Biology subjects

Malik, D.

Publications and source records attributed to Malik, D..

8 recordsLinked to original sources

bioRxiv2026

EML4-ALK Fusion Rewires Transcriptomic, miRNA, and CAF-Associated Programs in Non-Small Cell Lung Cancer

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/717853v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@a696f3org.highwire.dtl.DTLVardef@1005c11org.highwire.dtl.DTLVardef@9c65bborg.highwire.dtl.DTLVardef@1dafb2d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG This study establishes an integrative framework that combines paired mRNA/miRNA profiling with immune microenvironmental features to clarify how EML4-ALK fusions shape transcriptomic and post-transcriptional networks in Non-small cell lung cancer (NSCLC). Using paired mRNA-seq and miRNA-seq data generated from the same patients, we compared fusion-positive and fusion-negative NSCLC across three interconnected layers: (i) transcriptome architecture, including differential expression, pathway, and network analyses; (ii) the miRNA-mRNA regulatory axis, encompassing dysregulated miRNAs, target repression and sponging, and fusion-specific regulatory pairs; and (iii) the tumor microenvironment, with emphasis on immune and stromal infiltration, particularly cancer-associated fibroblast (CAF)-linked extracellular matrix (ECM) and adhesion programs. Our analyses revealed a distinct reprogramming pattern in fusion-positive NSCLC, marked by activation of metabolic and proteostasis pathways, including N-glycan metabolism coupled to ER export, together with attenuation of immune-stromal communication, adhesion, ECM, calcium signaling, and PI3K/VEGF-axis transcription relative to fusion-negative NSCLC. We also identified fusion-associated microRNA perturbations, including an exclusively upregulated miR-3065-centered regulatory hub predicted to repress ECM- and adhesion-related genes (PDGFRB, CTSK, COL4A2, SPARC, FBN1, and LUM) in fusion-positive tumors, in contrast to broader miRNA network rewiring in fusion-negative tumors targeting ciliary and mitotic hubs. Tumor microenvironment analysis further distinguished the subtypes, with fusion-positive tumors showing reduced CAF infiltration relative to fusion-negative tumors and concordant gene-CAF associations. By linking mechanistic insight with candidate biomarkers and targetable pathway nodes, this work provides a basis for precision strategies in both fusion-positive and fusion-negative cohorts and broadens the therapeutic perspective beyond kinase inhibition alone.

systems biology↗

bioRxiv2026

Fusion-driven post-transcriptional network orchestrates ferroptosis resistance, dormancy, and immune remodeling in PRCC-TFE3 renal cell carcinoma

TFE3-rearranged papillary renal cell carcinoma (pRCC) remains poorly understood due to its rarity and complex biology. By integrating matched mRNA and miRNA sequencing from the TCGA-KIRP cohort, this study reveals a fusion-specific post-transcriptional program orchestrating ferroptosis resistance, metabolic adaptation, adhesion loss, immune remodeling, and dormancy-associated signaling. Fusion-positive tumors exhibited coordinated upregulation of antioxidant and mTORC1 components (SOD2, GPX4, G6PD, NQO1, FNIP2, RRAGC), reinforced by loss of miRNA-mediated repression. In parallel, elevated miRNAs (miR-185, miR-148a, miR-130b, miR-342) suppressed MAPK, Wnt, and tight-junction genes, generating a low-proliferative, adhesion-deficient state. AGO2-compatible miRNA-mRNA structural modeling validated key duplexes, linking miRNA regulatory specificity to fusion-driven transcriptional outputs. Immune profiling revealed reduced CD3 T cells but enrichment of CD8 and NK cells, supporting a remodeled yet persistence-permissive microenvironment. Finally, connectivity mapping analysis identified candidate leads targeting the MAPK-Wnt axis. These findings define a multilayered RNA regulatory architecture unique to PRCC-TFE3 tumors.

systems biology↗

bioRxiv2025

Integrative Transcriptomic and miRNA Analysis Reveals Immune Suppression and Metabolic Reprogramming in FGFR3-TACC3 Fusion-Positive versus Fusion-Negative Bladder Cancer

