Biology subjects

Chan, S. Y.

Publications and source records attributed to Chan, S. Y..

15 recordsLinked to original sources

bioRxiv2026

Epigenetic and brain age across development: Performance and associations in the MIND consortium

Understanding how biological age measures perform across development lays the groundwork for investigations into lifespan trajectories of healthy aging. We provide the most comprehensive assessment of epigenetic and brain age models across development (birth to 24 years; [≤]20,917 observations across 15 cohorts), evaluating how these models associate with chronological age and with each other, and how these associations change across development. Chronological age-prediction accuracy of epigenetic and brain age models was modest and varied substantially. Accuracy improved with age and stabilized by middle childhood. Few brain and fewer epigenetic clocks performed stably and well across all developmental stages. Performance was better when age range and tissue corresponded between training and testing data. Associations between epigenetic-brain age residuals were small, and changed little across development, tissues or clock generation. Given this developmentally dynamic system of epigenetic-brain age performances and associations, we give key recommendations to improve developmental research in this field.

neuroscience↗

bioRxiv2026

Developing a multi-modal neuroimaging-based BrainAge model across childhood

BrainAge models hold promise as a clinical biomarker for developmental brain health, especially in childhood when there is the potential for early intervention. To distinguish between normative developmental variance and pathological divergence, BrainAge models should reflect the dynamic and diverse neurodevelopmental processes that occur in distinct developmental windows across childhood. We utilized multi-modal neuroimaging data from three pediatric cohorts covering ages 4 to 13 years (n = 1005, 2126 scans), split into Train and Test datasets. Twelve sex-stratified BrainAge models were built stratified by type and different combinations of neuroimaging features. Model types were "Full-Span" models covering the full age range, and "Phase-Specific" models split into early- and late-childhood. We first compared BrainAge estimates in the Test dataset amongst our candidate models, then benchmarked the best-performing model against published pre-trained models and DNA-based biological age measures. Our findings show that a BrainAge model that was phase-specific and consisted of both structural and functional features (cortical thickness, subcortical volumes, and functional network integration measures) showed good prediction of age and best distinguished between healthy and symptomatic subgroups. We present a proof-of-concept for developmental models supporting building BrainAge models of higher temporal resolution that align to different childhood developmental phases.

neuroscience↗

bioRxiv2025

Dual-Channel Event Microscopy for Ultrafast Biological Imaging

Many fundamental biological processes--spanning immune-tumor interactions, neuronal signaling, and microvascular flow--exhibit fast, multiscale dynamics among diverse cell types within three-dimensional tissue environments. Capturing such activity requires imaging systems that simultaneously achieve high temporal resolution, multicolor capability, and volumetric coverage over large fields of view (FOVs). However, existing modalities remain limited by trade-offs among imaging speed, spectral capacity, depth of field (DOF), and spatial resolution. Here, we present Dual-Channel Event Microscopy (DEM), which integrates digital micromirror device (DMD)-based pulsed illumination, extended-DOF optics, and event-based sensing for ultrafast, dual-channel volumetric imaging across a 2.3 x 1.3 mm2 FOV with an effective 200 {micro}m DOF. Using dual-color fluorescent phantoms and microsphere flow assays, DEM achieves accurate spectral separation and reconstruction of rapid motion at kilohertz frame rates. In vivo, DEM enables simultaneous visualization of neutrophils and premalignant tumors in freely swimming zebrafish. In immobilized specimens, it provides robust, sensor-level optical sectioning near the heart, suppressing diffuse background to reveal fine vascular networks and active blood circulation into and out of the cardiac chambers. DEM further enables quantitative mapping of blood-flow dynamics in the zebrafish tail, resolving arterial-venous differences and capturing heartbeat-driven oscillations that reflect cardiac pumping with high temporal fidelity. By uniting ultrafast acquisition, dual-channel capability, volumetric coverage, and intrinsic optical sectioning within a single event-driven architecture, DEM offers a powerful platform for visualizing rapid multicellular interactions and physiological dynamics in living systems.

