Biology subjects

Bahl, S.

Publications and source records attributed to Bahl, S..

3 recordsLinked to original sources

bioRxiv2025

Genetic and Epigenetic Reprogramming of Transposable Elements Drives ecDNA-Mediated Metastatic Prostate Cancer

Extrachromosomal DNAs (ecDNAs), which replicate and segregate in a non-Mendelian manner, serve as vectors for accelerated tumor evolution. By integrating chromatin accessibility, whole-genome sequencing, and Hi-C-based genome topology data from a cohort of metastatic Castration-Resistant Prostate Cancer (mCRPC) cases, we show that epigenetically activated repeat DNA, amplified in ecDNAs, drive oncogene overexpression. Specifically, we identify a subgroup of mCRPCs (20%) characterized by clusters of accessible LINE1 repeat DNA elements flanking the androgen receptor (AR) gene. These LINE1 elements are co-amplified with AR and provide binding sites for prostate-lineage transcription factors, including AR, FOXA1 and HOXB13. Accessible LINE1 elements establish novel 3D chromatin interactions with the AR gene, forging a new regulatory plexus driving AR overexpression and confers resistance to androgen signaling inhibitors. Our findings indicate how tumor evolution is driven by the convergence of genetic and epigenetic alterations on repeat DNA, activating and amplifying them to allow oncogene overexpression. Statement of significanceWe show how tumor evolution is driven by the convergence of genetic and epigenetic alterations on repeat DNA elements, resulting in their activation as regulatory elements and co-amplification in ecDNAs with oncogenes in mCRPC.

cancer biology↗

bioRxiv2025

iSHARC: Integrating scMultiome data for heterogeneity and regulatory analysis in cancer

SummaryThe 10x Genomics single cell Multiome (scMultiome) assay enables the simultaneous profiling of chromatin accessibility and gene expression from the same nucleus, and has increasingly been utilized in revealing cellular heterogeneity and gene regulation in cancers. However, a dedicated bioinformatics pipeline specifically designed for this type of data is still lacking. Here we present iSHARC, a streamlined pipeline for quality control, modality integration, clustering, cell type annotation, and regulatory mechanism analysis of individual scMultiome data, as well as for integrating multiple samples. The main advantages of iSHARC are: 1) easy implementation, execution and extension through a modular Snakemake workflow management system; 2) flexible analysis and parameters customization via a single configuration file; and 3) comprehensive accessibility by providing different access points to results and detailed summary reports from a single run. Availability and implementationThis pipeline is an open-source software under the MIT license and it is freely available at https://github.com/yzeng-lol/iSHARC. Contactyong.zeng@uhn.ca or hansen.he@uhn.ca or mathieu.lupien@uhn.ca Supplementary informationSupplementary data are appended.

bioinformatics↗

bioRxiv2024

Genomic and epigenomic maps of mouse centromeres and pericentromeres

Satellite DNA makes up [~]11% of the mouse genome, predominantly located in centromeric and pericentric regions, which are crucial for chromosome segregation. While comprehensive assemblies of these regions have been established in the human genome, they are still lacking in the mouse genome. In this study, we used PacBio long-read sequencing, CUT&RUN sequencing, DNA methylation analysis, and RNA sequencing to generate genomic and epigenomic maps of these regions. We find that centromeric regions are primarily occupied by 120-mer Minor satellites, with other Minor Satellite length variants, 112-mers and 112-64-dimers, localized at centromere-pericentric junctions. Pericentromeric regions are mainly composed of homogeneous Major satellites, while pericentric-chromosomal junctions contain a higher density of divergent satellites. Additionally, the density of non-satellite repeats increases progressively from centromeres to pericentromeres, and further toward chromosomal arm junctions. We found that 120-mer Minor satellites in the core centromere are highly enriched with CENP-A, while the 112-mers and 112-64-dimers show lower CENP-A levels. Homogeneous Major satellites are more enriched with H3K9me3 heterochromatin, whereas divergent Major satellites are preferentially associated with H3K27me3. Furthermore, DNA methylation levels are lower in centromeres compared to pericentric regions. We also observed that only a small subset of satellites is transcribed into RNA, particularly regions exhibiting lower DNA methylation density. Our comprehensive assembly and characterization of the genomic and epigenomic landscape of mouse centromeric and pericentric regions have major implications for satellite biology and ongoing mouse telomere-to-telomere (T2T) assembly efforts.

genomics↗