Biology subjects

Claerr, I.

Publications and source records attributed to Claerr, I..

3 recordsLinked to original sources

bioRxiv2024

The transcription factor ZNF469 regulates collagen production in liver fibrosis

Non-alcoholic fatty liver disease (NAFLD) - characterized by excess accumulation of fat in the liver - now affects one third of the worlds population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.

molecular biology↗

bioRxiv2023

Cell type-focused compound screen in human organoids reveals molecules and pathways controlling cone photoreceptor death

Human organoids that mirror their corresponding organs in cell-type diversity present an opportunity to perform large-scale screens for compounds that protect disease-affected or damage healthy cell types. However, such screens have not yet been performed. Here, we generated 20,000 human retinal organoids with GFP-labeled cone photoreceptors. Since degeneration of cones is a leading cause of blindness, we induced cone death and screened 2,707 compounds with known targets, for those that saved cones or those that further damaged cones. We identified inhibitors of CK1 or MAPK11 that protected cones, HSP90 inhibitors that saved cones in the short term but damaged them in the longer term, and broad HDAC inhibition by many compounds that significantly damaged cones. This work provides a database for cone-damaging compounds and describes compounds that can be starting points to develop neuroprotection for cones in diseases such as macular degeneration.

neuroscience↗

bioRxiv2022

In silico labeling enables kinetic myelination assay in brightfield

Recent advances with deep neural networks have shown the feasibility of acquiring brightfield images with transmitted light and applying in-silico labeling to predict fluorescent images. We have developed a novel in-silico labeling method based on a generative adversarial network and outperforms the state-of-the-art Unet method in generating realistic fluorescent images and quantitatively recapitulating real staining signals, as demonstrated in a complex co-culture myelination assay. Furthermore, we have performed the assay in live mode with multiple kinetic points, applied in-silico labeling to predict fluorescent images from brightfield and quantified the kinetic phenotypic changes. Thus, the proposed approach provides a potential tool to study the kinetics of cellular phenotypic changes with brightfield imaging.

cell biology↗