Biology subjects

Loh, K.

Publications and source records attributed to Loh, K..

4 recordsLinked to original sources

bioRxiv2025

DINOcell: Learning Generalizable Perturbation Effects through Self-Distillation

AO_SCPLOWBSTRACTC_SCPLOWPredicting cellular responses to therapeutics is a promising approach for novel target discovery. However, state-of-the-art computational models designed to predict perturbation effects struggle to generalize and outperform simple baselines. We present DINOcell, a weakly supervised framework that adapts self-distillation to single-cell transcriptomics for predicting perturbation effects. We demonstrate that DINOcell outperforms baselines in predicting the effects of single gene perturbations. Furthermore, DINOcell accurately predicts non-additive effects of combination perturbations, indicating its capacity to model complex genetic interactions. Finally, we show that DINOcell learns representations that capture biological signals and is a promising, generalizable approach for in silico perturbation modeling, providing a valuable tool for accelerating therapeutic target discovery.

bioinformatics↗

bioRxiv2025

Long-read sequencing-based atlas of tissue-specific expression of Drp1 transcript variants

Dynamin-related protein 1 (Drp1), encoded by DNM1L, is essential for mitochondrial fission, but its functional roles remain unclear due to isoform-specific effects from alternative splicing. Short-read RNA sequencing fails to resolve full-length isoforms involving distant exons, limiting our understanding. Here, we applied targeted long-read sequencing to profile full-length DNM1L transcripts in human left ventricle and iPSC-derived cardiomyocytes, recovering all annotated isoforms with conserved expression patterns and isoforms 1-4 being most abundant. Functional assays revealed that isoform abundance does not predict enzymatic activity. Extending this to six mouse tissues, we identified distinct, tissue-enriched expression profiles. Functional rescue in Drp1-knockout mouse embryonic fibroblasts showed isoform-dependent differences in mitochondrial fission. Isoforms lacking the A-insert (e.g., b and d) robustly rescued fission, while isoforms enriched in brain or muscle showed only partial rescue, suggesting exons 2 and 3 negatively regulate Drp1 activity. Our cross-species atlas integrates long-read transcriptomics with functional validation, revealing how isoform diversity underpins tissue-specific mitochondrial dynamics and physiological roles of Drp1. SummaryUsing long-read sequencing, we mapped full-length DNM1L/Dnm1l isoforms in human and mouse tissues, uncovering tissue-specific expression and isoform-dependent mitochondrial fission activity. This reveals how alternative splicing shapes Drp1 function, with implications for understanding its role in health and disease.

cell biology↗

bioRxiv2023

Melanotransferrin Functions as a Pro-Oncogenic WNT Agonist: A Yin-Yang Relationship in Melanoma with the WNT Antagonist and Metastasis Suppressor, NDRG1

A persistent mystery in the melanoma field has been the function of one of the first melanoma tumor antigens characterized, namely p97 (melanotransferrin; MTf). While MTf expression increases melanoma cell proliferation, migration, and tumorigenesis, the molecular mechanism responsible is unknown. On the other hand, N-myc down-stream regulated gene 1 (NDRG1) is a potent metastasis suppressor and WNT antagonist. Expression of NDRG1 in melanoma cells suggests a role in inhibiting metastasis, with this study investigating MTfs role in oncogenic signaling. We demonstrate MTf acts as a pro-oncogenic WNT agonist, which down-regulates NDRG1, while silencing MTf increases NDRG1 expression. In contrast, silencing NDRG1 increases MTf expression. These observations demonstrate a bidirectional negative feedback loop and "Yin-Yang" relationship between MTf and NDRG1. Mechanistically, MTf was directly associated with the WNT co-receptor, lipoprotein-receptor 6 (LRP6), and increased total LRP6 expression, activated p-LRP6 (Ser1490), {beta}-catenin, and activated {beta}-catenin (Ser552) levels, with MTf expression inducing their nuclear accumulation. Additionally, MTf expression increased downstream WNT targets, namely cyclin D1 and c-Myc, with c-Myc down-regulating NDRG1 expression. Silencing c-Myc prevented the Yin-Yang relationship between NDRG1 and MTf, indicating c-Myc played a key role in their inverse regulation. Melanoma patient specimens demonstrated that a low NDRG1/MTf ratio was significantly (p = 0.008) associated with lower survival and metastasis. Chemotherapeutic agents that up-regulated NDRG1 depressed MTf and nuclear LRP6 and potently inhibited melanoma xenograft growth in vivo. This study demonstrates MTf acts as a WNT agonist, with a Yin-Yang relationship being observed with the WNT antagonist, NDRG1.

cancer biology↗

bioRxiv2021

Elevated Neuropeptide Y1 Receptor Signaling Contributes to β-cell Dysfunction and Failure in Type 2 Diabetes

Loss of functional {beta}-cell mass is a key factor contributing to the poor glycaemic control in type 2 diabetes. However, therapies that directly target these underlying processes remains lacking. Here we demonstrate that gene expression of neuropeptide Y1 receptor and its ligand, neuropeptide Y, was significantly upregulated in human islets from subjects with type 2 diabetes. Importantly, the reduced insulin secretion in type 2 diabetes was associated with increased neuropeptide Y and Y1 receptor expression in human islets. Consistently, pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected {beta}-cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, Y1 receptor antagonist BIBO3304 treatment improved {beta}-cell function and preserved functional {beta}-cell mass, thereby resulting in better glycaemic control in both high-fat-diet/multiple low-dose streptozotocin- and db/db type 2 diabetic mice. Collectively, our results uncovered a novel causal link of increased islet NPY-Y1 receptor signaling to {beta}-cell dysfunction and failure in human type 2 diabetes. These results further demonstrate that inhibition of Y1 receptor by BIBO3304 represents a novel and effective {beta}-cell protective therapy for improving functional {beta}-cell mass and glycaemic control in type 2 diabetes.

cell biology↗