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Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet β cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and β cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3–5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by β cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the β cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by β cells. RFX6 perturbation in primary human islet cells alters β cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6 expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.Integration of multiomics data with functional analysis of pancreatic tissues from individuals with early-stage type 2 diabetes indicates that the genetic risk converges on RFX6, which regulates chromatin architecture at multiple risk loci. [ABSTRACT FROM AUTHOR]

Author(s): Shilpi Khare [1]; Advait S. Nagle [1]; Agnes Biggart [1]; Yin H. Lai [1]; Fang Liang [1]; Lauren C. Davis [1]; S. Whitney Barnes [1]; Casey J. N. Mathison [...]

Epigenetic inheritance in mammals is characterized by high-fidelity replication of CpG methylation patterns during development (1,2). UHRF1 (also known as ICBP90 in humans and Np95 in mouse) (3) is an [...]

Author(s): Laurent O. Martinez [1]; Sébastien Jacquet [1]; Jean-Pierre Esteve [2]; Corinne Rolland [1]; Elena Cabezón [3]; Eric Champagne [4]; Thierry Pineau [5]; Valérie Georgeaud [1]; John E. Walker [3]; [...]

Author(s): John R. Walker [1, 2]; Richard A. Corpina [1, 2]; Jonathan Goldberg [1, 3] Damage to DNA in the form of double-strand breaks (DSBs) compromises the integrity of cells, [...]

The three catalytic beta-subunits that constitute bovine mitochondrial F(1)-ATPase reveal differences in conformation and nucleotide binding properties, as revealed by the crystal structure of bovine mitochondrial F(1)-ATPase at a resolution of 2.8 angstroms. This indicates the presence of a catalytic mechanism in intact ATP synthase. The subunits are in three different states during a catalytic cycle. Rotation of the alpha(3)beta(3) subassembly with respect to the gamma-subunit's alpha-helical region allows interconversion between states.