Project description:Liver fibrosis is a severe disease with few treatment options due to the poor quality of the available animal and in vitro models. To address this, human hepatic organoids were grown in microwells (i.e., microHOs) to provide a robust, live cell imaging platform for serially evaluating the anti-fibrotic effects of drug candidates. Here, we developed a multi-parameter image analysis workflow that enabled anti-fibrotic efficacy and drug toxicity to be serially assessed in microHOs, and endpoint analyses (flow cytometry and scRNA-Seq) were used to characterize drug effects on different cell types. Transcriptomic analysis revealed that the efficacy of five anti-fibrotic agents occurred via two different mechanisms: two inhibited TGF-induced intracellular signaling while three altered TGF-induced mesenchymal cell differentiation. microHO data facilitated drug re-purposing by enabling the effects of different drugs to be directly compared. This study provides a first demonstration that a hypothesis generating multi-agent AI system (AI co-scientist) can assist in re-purposing drugs for a disease with few treatment options. Two of three AI co-scientist-recommended drugs targeting epigenomic modifiers exhibited significant anti-fibrotic activity; and one is an FDA-approved drug (Vorinostat) that also promoted liver parenchymal cell regeneration. Hence, the use of AI co-scientist coupled with this enhanced microHO platform identified a new generation of liver fibrosis treatments that also promote liver regeneration.
2025-12-10 | GSE306096 | GEO
Project description:Multi-omics data reveal the origin of cardiac myxoma
Project description:In mammals, circadian rhythms are entrained to the light cycle and drive daily oscillations in levels of NAD+ a co-substrate of the class III histone deacetylase SIRT1 that associates with clock transcription factors. While NAD+ also participates in redox reactions, the extent to which NAD(H) couples nutrient state with circadian transcriptional cycles remains unknown. Here we show that nocturnal animals subjected to time-restricted feeding of a calorie-restricted diet (TRF-CR) only during nighttime display reduced body temperature and elevated hepatic NADH during daytime. Genetic uncoupling of nutrient state from NADH redox state through transduction of the water-forming NADH oxidase from Lactobacillus brevis (LbNOX) increases daytime body temperature and blood and liver acyl-carnitines. LbNOX expression in TRF-CR mice induces oxidative gene networks controlled by BMAL1 and PPARa and suppresses amino acid catabolic pathways. Enzymatic analyses reveal that NADH inhibits SIRT1 in vitro, corresponding with reduced deacetylation of SIRT1 substrates during TRF-CR in vivo. Remarkably, Sirt1 liver nullizygous animals subjected to TRF-CR display persistent hypothermia even when NADH is oxidized by LbNOX. Our findings reveal that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1.
Project description:To further reveal the major cell types of developing pIVC embryos and underlying epigenetic dynamics, the optimized single-cell based multi-omics sequencing method scChaRM-seq was performed (Yan et al., 2021b). 1,862 single cells Bisulfite-seq datasets were further analyzed. We then performed multi-omics profiling analysis using data obtained from9 pIVC embryos at 8 sequential developmental stages.
Project description:To uncover the role of opioid induced dysbiosis in disrupting intestinal homeostasis, we conducted a multi-omics analysis with gut microbial, metabolite and intestinal transcriptomics data
Project description:To uncover the role of opioid induced dysbiosis in disrupting intestinal homeostasis, we conducted a multi-omics analysis with gut microbial, metabolite and intestinal transcriptomics data
Project description:To further reveal the major cell types of developing pIVC embryos and underlying epigenetic dynamics, the optimized single-cell based multi-omics sequencing method scChaRM-seq was performed (Yan et al., 2021b). After stringent filtration, 3,682 single cells RNA-seq datasets were further analyzed We then performed multi-omics profiling analysis using data obtained from9 pIVC embryos at 8 sequential developmental stages.
Project description:Lung development generates a complex tree-like architecture through proximal-distal patterning and branching morphogenesis. However, the gene regulatory programs governing embryonic lung development remain poorly understood. Here, we present a comprehensive single-cell multi-omics atlas of mouse embryonic lungs, integrating gene expression and chromatin accessibility profiles. Through systematic analysis, we identify 13 distinct cell types and map cis-regulatory elements, peak-to-gene linkages, and transcription factors underlying lung development. Leveraging this multi-modal dataset, we uncover lineage-determining transcription factors driving cell differentiation, including the Activated Protein-1 complex. We further delineate gene regulatory networks involving diverse transcription regulators, including CCCTC-binding factor. Using the Ctcf conditional knockout mouse, coupled with histological and multi-omics analyses, we demonstrate that CCCTC-binding factor orchestrates lung progenitor maintenance and branching morphogenesis by modulating both gene expression and chromatin accessibility. Thus, our study provides a multi-omics resource and mechanistic insights for transcriptional regulation of lung morphogenesis.
Project description:Lung development generates a complex tree-like architecture through proximal-distal patterning and branching morphogenesis. However, the gene regulatory programs governing embryonic lung development remain poorly understood. Here, we present a comprehensive single-cell multi-omics atlas of mouse embryonic lungs, integrating gene expression and chromatin accessibility profiles. Through systematic analysis, we identify 13 distinct cell types and map cis-regulatory elements, peak-to-gene linkages, and transcription factors underlying lung development. Leveraging this multi-modal dataset, we uncover lineage-determining transcription factors driving cell differentiation, including the Activated Protein-1 complex. We further delineate gene regulatory networks involving diverse transcription regulators, including CCCTC-binding factor. Using the Ctcf conditional knockout mouse, coupled with histological and multi-omics analyses, we demonstrate that CCCTC-binding factor orchestrates lung progenitor maintenance and branching morphogenesis by modulating both gene expression and chromatin accessibility. Thus, our study provides a multi-omics resource and mechanistic insights for transcriptional regulation of lung morphogenesis.