Biology subjects

Riazalhosseini, Y.

Publications and source records attributed to Riazalhosseini, Y..

7 recordsLinked to original sources

bioRxiv2026

A map of RBP-miRNA regulatory connections for deciphering the mechanisms of transcriptome remodeling in cancer

Micro-RNAs (miRNAs) are key post-transcriptional regulators of gene expression that influence cancer progression and outcome. Whereas transcriptional dysregulation of miRNA abundance underlies abnormal functionality of some miRNAs in cancer, emerging data points to RNA-binding proteins (RBPs) as prominent post-transcriptional regulators of miRNA activity. Here, by modelling the regulon activities of well-characterized miRNA families in RNA-seq data of a comprehensive collection of RBP inhibition experiments, human cell lines and tissues, we report a map of regulatory connections between 34 RBPs and 28 miRNAs. Furthermore, through a global analysis of the abundance as well as the activity of miRNAs in thousands of tumor and control samples from 17 human cancers, we show that RBP-driven regulation of miRNA activity is common in tumors and contributes to the heterogeneity in miRNA activity profiles. We uncover a set of RBPs that regulate the activity of tumor-suppressor and oncogenic miRNAs, including miR-29-3p, miR-17-5p and miR-19-3p. Of particular interest, we describe a pan-cancer negative regulatory role for DDX55 on the activity of the miR-29-3p family, a critical miRNA family with tumor suppressor functions that is involved in most human cancers. Our functional studies confirm that DDX55 inhibition restores the gene-silencing activity of miR-29-3p and reduces cancer cell viability. Overall, our study provides the first pan-cancer investigation of functional regulatory connections between RBPs and miRNAs, and highlights RBPs whose interventional modulation may serve as a new approach to reprogram abnormal miRNA activities in cancer.

genomics↗

bioRxiv2026

Lysyl oxidase drives ccRCC progression by coordinating HIF-2α transcription program with tumor microenvironment

Clear cell renal cell carcinoma (ccRCC) is driven by persistent HIF-2 transcription program initiated by VHL loss, yet molecular mediators sustaining this program are poorly defined. Using single-cell transcriptomics, we identified lysyl oxidase (LOX) as a driver of ccRCC progression, selectively enriched in a hypoxia/epithelial-mesenchymal transition (EMT) gene program associated with poor outcome. While LOX oxidizes and stabilizes HIF-2 by antagonizing HUWE1-mediated ubiquitination and degradation, thereby sustaining HIF-2-driven transcription in cancer cells, it also remodels extracellular matrix (ECM) and promotes angiogenesis in the tumor microenvironment (TME). Genetic or pharmacological inhibition of LOX destabilizes HIF-2, disrupts ECM, inhibits angiogenesis, and suppresses tumor initiation, growth, and metastasis in vivo. LOX inhibition enhances anti-angiogenic therapy response and remains effective in belzutifan-resistant HIF-2 G323E-mutant tumors. Nuclear LOX protein correlates with nuclear HIF-2 in high-grade patient tumors. Together, LOX coordinates HIF-2 transcription program with TME and is a therapeutic target in ccRCC.

cancer biology↗

bioRxiv2026

Semantic fragment representations for coordinate-free analysis of genomics data

Many genomic assays begin with individual DNA fragments, but standard analysis quickly collapses those molecules into counts over genomic intervals. Rich information carried by each fragment, including its sequence, fragment body, cleavage boundaries, and local flanking context, is lost in this process. This loss is especially apparent in mixed-source and heterogeneous samples, where individual fragments originate from disparate cell types and can retain information about their cell of origin. To address this, we present LEAF-1, a fragment-level foundation model pre-trained on approximately 58 billion fragments spanning bulk ATAC-seq, single-cell ATAC-seq, and cell-free DNA profiles, representing each DNA molecule as a point in a learned semantic space defined by sequence context, assay modality, and explicit cleavage-boundary tokens. In sparse scATAC-seq datasets, mean-pooled LEAF-1 embeddings readily classify human cell types from as few as [~]1,000 fragments per cell, with high-scoring fragments linked to cell-type-associated transcription-factor programs. Similarly, in cell-free DNA profiling, LEAF-1 outperformed state-of-the-art coordinate-binning strategies and general-purpose DNA language model baselines across cancer detection tasks. Applying attention-based multiple-instance learning to LEAF-1 embeddings further improved cancer detection, reaching an area under the receiver operating characteristic (ROC) curve (AUC) of 0.95. This pan-cancer model generalizes beyond cancer types it is trained on, as we show by profiling plasma samples from clear cell renal cell carcinoma patients and healthy volunteers and applying the frozen classifier without retraining, achieving an AUC of 0.83. These results show that semantic learning over individual DNA fragments preserves biochemical, cell-associated, and disease-associated signals that are otherwise lost during coordinate-based aggregation.

