Biology subjects

Lin, D. T.

Publications and source records attributed to Lin, D. T..

6 recordsLinked to original sources

bioRxiv2025

Orphan Non-Coding RNAs Drive Tumorigenesis and Enable Pre-Diagnostic Detection in HPV-Negative Head and Neck Cancer

HPV-negative head and neck squamous cell carcinoma (HNSCC) lacks reliable biomarkers for early detection and molecular stratification. We recently described orphan non-coding RNAs (oncRNAs) as a class of cancer-emergent small RNAs that arise from cryptic promoters largely silent in normal tissues. Here, we define the comprehensive landscape of oncRNAs in HNSCC. Using TCGA and CPTAC-3 data, we demonstrate that these transcripts are not only tumor-specific but provide digital fingerprints that accurately stratify tumors by anatomical site. Moving from association to function, we investigated whether these emergent transcripts actively drive tumorigenesis. We focused on oncRNA64585, a transcript highly enriched in oral cavity tumors and associated with tumor progression. Its depletion significantly impaired proliferation in vitro and suppressed tumor growth in syngeneic murine models. Mechanistically, transcriptomic and chromatin accessibility profiling revealed that oncRNA64585 regulates transcriptional programs governing cell cycle progression and apoptosis through interaction with the Polycomb Repressive Complex 2 (PRC2). Finally, we demonstrate the clinical utility of these signatures: oncRNA profiles in plasma predicted oral cavity cancer with >90% accuracy up to four years prior to clinical diagnosis. These findings establish oncRNAs as active drivers of HNSCC biology and potent tools for early detection and therapeutic targeting.

cancer biology↗

bioRxiv2025

RAMEN: Dissecting individual, additive and interactive gene-environment contributions to DNA methylome variability in cord blood

DNA methylation (DNAme) is the most commonly studied epigenetic mark in human populations. DNAme has gained attention in the Developmental Origins of Health and Disease field due to its gene expression regulation and potential long-term stability. Genetic variation and environmental exposures are amongst the main factors influencing inter-individual DNAme variability. However, the proportion and genomic distribution of their individual, additive and interactive effects on the DNA methylome remains unclear. Here, we introduce RAMEN, a Findable, Accessible, Interoperable, and Reusable (FAIR) framework tailored for DNAme microarrays. Using machine learning and statistical techniques, RAMEN models and dissects gene-environment contributions to genome-wide Variably Methylated Regions (VMRs), while controlling for spurious associations. To comprehensively test the power of RAMEN, we analyzed and characterized VMRs from cord blood samples from two independent cohorts (CHILD and PREDO; overall n=1,662). We identified genetics as a consistent key contributor to DNAme variability, usually in additive and interactive combinations with the environment, with genetic terms explaining the largest proportion of DNAme variance, compared to environmental and interaction terms. Operationalizing RAMEN as an R package to conduct scalable genome-exposome contribution analyses, our results highlighted the importance of genetic variation in sculpting DNAme patterns in early life.

bioinformatics↗

bioRxiv2025

Single-cell transcriptomic analysis of HPV-related multiphenotypic sinonasal carcinoma uncovers MYB-HPV association

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a rare tumor that morphologically resembles high grade adenoid cystic carcinoma (ACC), yet exhibits indolent clinical behavior. Both demonstrate MYB proto-oncogene upregulation, but HMSC lacks the MYB translocation typically seen in ACC. Transcriptional changes in HMSC tumors remain uncharacterized. We performed single-cell RNA sequencing (scRNA-seq) on a human HMSC tumor and compared expression profiles with published ACC and oropharyngeal squamous cell carcinoma (OPSCC) scRNA-seq datasets. Primary malignant cells from HMSC (n=134) and ACC (n=980) clustered separately, and HMSC lacked bicellular differentiation into luminal and myoepithelial cells, distinguishing it from ACC. A greater proportion of HMSC cells expressing HPV-related genes (HPVon) expressed MYB (83% vs. 62%, p=0.022) and MYB targets (p=6.4*10-6), suggesting an HPV-MYB association. This finding was validated in HPV-positive OPSCC, with 7/10 tumors showing MYB upregulation in HPVon versus HPVoff cells (p<0.05). A 264-gene signature from HPVon HMSC cells was also associated with worse prognosis in HPV+ OPSCC (p<0.003), suggesting an alternate role for HPV that has not been well characterized. Further validation of the HPV-MYB association and prognostically relevant HPV gene signature may improve patient stratification and therapeutic strategies in HPV-related malignancies.

cancer biology↗

bioRxiv2022

Epigenome-wide association study analysis of calorie restriction in humans, CALERIE™ Trial analysis

