Budhwar, R. | Search bioRxiv

bioRxiv2026

Remodelling of chromatin architecture and super-enhancer landscape in lamin A/C depleted HGSOC

Lamins are nuclear intermediate filament proteins that maintain nuclear architecture through interactions with the chromatin. The A- and B-type lamins tether the genome at the peripheral lamina underlying the inner nuclear membrane in the form of heterochromatic lamina-associated domains (LADs). However, LADs associated with A-type lamins are confined not only to lamina but also to the nuclear core, thereby pointing to their distinct and multifarious roles in chromatin organisation and regulation. Previous studies involving lamin B1 depletion depicted the detachment of LADs from the nuclear periphery, accompanied by alteration of chromatin distribution while preserving the topologically associating domains (TADs) in structurally intact form. In this piece of work, we have shown, for the first time in HGSOC, the effects of lamin A/C knockdown on chromatin organisation, which was characterised by significant detethering of gene-poor chromatin from the periphery along with active (A) to inactive (B) compartment switching. This was associated with a rewiring of oncogenic super-enhancer elements corroborated by the differential gene expression profile. Overall analysis tipped the scale in favour of reduced cellular proliferation upon lamin A/C knockdown. This finding was strengthened by the observed proliferative potential of spheroids ex vivo and tumours in a mouse xenograft model.

cancer biology↗

bioRxiv2024

Theileria annulata Infection Promotes p53 suppression, Genomic Instability and DNA deaminase APOBEC3H upregulation leading to cancer-like phenotype in host cells

Theileria annulata-infected host leukocytes display cancer-like phenotypes, though the precise mechanism is yet to be fully understood. The occurrence of cancer-like phenotypes in Theileria-infected leukocytes may be attributed to various factors, including genomic instability and acquired mutations, a crucial trait that underpins the genetic foundation of cancer. This paper presents WGS data and bioinformatic analyses to reveal point mutations and large-scale alterations in six clinically relevant T. annulata-infected cell lines. We identified 7867 exon-linked somatic mutations common to all cell lines, and cancer association analysis showed significant accumulation in oncogenes (FLT4, NOTCH2, MAP3K1, DAXX, FCGR2B, ROS1) and tumor suppressor genes (BARD1, KMT2C, GRIN2A, BAP1) implicated in established critical cancer processes. We demonstrated that a crizotinib-induced blockade of the ROS1 oncogenic protein, which harbored the most mutations, led to the death of infected leukocytes. This is consistent with the significant role of ROS1 in parasite-induced leukocyte transformation. In addition, we found somatic mutations in genes involved in genome instability and the DDR pathway. Our findings support the notion that ROS1 and Nutulin 3a are valid targets for intervention, and the suppression of TP53, a crucial tumor suppressor gene, may play a significant role in cell immortalization. We also show that upon infection with the parasite, bovine cells upregulate the expression of APOBEC3H, a DNA mutator likely responsible for the detected mutations. Our study highlights how T. annulata transforms leukocytes to gain selective advantage via mutation, and our observations could steer future research towards a mechanistic understanding of disease pathogenesis.

cell biology↗