FGFR3-TACC3 gene fusion drives a molecularly distinct subset of bladder cancer characterized by post-transcriptional immune evasion and metabolic rewiring. To elucidate the transcriptomic and regulatory consequences of this fusion, we performed an integrative analysis of mRNA and miRNA expression profiles in fusion-positive versus fusion-negative bladder tumors using TCGA-derived RNA-Seq and miRNA-Seq data. Fusion-positive tumors exhibited upregulation of mitochondrial oxidative phosphorylation and ribosomal genes (e.g., COX5B, ATP5F1D, RPS15) and marked downregulation of immune regulatory genes (e.g., CD4, STAT3, IL6, CD86, PTPRC). Pathway enrichment revealed suppression of JAK/STAT, PD-L1 signaling, and cytokine networks, consistent with a fusion-driven immunosuppressive phenotype. We identified fusion-specific miRNA-mRNA regulatory interactions, including upregulated miRNAs (miR-1226-3p, miR-149-5p, miR-301b-3p) that target immune transcripts and downregulated miRNAs (miR-199b-5p, miR-214-3p) that normally suppress mitochondrial and ribosomal genes. In contrast, fusion-negative tumors displayed an immunoreactive signature marked by elevated IFNG, CXCL10, and IRF1 expression and downregulation of immune-suppressive miRNAs (miR-125a-5p, miR-23b-3p). Minimum free energy analysis and AlphaFold3-based AGO2-RISC docking confirmed structural feasibility of 3D duplex formation for 13 miRNA-target pairs, supporting active silencing complexes. Immune deconvolution revealed reduced infiltration of cytotoxic T cells, NK cells, and dendritic cells in fusion-positive tumors, while fusion-negative tumors showed robust immune cell presence. Key gene-immune cell correlations further confirmed differential immune architecture: SRC and CD4 were strongly linked to suppressed infiltration in fusion-positive tumors, while IFNG and CXCL10 positively correlated with T and NK cell abundance in fusion-negative cases. ROC analysis highlighted COMT, RPS15, and miR-187-3p as robust classifiers of fusion-positive tumors (AUC > 0.9), and CXCL10, CD74, and miR-142 for fusion-negative tumors. Connectivity Map analysis highlighted Lofexidine and Lenalidomide as candidate compounds predicted to reverse fusion-specific transcriptional programs. Collectively, our findings define immune suppression and metabolic reprogramming as core features of FGFR3-TACC3 fusion-positive bladder cancer and nominate fusion-specific miRNA-mRNA interactions as candidate biomarkers and therapeutic targets.

cancer biology↗

bioRxiv2025

Mechanisms of chromatin remodeling by a Snf2-type ATPase

Chromatin remodeling enzymes play a crucial role in the organization of chromatin, enabling both stability and plasticity of genome regulation. These enzymes use a Snf2-type ATPase motor to move nucleosomes, but how they translocate DNA around the histone octamer is unclear. Here we use cryo-EM to visualize the continuous motion of nucleosomal DNA induced by human chromatin remodeler SNF2H, an ISWI family member. Our work reveals conformational changes in SNF2H, DNA and histones during nucleosome sliding and provides the structural basis for DNA translocation. ATP hydrolysis induces conformational changes in SNF2H that pull the DNA tracking strand, distorting DNA and histones at SHL2. This is followed by SNF2H rotation on the nucleosome, which first pulls the DNA guide strand and creates one-base pair bulge at SHL2, and then releases the pulled DNA. Given the high conservation of the catalytic motors among ATP-dependent chromatin remodelers, the mechanisms we describe likely apply to other families.

biophysics↗

bioRxiv2023

Histone modifications regulate pioneer transcription factor cooperativity

Pioneer transcription factors have the ability to access DNA in compacted chromatin. Multiple transcription factors can bind together to a regulatory element in a cooperative way and cooperation between pioneer transcription factors Oct4 and Sox2 is important for pluripotency and reprogramming. However, the molecular mechanisms by which pioneer transcription factors function and cooperate remain unclear. Here we present cryo-EM structures of human Oct4 bound to a nucleosome containing human Lin28B and nMatn1 DNA sequences, which bear multiple binding sites for Oct4. Our structural and biochemistry data reveal that Oct4 binding induces changes to the nucleosome structure, repositions the nucleosomal DNA and facilitates cooperative binding of additional Oct4 and of Sox2 to their internal binding sites. The flexible activation domain of Oct4 contacts the histone H4 N-terminal tail, altering its conformation and thus promoting chromatin decompaction. Moreover, the DNA binding domain of Oct4 engages with histone H3 N-terminal tail, and posttranslational modifications at H3K27 modulate DNA positioning and affect transcription factor cooperativity. Thus, our data show that the epigenetic landscape can regulate Oct4 activity to ensure proper cell reprogramming.