bioengineering↗

bioRxiv2025

Bidirectional Crosstalk Between Sleep and Pulmonary Arterial Hypertension

BackgroundPulmonary Arterial Hypertension (PAH) is a devastating cardiopulmonary disease characterized by pulmonary vascular remodeling due to vascular cells dysfunction. Among other clinical signs, emerging data suggest poor sleep quality in patients with PAH; however, how poor sleep impacts hemodynamic burden, symptom severity, and pulmonary vascular remodeling during PAH progression remains unknown. MethodsWe used two models of sleep disturbances (sleep fragmentation and chronic jet lag) and different mouse models of PAH to determine the effects of poor sleep on PAH. We carried out timepoint quantitative RT-PCR analyses to define the clock gene oscillations in human pulmonary artery smooth muscle cells (PASMCs) isolated from non-PAH and PAH patients. Bulk RNA-sequencing analysis, immunostaining, and proliferation assays were used to explore the mechanisms by which poor sleep impacts PAH. Electroencephalogram and Electromyogram recordings (EEG/EMG) were used to determine whether PAH affects sleep in mice. ResultsPoor sleep exacerbated right ventricular dysfunction, pulmonary vascular remodeling, and PAH. RNA-seq and immunostaining analyses showed that poor sleep induces lung inflammation. Inflammation affected the pulmonary vascular molecular clock to drive PASMC hyperproliferation and increased migration. SMC-specific deletion of Bmal1 protected mice from RV dysfunction, pulmonary vascular remodeling, and PAH. EEG/EMG measurements demonstrated that PAH causes poor sleep quality in mice. Lastly, we showed that improving sleep via melatonin delivery and blunting inflammation with clodronate inhibited pulmonary vascular remodeling and PAH. ConclusionsOur study demonstrates that PAH causes poor sleep which in turn induces inflammation, increases PASMC proliferation, and exacerbates PAH. This suggests that the relationship between PAH and poor sleep is a self-amplifying cycle, and that a combination of hypnotic and anti-inflammatory drugs may give PAH patients better clinical outcomes. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIPAH causes poor sleep quality which in turn induces lung inflammation, PASMC proliferation, and exacerbated PAH. C_LIO_LIBmal1 rhythmicity is disrupted, and its expression is increased in lungs of patients with PAH. C_LIO_LISMC-specific deletion of Bmal1 protects from PAH. C_LIO_LIImproving sleep quality and blunting inflammation attenuates PAH. C_LI What Are the Clinical Implications?O_LIBmal1 represents a promising disease-modifying agent with potential for clinical translation in the treatment of PAH. C_LIO_LIA combination of hypnotic and anti-inflammatory drugs has therapeutic potential to treat PAH. C_LI

pathology↗

bioRxiv2025

Adropin protects against cardiac metabolic remodeling and dysfunction in HFpEF

Cardiometabolic heart failure with preserved ejection fraction (HFpEF) is a heterogenous metabolic disease, which in the heart presents as left ventricle diastolic dysfunction, ventricular stiffness, and myocardial structural remodeling. Deleterious changes in cardiac metabolism are central to HFpEF pathophysiology, and proposed treatments for the disease have focused on repairing these defects. In this study, we used a preclinical mouse model that recapitulates cardiometabolic HFpEF to elucidate the molecular mechanisms driving cardiac dysfunction, and tested whether recombinant Adropin (a liver- and brain-derived endogenous peptide hormone) could reverse observed defects. We show that long-term treatment with Adropin reversed multiple markers of HFpEF-related cardiac dysfunction (including fibrosis, diastolic dysfunction, and cardiomyocyte hypertrophy). Using untargeted metabolomics, we found that Adropin treatment reduced hexosamine biosynthesis pathway activity, leading to a reduction in the O-GlcNAcylation of the cardiac fatty acid oxidation enzyme long chain acyl-CoA dehydrogenase (LCAD). Reducing LCAD O-GlcNAcylation increased LCAD activity in vitro, and reduced the accumulation of long-chain acylcarnitines in HFpEF mouse hearts in vivo. Our results suggest that Adropin may restore cardiac metabolic function in HFpEF, and that targeting this pathway may be a novel therapeutic avenue for this disease. CLINICAL PERSPECTIVE- Adropin is a circulating liver- and brain-derived peptide that regulates energy metabolism in the heart and other high metabolic-demand tissues. The plasma abundance of Adropin is decreased in diabetic, hypertensive, and aged individuals; all comorbid risk factors for the development of heart failure with preserved ejection (HFpEF). We therefore examined the potential role of Adropin in HFpEF pathophysiology. - Patients with HFpEF display significant reductions in circulating Adropin levels, matching those seen in comorbid diseases. In a mouse model of HFpEF, treatment with recombinant Adropin reduced diastolic dysfunction, cardiac fibrosis, and cardiomyocyte hypertrophy. - These data suggest that targeting the Adropin pathway may represent a new therapeutic approach in HFpEF.