genomics↗

bioRxiv2024

Microbiome diversity, intra-mucosal bacteria and immune integration within normal and asthmatic airway mucosa

Asthma is characterized by reduced bronchial bacterial diversity and airway mucosal disruption. We examined spatial distributions of microbial sequences and host mucosal transcripts in bronchial biopsies from healthy controls and adult asthmatics. Bacteria were discovered by 16S ribosomal RNA staining in the lamina propria of all biopsies, with counts positively associated to lumenal bacterial diversity. Weighted correlation network analysis identified fifteen co-expression networks, including distinct programs of adaptive and innate immunity in differing spatial distributions. Stromal bacterial counts correlated significantly with eight of the network eigenvectors in directions compatible with beneficial relationships. The results suggest that dysbiosis may affect mucosal immunity through impaired interactions beneath the epithelial border. Intra-mucosal companion bacteria may be a potential substrate for selective management of immunity in a wide range of diseases. One-Sentence SummaryThe lung microbiome extends within the airway mucosa and associates spatially and functionally with immune networks.

microbiology↗

bioRxiv2024

Loss of VHL-mediated pRb regulation promotes clear cell renal cell carcinoma

The von Hippel-Lindau (VHL) tumor suppressor is a component of E3 ubiquitin ligase complexes that target cellular substrates for proteasome-mediated degradation. VHL inactivation by genetic aberrations is observed in most sporadic cases of clear cell renal cell carcinoma (ccRCC). VHL loss leads to constitutive stabilization of E3 ligase targets, including hypoxia inducible factor (HIF), in VHL-associated tumors. HIF stabilization upon VHL loss promotes transactivation of hypoxia responsive genes, which contributes to ccRCC development. However, several HIF-independent VHL targets have also been implicated in the promotion of tumorigenesis. Using proximity labeling to identify proteasomal VHL interactors, we identified retinoblastoma protein (pRb) as a novel substrate of VHL. Mechanistically, VHL interacts with pRb in an oxygen-sensitive manner, promoting its ubiquitin-mediated degradation. Concordantly, VHL-inactivation results in pRb hyperstabilization. Functionally, the hyperstabilization of pRb in ccRCC promoted tumorigenesis in vitro and in mouse models. We also show that downstream transcriptional changes induced by pRb hyperstabilization may contribute to ccRCC tumor development. Together, our findings reveal a novel VHL-related pathway which can be therapeutically targeted to inhibit ccRCC tumor development.

cancer biology↗

bioRxiv2023

Targeting LINC00152 activates cAMP/Ca2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer

Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER+) breast cancer, constituting around 75% of all cases. However, emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance via blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of cAMP/PKA/CREB axis and increased expression of TRPC1 Ca2+ channel. This causes cytosolic Ca2+ overload and generation of reactive oxygen species (ROS) that is, on one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels. These ultimately induce lipid peroxidation and ferroptotic cell death in combination with tamoxifen. Overexpressing PDE4D rescues LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of ferroptosis induction and tamoxifen sensitization, thereby revealing LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.

cancer biology↗

bioRxiv2021

Pan-cancer analysis of mRNA stability for decoding tumour post-transcriptional programs

RNA stability is a crucial and often overlooked determinant of gene expression. Some of the regulators of mRNA stability are long known as key oncogenic or tumour suppressor factors. Nonetheless, the extent to which mRNA stability contributes to transcriptome remodeling in cancer is unknown, and the factors that modulate mRNA stability during cancer development and progression are largely uncharacterized. Here, by decoupling transcriptional and post-transcriptional effects in RNA-seq data of 7760 samples from 18 cancer types, we present a pan-cancer view of the mRNA stability changes that accompany tumour development and progression. We show that thousands of genes are dysregulated at the mRNA stability level, and identify the potential factors that drive these changes, including >80 RNA-binding proteins (RBPs) and microRNAs (miRNAs). Most RBPs and miRNAs have cancer type-specific activities, but a few show recurrent inactivation across multiple cancers, including the RBFOX family of RBPs and miR-29. Analysis of cell lines with phenotypic activation or inhibition of RBFOX1 and miR-29 confirms their role in modulation of genes that are dysregulated across multiple cancers, with functions in calcium signaling, extracellular matrix organization, and stemness. Overall, our study highlights the critical role of mRNA stability in shaping the tumour transcriptome, with recurrent post-transcriptional changes that are ~30% as frequent as transcriptional events. These results provide a resource for systematic interrogation of cancer-associated stability drivers and pathways.

genomics↗