biophysics↗

bioRxiv2021

Polyamine elevation and nitrogen stress are toxic hallmarks of chronic sleep loss in Drosophila melanogaster

Chronic sleep loss profoundly impacts health in ways coupled to metabolism; however, much existing literature links sleep and metabolism only on acute timescales. To explore the impact of chronically reduced sleep, we conducted unbiased metabolomics on heads from three Drosophila short-sleeping mutants. Common features included elevated ornithine and polyamines; and lipid, acyl-carnitine, and TCA cycle changes suggesting mitochondrial dysfunction. Biochemical studies of overall, circulating, and excreted nitrogen in sleep mutants demonstrate a specific defect in eliminating nitrogen, suggesting that elevated polyamines may function as a nitrogen sink. Both supplementing polyamines and inhibiting their synthesis with RNAi regulated sleep in control flies. Finally, both polyamine-supplemented food and high-protein feeding were highly toxic to sleep mutants, suggesting their altered nitrogen metabolism is maladaptive. Together, our results suggest polyamine accumulation specifically, and nitrogen stress in general, as potential mechanisms linking chronic sleep loss to adverse health outcomes.

neuroscience↗

bioRxiv2021

Apparent growth paradox of Staphylococcus epidermidis in response to extremely low frequency electromagnetic radiation exposure

Staphylococcus epidermidis is a normal part of the human microbiome; however, it is an opportunistic pathogen and can cause infections when the delicate balance of this microbiome is disrupted. Furthermore, infections caused by this bacterium can be hard to treat as a result of antibiotic resistance and biofilm production. This experiment aimed to determine whether electromagnetic field radiation (ELF-EMF) could be a deterrent of bacterial growth, as an alternative treatment to antibiotics. A non-pathogenic strain of S. epidermidis was used for experimentation, which took place in a school laboratory setting. The experimental group was exposed to ELF-EMF, while the control group did not receive the ELF-EMF treatment. The number of bacterial colonies, represented as colony forming units (CFUs) and area of random colonies were calculated to determine the effect of this treatment. There was no dramatic difference of colony formation on days 0, 1, and 2 of the four day period of ELF-EMF exposure. However, colony formation for days 3 and 4 showed a significant difference between the control and the experimental groups, as the experimental group had a significantly higher CFU count than the control. The average CFU count for day 3 in the control group was 420.6 and 1,097.4 for the experimental group (p<0.0001, t=12.9803). On the final day of the experimentation (Day 4) the average CFU count for the control group was 424.6 and 896.4 for the experimental group (p<0.0001, t=5.8926). The area for five randomly chosen colonies from each petri dish was calculated on the fourth day of experimentation. The area for the experimental group was significantly lower than that control (p<0.0001, with t=6.8659). The average area for the control group was 1.3249 mm2 and a lower average of 0.6375mm2 for the experimental group. These results demonstrate that the ELF-EMF treatment had an inhibitory effect on the area growth of S. epidermidis, but not on the colony-forming ability of S. epidermidis. This suggests that ELF-EMF influences the means by which the bacterium S. epidermidis grows.

microbiology↗

bioRxiv2020

CRY1-CBS binding regulates circadian clock function and metabolism

Circadian disruption influences metabolic health. Metabolism modulates circadian function. However, the mechanisms coupling circadian rhythms and metabolism remain poorly understood. Here we report that Cystathionine {beta}-synthase (CBS), a central enzyme in one-carbon metabolism, functionally interacts with the core circadian protein Cryptochrome1 (CRY1). In cells, CBS augments CRY1 mediated repression of the CLOCK/BMAL1 complex and shortens circadian period. Notably, we find that mutant CBS-I278T protein, the most common cause of homocystinuria, does not bind CRY1 or regulate its repressor activity. Transgenic CbsZn/Zn mice, while maintaining circadian locomotor activity period, exhibit reduced circadian power and increased expression of E-BOX outputs. CBS function is reciprocally influenced by CRY1 binding. CRY1 modulates enzymatic activity of the CBS. Liver extracts from Cry1-/- mice show reduced CBS activity that normalizes after the addition of exogenous wild type (WT) CRY1. Metabolomic analysis of WT, CbsZn/Zn, Cry1-/-, and Cry2-/- samples highlights the metabolic importance of endogenous CRY1. We observed temporal variation in one-carbon and transsulfuration pathways attributable to CRY1 induced CBS activation. CBS-CRY1 binding provides a post-translational switch to modulate cellular circadian physiology and metabolic control.

molecular biology↗