RESUMEN
Functional enhancer annotation is a valuable first step for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants for investigation. However, unbiased enhancer discovery in physiologically relevant contexts remains a major challenge. To discover regulatory elements pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers uncovered, we focused on a long-range enhancer â¼664 kb from the ONECUT1 promoter, as coding mutations in ONECUT1 cause pancreatic hypoplasia and neonatal diabetes. Homozygous enhancer deletion in hPSCs was associated with a near-complete loss of ONECUT1 gene expression and compromised pancreatic differentiation. This enhancer contains a confidently fine-mapped type 2 diabetes (T2D) associated variant (rs528350911) which disrupts a GATA motif. Introduction of the risk variant into hPSCs revealed substantially reduced binding of key pancreatic transcription factors (GATA4, GATA6 and FOXA2) on the edited allele, accompanied by a slight reduction of ONECUT1 transcription, supporting a causal role for this risk variant in metabolic disease. This work expands our knowledge about transcriptional regulation in pancreatic development through the characterization of a long-range enhancer and highlights the utility of enhancer discovery in disease-relevant settings for understanding monogenic and complex disease.
RESUMEN
Complex band structure (CBS) emerges when translational symmetry is broken and material states with complex wavevectors become admissible. The resulting complex bands continuously connect conventional bands and their shapes are directly related to measurable physical quantities. To date, interpretations of complex bands usually assume they are semielliptical because this is the shape produced by the Su-Schrieffer-Heeger (SSH) model. However, numerous studies have reported CBSs with distinctly non-semielliptical shapes, including loops (essentially deformed, asymmetric semiellipses), spikes, and vertical lines. The primary goal of this work is to explore the phenomenology of these shapes such that deeper physical insight can be obtained from a qualitative inspection of a material's CBS. By using several variations on the SSH model, we find that (i) vertical lines are unphysical numerical artifacts, (ii) spikes indicate perfectly evanescent states in the material that couple adjacent layers but do not transfer amplitude, and (iii) asymmetric loops result from hybridization. Secondarily, we also develop a strategy for eliminating any unphysical vertical lines from calculations, thereby improving computational techniques for CBS.
