Biology subjects

Taghbalout, A.

Publications and source records attributed to Taghbalout, A..

3 recordsLinked to original sources

bioRxiv2024

Extrachromosomal DNA Associates with Nuclear Condensates and Reorganizes Chromatin Structures to Enhance Oncogenic Transcription

Extrachromosomal, circular DNA (ecDNA) is a prevalent oncogenic alteration in cancer genomes, often associated with aggressive tumor behavior and poor patient outcome. While previous studies proposed a chromatin-based mobile enhancer model for ecDNA-driven oncogenesis, its precise mechanism and impact remains unclear across diverse cancer types. Our study, utilizing advanced multi-omics profiling, epigenetic editing, and imaging approaches in three cancer models, reveals that ecDNA hubs are an integrated part of nuclear condensates and exhibit cancer-type specific chromatin connectivity. Epigenetic silencing of the ecDNA-specific regulatory modules or chemically disrupting liquid-liquid phase separation breaks down ecDNA hubs, displaces MED1 co-activator binding, inhibits oncogenic transcription, and promotes cell death. These findings substantiate the trans-activator function of ecDNA and underscore a structural mechanism driving oncogenesis. This refined understanding expands our views of oncogene regulation and opens potential avenues for novel therapeutic strategies in cancer treatment.

genomics↗

bioRxiv2021

DNA methylation calling tools for Oxford Nanopore sequencing: a survey and human epigenome-wide evaluation

BackgroundNanopore long-read sequencing technology greatly expands the capacity of long-range single-molecule DNA-modification detection. A growing number of analytical tools have been actively developed to detect DNA methylation from Nanopore sequencing reads. Here, we examine the performance of different methylation calling tools to provide a systematic evaluation to guide practitioners for human epigenome-wide research. ResultsWe compare five analytic frameworks for detecting DNA modification from Nanopore long-read sequencing data. We evaluate the association between genomic context, CpG methylation-detection accuracy, CpG sites coverage, and running time using Nanopore sequencing data from natural human DNA. Furthermore, we provide an online DNA methylation database (https://nanome.jax.org) with which to display genomic regions that exhibit differences in DNA-modification detection power among different methylation calling algorithms for nanopore sequencing data. ConclusionsOur study is the first benchmark of computational methods for mammalian whole genome DNA-modification detection in Nanopore sequencing. We provide a broad foundation for cross-platform standardization, and an evaluation of analytical tools designed for genome-scale modified-base detection using Nanopore sequencing.

bioinformatics↗

bioRxiv2019

Casilio-ME: Enhanced CRISPR-based DNA demethylation by RNA-guided coupling methylcytosine oxidation and DNA repair pathways

We have developed a methylation editing toolbox, Casilio-ME, that enables not only RNA-guided methylcytosine editing by targeting TET1 to genomic sites, but also by co-delivering TET1 and protein factors that couple methylcytosine oxidation to DNA repair activities, and/or promote TET1 to achieve enhanced activation of methylation-silenced genes. Delivery of TET1 activity by Casilio-ME1 robustly altered the CpG methylation landscape of promoter regions and activated methylation-silenced genes. We augmented Casilio-ME1 to simultaneously deliver the TET1-catalytic domain and GADD45A (Casilio-ME2) or NEIL2 (Casilio-ME3) to streamline removal of oxidized cytosine intermediates to enhance activation of targeted genes. Using two-in-one effectors or modular effectors, Casilio-ME2 and Casilio-ME3 remarkably boosted gene activation and methylcytosine demethylation of targeted loci. We expanded the toolbox to enable a stable and expression-inducible system for broader application of the Casilio-ME platforms. This work establishes an advanced platform for editing DNA methylation to enable transformative research investigations interrogating DNA methylomes.

genomics↗