physiology↗

bioRxiv2024

Frataxin deficiency in the astrocytes drives neurocognitive impairment in sickle cell disease mice

Individuals with sickle cell disease (SCD) suffer from a high burden of cerebrovascular lesions and cognitive impairment that vastly impact quality of life. Cerebrovascular lesions are characterized by microstructural neuroaxonal damage, but their pathogenesis has not been fully elucidated. Herein, we report that SCD mice (SS) have reduced expression of frataxin (FXN), a mitochondrial protein, in their astrocytes compared to control (AA) mice. Next, we generated chimeric mice with SS bone marrow and astrocyte-specific deletion of FXN (SSFXN-KO). Ex-vivo diffusion tensor magnetic resonance imaging and immunohistopathology of the brain showed that the SSFXN-KO mice have increased white matter neuroaxonal damage compared to the SS bone marrow chimera mice with wild-type FXN expression (SSFXN-WT). The SSFXN-KO mice also displayed poorer cognitive function as measured by the functional Y-maze and novel object recognition tests. Pharmacological induction of FXN by administration of insulin growth factor-1 improved cognitive function in the SSFXN-KO mice. Overall, our data demonstrate that FXN is a critical factor regulating neuroaxonal health and cognitive function in SCD mice. FXN may therefore be a novel pharmacologic target to prevent cerebrovascular complications in SCD.

neuroscience↗

bioRxiv2024

Immunosuppression Drugs Exhibit Differential Effects on Endothelial Cell Function

Immunosuppressive medications are widely used to treat patients with neoplasms, autoimmune conditions, and solid organ transplants. Prior studies indicate that immunosuppression drugs can cause adverse vascular remodeling. Given the systemic effects of the drugs, elucidating cell-type specific drug-effects has been challenging. We utilized induced pluripotent stem-cell derived endothelial cells to investigate the role of widely used immunosuppression drugs on endothelial function. We found that among immunosuppression agents, sirolimus reduced basic endothelial cell functions including cell migration, proliferation, acetylated LDL uptake, and angiogenesis properties; while tacrolimus only reduced nitric oxide release. This model allows for investigation of differential effect of immunosuppression drugs on endothelial function that can elucidate mechanisms contributing to adverse vascular profiles observed clinically.

cell biology↗

bioRxiv2024

Post-transcriptional regulation of IFI16 promotes inflammatory endothelial pathophenotypes observed in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease driven by endothelial cell inflammation and dysfunction, resulting in the pathological remodeling of the pulmonary vasculature. Innate immune activation has been linked to PAH development; however, the regulation, propagation, and reversibility of the induction of inflammation in PAH is poorly understood. Here, we demonstrate a role for interferon inducible protein 16 (IFI16), an innate immune sensor, as a modulator of endothelial inflammation in pulmonary hypertension, utilizing human pulmonary artery endothelial cells (PAECs). Inflammatory stimulus of PAECs with IL-1{beta} up-regulates IFI16 expression, inducing proinflammatory cytokine up-regulation and cellular apoptosis. IFI16 mRNA stability is regulated by post-transcriptional m6A modification, mediated by Wilms tumor 1-associated protein (WTAP), a structural stabilizer of the methyltransferase complex, via regulation of m6A methylation of IFI16. Additionally, m6A levels are increased in the peripheral blood mononuclear cells of PAH patients compared to control, indicating that quantifying this epigenetic change in patients may hold potential as a biomarker for disease identification. In summary, our study demonstrates IFI16 mediates inflammatory endothelial pathophenotypes seen in pulmonary arterial hypertension.

cell biology↗

bioRxiv2024

Mitigation of Stress-induced Structural Remodeling and Functional Deficiency in iPSC-CMs with PLN R9C Mutation by Promoting Autophagy

