remain unclear. Here, we integrate three transcriptomic datasets to identify insulin-responsive genes and define their functions in human adipocytes using a multiparametric lipid turnover screen. Ou...
Scott Frendo-Cumbo, Danae Zareifi, Joëlle Bigay et al.· Nature Communications· 1 citation
Type 2 diabetes is a complex metabolic disease with a strong genetic component, yet this genetic risk is driven by common variants in up to 600 loci with small effect sizes. Variants in the STEAP2 locus, encoding ‘Six-transmembrane epithelial antigen of the prostate-2’, are highly associated with altered glycemic trait...
Avery Hawthorne, Kai Kelly, Mark Tigue et al.· bioRxiv· 0 citations
These strategies—development of synthetic adipose-specific mini-promoters and light-inducible regulation—may serve as a basis for developing precision metabolic medicine as these approaches allow spatiotemporal control of transgene expression.
Stanislav Boychenko, A. Dakhnevich, T. Semerikova et al.· Applied Biosciences· 0 citations
Statins are a commonly prescribed cholesterol-lowering drug class that can increase the risk of new-onset diabetes (NOD). The underlying molecular mechanisms have yet to be fully elucidated. We aimed to identify molecular factors associated with differential susceptibility to NOD and determine their effects on β-...
Yu-Lin Kuang, C. Locatelli, Yu-Qing Zhang et al.· Cardiovascular Diabetology· 0 citations
miRNAs are important metabolic regulators and are altered at both the cellular and secreted levels in diseases, including type 2 diabetes (T2D). However, to what extent these alterations are in response to factors in the in vivo milieu or are cell-intrinsic remains unclear. Here we used a disease-in-a-dish model in whi...
Allah Nawaz, Marsel Lino, N. Haider et al.· Signal Transduction and Targ...· 0 citations
The insulin gene (INS) encodes a peptide hormone critical for glucose homeostasis, and its dysregulation underlies both type 1 and type 2 diabetes mellitus. This review compares the structural organization and functional regulation of the insulin gene in humans and mice, highlighting key species differences including t...
A. Mazloum, N. Batashkov, Veronika S. Ledyaeva et al.· Frontiers in Endocrinology· 0 citations
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