Biology subjects

Jacob, C. B.

Publications and source records attributed to Jacob, C. B..

3 recordsLinked to original sources

bioRxiv2024

Morphological map of under- and over-expression of genes in human cells

Cell Painting images offer valuable insights into a cells state and enable many biological applications, but publicly available arrayed datasets only include hundreds of genes perturbed. The JUMP (Joint Undertaking in Morphological Profiling) Cell Painting Consortium perturbed roughly 75% of the protein-coding genome in human U-2 OS cells, generating a rich resource of single-cell images and extracted features. These profiles capture the phenotypic impacts of perturbing 15,243 human genes, including overexpressing 12,609 genes (using open reading frames, ORFs) and knocking out 7,975 genes (using CRISPR-Cas9). We mitigated technical artifacts by rigorously evaluating data processing options and validated the datasets robustness and biological relevance. Analysis of phenotypic profiles revealed novel gene clusters and functional relationships, including those associated with mitochondrial function, cancer, and neural processes. The JUMP Cell Painting genetic dataset is a valuable resource for exploring gene relationships and uncovering novel functions.

bioinformatics↗

bioRxiv2023

Pharmacological modulation of developmental and synaptic phenotypes in human SHANK3 deficient stem cell-derived neuronal models

One sentence summaryThis study describes the use of SHANK3 deficient stem cell-derived neuronal models to screen and characterize small molecules that partially rescued developmental and synaptic defects related to Phelan-McDermid syndrome (PMDS). Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the SHANK3 gene. The resulting deficiency of the postsynaptic density scaffolding protein SHANK3 is associated with autism spectrum disorder (ASD). We examined 12 different PMDS patient and CRISPR-engineered stem cell-derived neuronal models and controls and found that reduced expression of SHANK3 leads to neuronal hyperdifferentiation, increased synapse formation, and decreased neuronal activity. We performed automated imaging-based screening of 7,120 target-annotated small molecules and identified three compounds that rescued SHANK3-dependent neuronal hyperdifferentiation. One compound, Benproperine, rescued the decreased colocalization of Actin Related Protein 2/3 Complex Subunit 2 (ARPC2) with {beta}-actin and rescued increased synapse formation in SHANK3 deficient neurons when administered early during differentiation. Neuronal activity was only mildly affected, highlighting Benproperines effects as a neurodevelopmental modulator. This study demonstrates that small molecular compounds that reverse developmental phenotypes can be identified in human neuronal PMDS models.

neuroscience↗

bioRxiv2023

JUMP Cell Painting dataset: morphological impact of 136,000 chemical and genetic perturbations

Image-based profiling has emerged as a powerful technology for various steps in basic biological and pharmaceutical discovery, but the community has lacked a large, public reference set of data from chemical and genetic perturbations. Here we present data generated by the Joint Undertaking for Morphological Profiling (JUMP)-Cell Painting Consortium, a collaboration between 10 pharmaceutical companies, six supporting technology companies, and two non-profit partners. When completed, the dataset will contain images and profiles from the Cell Painting assay for over 116,750 unique compounds, over-expression of 12,602 genes, and knockout of 7,975 genes using CRISPR-Cas9, all in human osteosarcoma cells (U2OS). The dataset is estimated to be 115 TB in size and capturing 1.6 billion cells and their single-cell profiles. File quality control and upload is underway and will be completed over the coming months at the Cell Painting Gallery: https://registry.opendata.aws/cellpainting-gallery. A portal to visualize a subset of the data is available at https://phenaid.ardigen.com/jumpcpexplorer/.

bioinformatics↗