BACKGROUNDCalorie restriction (CR) increases healthy lifespan and is accompanied by slowing or reversal of aging-associated DNA methylation (DNAm) changes in animal models. In the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) human trial we evaluated associations of CR and changes in whole-blood DNAm. METHODSCALERIE randomized 220 healthy, non-obese adults in a 2:1 allocation to two years of CR or ad libitum (AL) diet. The average CR in the treatment group through 24-months of follow-up was 12%. Whole blood (baseline, 12 and 24 month) DNAm profiles were measured. Epigenome-wide association study (EWAS) analysis tested CR-induced changes from baseline to 12- and 24-months in the n=197 participants with available DNAm data. RESULTSNo CpG-site-specific changes with CR reached epigenome-wide significance (FDR<0.05). Secondary analyses of CpG sites identified in published EWAS suggest, we found that CR induced DNAm changes opposite those associated with body mass index (BMI) and smoking (p<0.003 at 12- and 24-month follow-ups). In contrast, CR altered DNAm at chronological-age associated CpG sites in the direction of older age (p<0.003 at 12- and 24-month follow-ups). CONCLUSIONAlthough individual CpG site DNAm changes in response to CR were not identified, analyses of sets CpGs identified in prior EWAS revealed CR-induced changes to blood DNAm. Altered CpG sets were enriched for insulin-production, glucose-tolerance, inflammation, and DNA-binding and -regulation pathways, several of which are known to be modified by CR. DNAm changes may contribute to CR effects on aging.

genomics↗

bioRxiv2022

HIV, Pathology and epigenetic age acceleration in different human tissues

BackgroundEpigenetic clocks based on patterns of DNA methylation have great importance in understanding aging and disease; however, there are basic questions to be resolved in their application. It remains unknown whether epigenetic age acceleration (EAA) within an individual shows strong correlation between different primary tissue sites, the extent to which tissue pathology and clinical illness correlates with EAA in the target organ, and if EAA variability across tissues differs according to sex. Considering the outsized role of age-related illness in Human Immunodeficiency Virus-1 (HIV), these questions were pursued in a sample enriched for tissue from HIV-infected individuals. MethodsWe used a custom methylation array to generate DNA methylation data from 661 samples representing 11 human tissues (adipose, blood, bone marrow, heart, kidney, liver, lung, lymph node, muscle, spleen, and pituitary gland) from 133 clinically-characterized, deceased individuals, including 75 infected with HIV. We developed a multimorbidity index based on the clinical disease history. ResultsEpigenetic age was moderately correlated across tissues. Blood had the greatest number and degree of correlation, most notably with spleen and bone marrow. However, blood did not correlate with epigenetic age of liver. EAA in liver was weakly correlated with EAA in kidney, adipose, lung, and bone marrow. Clinically, hypertension was associated with EAA in several tissues, consistent with the multi-organ impacts of this illness. HIV infection was associated with positive age acceleration in kidney and spleen. Male sex was associated with increased epigenetic acceleration in several tissues. Preliminary evidence indicates that Amyotrophic Lateral Sclerosis is associated with positive EAA in muscle tissue. Finally, greater multimorbidity was associated with greater EAA across all tissues. ConclusionBlood alone will often fail to detect EAA in other tissues. While hypertension is associated with increased EAA in several tissues, many pathologies are associated with organ-specific age acceleration.

molecular biology↗

bioRxiv2018

Variably methylated regions in the newborn epigenome: environmental, genetic and combined influences

BackgroundEpigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. We examined the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs), defined as consecutive CpGs showing the highest variability of DNAm in 4 independent cohorts (PREDO, DCHS, UCI, MoBa, N=2,934).\n\nResultsWe used Akaikes information criterion to test which factors best explained variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E) including maternal demographic, psychosocial and metabolism related phenotypes, genotypes in cis (G), or their additive (G+E) or interaction (GxE) effects. G+E and GxE models consistently best explained variability in DNAm of VMRs across the cohorts, with G explaining the remaining sites best. VMRs best explained by G, GxE or G+E, as well as their associated functional genetic variants (predicted using deep learning algorithms), were located in distinct genomic regions, with different enrichments for transcription and enhancer marks. Genetic variants of not only G and G+E models, but also of variants in GxE models were significantly enriched in genome wide association studies (GWAS) for complex disorders.\n\nConclusionGenetic and environmental factors in combination best explain DNAm at VMRs. The CpGs best explained by G, G+E or GxE are functionally distinct. The enrichment of GxE variants in GWAS for complex disorders supports their importance for disease risk.

genetics↗