Biology subjects

Bernardo, E.

Publications and source records attributed to Bernardo, E..

3 recordsLinked to original sources

bioRxiv2025

Latent plasticity of the human pancreas across development, health, and disease.

The pancreas plays a central role in major human diseases, yet our understanding of its cellular diversity and plasticity remains incomplete. Here, we present a single-cell multiomics atlas of the human pancreas, profiling over four million cells and nuclei from 57 donors across fetal development, adult homeostasis, and type 2 diabetes (T2D). Integrating sc/snRNA-seq, snATAC-seq, VASA-seq, spatial transcriptomics (Xenium), and multiplexed proteomics (CODEX), we resolve gene expression, chromatin accessibility, and spatial organization at high resolution. We identify transcriptionally plastic centroacinar-like cells (pCACs) in adults with fetal-like features, delineate endocrine and exocrine lineage trajectories during development, and uncover HNF1A-defined beta cell epigenetic states. In T2D, we observe shifts in beta cell subtypes and altered regulatory programs. Glucose perturbation of healthy islets reveals cell-type-specific adaptation and stress responses. This atlas provides a foundational framework to understand pancreas biology and the role of cellular plasticity in regeneration and disease.

genomics↗

bioRxiv2025

Adipocyte MKK3 Increases in Human Obesity protecting against Insulin Resistance by p38-beta activation

Obesity is a major global health concern, and a key predisposing factor for insulin resistance and type 2 diabetes mellitus. Adipocytes play a critical role in the development of obesity-induced insulin resistance, with several signaling pathways influencing insulin sensitivity. Among these, p38 MAP kinases are essential for adipose tissue physiology and the regulation of processes such as differentiation, thermogenesis, and inflammation. p38 activation is mediated by the upstream kinases MKK3 and MKK6 in response to inflammatory signals. While MKK6 inhibition promotes browning and thermogenesis and protects against obesity, the role of MKK3 remains unclear. Here, we investigated the function of MKK3 in adipose tissue. In human adipose tissue samples, MKK3 expression was positively correlated with body mass index (BMI) and negatively correlated with glycated hemoglobin, a marker of hyperglycemia. Using whole-body and adipose-specific Mkk3 and p38{beta} knockout mice, we found that Mkk3 activation in adipose tissue during obesity enhances insulin sensitivity. Mechanistically, adipose tissue from Mkk3- or p38{beta}-deficient mice exhibited elevated basal p70S6K activity compared with wild-type controls. This increased p70S6K activity was linked to higher serine phosphorylation of insulin receptor substrate 1 (IRS1) and impaired insulin-stimulated Akt phosphorylation, contributing to worsened insulin resistance. Collectively, our data suggest that activation of the MKK3/p38{beta} signaling axis in adipocytes may protect against high-fat diet-induced insulin resistance and diabetes.

molecular biology↗

bioRxiv2019

HNF1A recruits UTX to activate a differentiation program that suppresses pancreatic cancer

Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding the histone demethylase UTX, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutations phenocopy Utx deficient mutations, and both synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic and biochemical studies to show that HNF1A recruits UTX to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates a differentiation program, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. Finally, we identify a subset of non-classical PDAC samples that exhibit the HNF1A/UTX-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A-deficiency promotes PDAC. They also connect the tumor suppressive role of UTX deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.

genomics↗