BackgroundPhospholamban (PLN) is a key regulator of cardiac function connecting adrenergic signaling and calcium homeostasis. The R9C mutation of PLN is known to cause early onset dilated cardiomyopathy (DCM) and premature death, yet the detailed mechanisms underlie the pathologic remodeling process are not well defined in human cardiomyocytes. The aim of this study is to unravel the role of PLN R9C in DCM and identify potential therapeutic targets. MethodsPLN R9C knock-in (KI) and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated and comprehensively examined for their expression profile, contractile function, and cellular signaling under both baseline conditions and following functional challenges. ResultsPLN R9C KI iPSC-CMs exhibited near-normal morphology and calcium handling, slightly increased contractility, and an attenuated response to {beta}-adrenergic activation compared to wild-type (WT) cells. However, treatment with a maturation medium (MM) has induced fundamentally different remodeling in the two groups: while it improved the structural integrity and functional performance of WT cells, the same treatment result in sarcomere disarrangement, calcium handling deficiency, and further disrupted adrenergic signaling in PLN R9C KI cells. To understand the mechanism, transcriptomic analysis showed the enrichment of protein homeostasis signaling pathways specifically in PLN R9C KI cells in response to the MM treatment and increased contractile demands. Further studies also indicated elevated ROS levels, interrupted autophagic flux, and increased pentamer PLN aggregation in functionally challenged KI cells. These results were further confirmed in patient-specific iPSC-CM models, suggesting that functional stresses exacerbate the deficiencies in PLN R9C cells through disrupting protein homeostasis. Indeed, treating stressed patient cells with autophagy-accelerating reagents, such as metformin and rapamycin, has restored autophagic flux, mitigated sarcomere disarrangement, and partially rescued {beta}-adrenergic signaling and cardiac function. ConclusionsPLN R9C leads to a mild increase of calcium recycling and contractility. Functional challenges further enhanced contractile and proteostasis stress, leading to autophagic overload, structural remodeling, and functional deficiencies in PLN R9C cardiomyocytes. Activation of autophagy signaling partially rescues these effects, revealing a potential therapeutic target for DCM patients with the PLN R9C mutation. Graphic abstractsA graphic abstract is available for this article.

molecular biology↗

bioRxiv2024

Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension

Vascular inflammation critically regulates endothelial cell (EC) pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulation of lysosomal activity and cholesterol metabolism have known inflammatory roles in disease, but their relevance to PAH is unclear. In human pulmonary arterial ECs and in PAH, we found that inflammatory cytokine induction of the nuclear receptor coactivator 7 (NCOA7) both preserved lysosomal acidification and served as a homeostatic brake to constrain EC immunoactivation. Conversely, NCOA7 deficiency promoted lysosomal dysfunction and proinflammatory oxysterol/bile acid generation that, in turn, contributed to EC pathophenotypes. In vivo, mice deficient for Ncoa7 or exposed to the inflammatory bile acid 7-hydroxy-3-oxo-4-cholestenoic acid (7HOCA) displayed worsened PAH. Emphasizing this mechanism in human PAH, an unbiased, metabolome-wide association study (N=2,756) identified a plasma signature of the same NCOA7-dependent oxysterols/bile acids associated with PAH mortality (P<1.1x10-6). Supporting a genetic predisposition to NCOA7 deficiency, in genome-edited, stem cell-derived ECs, the common variant intronic SNP rs11154337 in NCOA7 regulated NCOA7 expression, lysosomal activity, oxysterol/bile acid production, and EC immunoactivation. Correspondingly, SNP rs11154337 was associated with PAH severity via six-minute walk distance and mortality in discovery (N=93, P=0.0250; HR=0.44, 95% CI [0.21-0.90]) and validation (N=630, P=2x10-4; HR=0.49, 95% CI [0.34-0.71]) cohorts. Finally, utilizing computational modeling of small molecule binding to NCOA7, we predicted and synthesized a novel activator of NCOA7 that prevented EC immunoactivation and reversed indices of rodent PAH. In summary, we have established a genetic and metabolic paradigm and a novel therapeutic agent that links lysosomal biology as well as oxysterol and bile acid processes to EC inflammation and PAH pathobiology. This paradigm carries broad implications for diagnostic and therapeutic development in PAH and in other conditions dependent upon acquired and innate immune regulation of vascular disease. One Sentence SummaryPulmonary arterial hypertension pathophenotypes arise from allele-specific NCOA7 regulation of lysosome function and inflammatory oxysterol generation, as demonstrated by genomic and metabolomic association studies coupled with genetic and pharmacologic mechanistic evidence. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/582142v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@896f6forg.highwire.dtl.DTLVardef@f31c2eorg.highwire.dtl.DTLVardef@bf46dcorg.highwire.dtl.DTLVardef@1c55686_HPS_FORMAT_FIGEXP M_FIG Graphical abstract. C_FIG

