Biology subjects

Derdak, S.

Publications and source records attributed to Derdak, S..

4 recordsLinked to original sources

bioRxiv2025

Spatial single-cell interactome and niche-specific molecular signatures in alcohol-related liver disease

Alcohol-related liver disease (ALD) remains a major global health burden with limited therapeutic options due to an incomplete understanding of its underlying molecular mechanisms and cellular crosstalk. Here, we applied ultra-high resolution (on 2 {micro}m spots) spatial transcriptomics to a cirrhotic liver tissue obtained from an end-stage ALD patient, analyzing >265,000 spatially resolved cells with further validation on single-cell and single-nuclei datasets from patients with ALD cirrhosis. Our analysis delineated distinct cellular sub-populations and molecular landscapes across fibrotic, vascular, and parenchymal niches of ALD cirrhosis. We identified robust zonation of hepatocytes, hepatic stellate cells, and diverse immune subpopulations, including enrichment of pro-inflammatory T cells and dendritic cells in the fibrotic niche and MARCO+ tissue-resident macrophages localizing mostly in parenchymal areas. Analysis of spatial metrics assigned expression of WNT4, RCAN3, PPIAL4G, PLA2G5, and SLC6A9 to the fibrotic environment in ALD. Differential expression and ligand-receptor interactome analyses revealed niche-specific signaling, with marked CCL19-CCR7 activity in fibrotic regions and DLL4-NOTCH3 crosstalk in vascular compartments. Notably, WNT4+ fibroblasts emerged as key mediators of extracellular matrix remodeling and chemoattraction, particularly via CCL19-mediated signaling towards CD8+ T cells, which was validated on single-cell resolution within the ALD cirrhotic liver in external datasets. These spatial and single-cell findings highlight novel potential therapeutic targets for patients with ALD cirrhosis.

systems biology↗

bioRxiv2022

Nanopore sequencing unveils the complexity of the cold-activated murine brown adipose tissue transcriptome

1.Alternative transcription increases transcriptome complexity by expression of multiple transcripts per gene and thus fine tunes cellular identity and function. Annotation and quantification of transcripts at complex loci using short-read sequencing is non-trivial. Recent long-read sequencing methods such as those from Oxford Nanopore Technologies (ONT) and Pacific Biosciences aim at overcoming these problems by sequencing full length transcripts. Activation of BAT thermogenesis involves major transcriptomic remodelling and positively affects metabolism via increased energy expenditure and endocrine factors. Here we comprehensively benchmark features of ONT long-read sequencing protocols compared to Illumina shortread sequencing assessing alignment characteristics, gene and transcript detection and quantification, differential gene and transcript expression, transcriptome reannotation and differential transcript usage (DTU). We find that ONT sequencing is superior to Illumina for transcriptome reassembly and reduces the risk of false-positive events due to the ability to unambiguously map reads to transcripts, at the expense of statistical power for calling differentially expressed features. We identified novel isoforms of genes undergoing DTU in cold-activated BAT including Cars2, Adtrp, Acsl5, Scp2, Aldoa and Pde4d, validated by RT-qPCR. Finally, we provide a reannotation of the murine iBAT transcriptome as a valuable resource for researchers interested in the molecular biology underlying the regulation of BAT.

molecular biology↗

bioRxiv2021

The ADAR1 editome reveals drivers of editing-specificity for ADAR1-isoforms

Adenosine deaminase acting on RNA (ADAR) (also known as ADAR1) promotes A-to-I conversion in double-stranded and highly structured RNAs. ADAR1 has two isoforms transcribed from different promoters: ADAR1p150, which is mainly cytoplasmic and interferon-inducible, and constitutively expressed ADAR1p110 that is primarily localized in the nucleus. Mutations in ADAR1 cause Aicardi - Goutieres syndrome (AGS), a severe autoinflammatory disease in humans associated with aberrant IFN production. In mice, deletion of ADAR1 or selective knockout of the p150 isoform alone leads to embryonic lethality driven by overexpression of interferon-stimulated genes. This phenotype can be rescued by concurrent deletion of cytoplasmic dsRNA-sensor MDA5. These findings indicate that the interferon- inducible p150 isoform is indispensable and cannot be rescued by the ADAR1p110 isoform. Nevertheless, editing sites uniquely targeted by ADAR1p150 but also mechanisms of isoform- specificity remain elusive. Here we combine RIP-seq on human cells expressing ADAR1 isoforms and combine this with analysis of isoform-specific editing patterns in genetically modified mouse cells to extensively investigate ADAR1-isoform binding- and editing characteristics. Moreover, using mutated ADAR variants, we examine the effect of two unique features of ADAR1p150 on its target specificity: 1) cytoplasmic localization and 2) Z-DNA binding domain . Our findings indicate that ZBD contributes only minimally to p150 editing-specificity and that isoform-specific editing is directed mainly by the cytoplasmic localization of the editase.

genomics↗

bioRxiv2020

New genes involved in Angelman syndrome-like: expanding the genetic spectrum

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10-15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis. New AS-like genes do not interact directly with UBE3A gene product but are involved in synapsis and neuron system development.

genetics↗