physiology↗

bioRxiv2024

Pulmonary primary oxysterol and bile acid synthesis as a predictor of outcomesin pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare and fatal vascular disease with heterogeneous clinical manifestations. To date, molecular determinants underlying the development of PAH and related outcomes remain poorly understood. Herein, we identify pulmonary primary oxysterol and bile acid synthesis (PPOBAS) as a previously unrecognized pathway central to PAH pathophysiology. Mass spectrometry analysis of 2,756 individuals across five independent studies revealed 51 distinct circulating metabolites that predicted PAH-related mortality and were enriched within the PPOBAS pathway. Across independent single-center PAH studies, PPOBAS pathway metabolites were also associated with multiple cardiopulmonary measures of PAH-specific pathophysiology. Furthermore, PPOBAS metabolites were found to be increased in human and rodent PAH lung tissue and specifically produced by pulmonary endothelial cells, consistent with pulmonary origin. Finally, a poly-metabolite risk score comprising 13 PPOBAS molecules was found to not only predict PAH-related mortality but also outperform current clinical risk scores. This work identifies PPOBAS as specifically altered within PAH and establishes needed prognostic biomarkers for guiding therapy in PAH. One-Sentence SummaryThis work identifies pulmonary primary oxysterol and bile acid synthesis as altered in pulmonary arterial hypertension, thus establishing a new prognostic test for this disease.

systems biology↗

bioRxiv2022

Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function

Deficiency of iron-sulfur (Fe-S) clusters promotes metabolic rewiring of the endothelium and the development of pulmonary hypertension (PH) in vivo. Joining a growing number of Fe-S biogenesis proteins critical to pulmonary endothelial function, recent data highlighted that frataxin (FXN) reduction drives Fe-S-dependent genotoxic stress and senescence across multiple types of pulmonary vascular disease. Trinucleotide repeat mutations in the FXN gene cause Friedreichs ataxia, a disease characterized by cardiomyopathy and neurodegeneration. These tissue-specific phenotypes have historically been attributed to mitochondrial reprogramming and oxidative stress. Whether FXN coordinates both nuclear and mitochondrial processes in the endothelium is unknown. Here, we aim to identify the mitochondria-specific effects of FXN deficiency in the endothelium that predispose to pulmonary hypertension. Our data highlight an Fe-S-driven metabolic shift separate from previously described replication stress whereby FXN knockdown diminished mitochondrial respiration and increased glycolysis and oxidative species production. In turn, FXN-deficient endothelial cells exhibited a vasoconstrictive phenotype consistent with PH. These data were observed in both primary pulmonary endothelial cells after pharmacologic inhibition of FXN and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study defines FXN as a shared upstream driver of pathologic aberrations in both metabolism and genomic stability. Moreover, our study highlights FXN-specific vasoconstriction, suggesting available and future therapies may be beneficial and targeted for PH subtypes with FXN deficiency. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/504849v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@12c5568org.highwire.dtl.DTLVardef@19b5f0borg.highwire.dtl.DTLVardef@17d0157org.highwire.dtl.DTLVardef@1e323a0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

The Role of EBP50 in Regulating Endothelial-To-Mesenchymal Transition in Pulmonary Hypertension

ObjectivePulmonary hypertension (PH) is a cardiopulmonary disease manifesting in increased pulmonary arterial pressure and right ventricular dysfunction. PH pathogenesis involves extensive pulmonary vascular remodeling precipitated, at least in part, by endothelial reprogramming. Mounting evidence points to endothelial-to-mesenchymal transition (EndMT) as an important potentiator of endothelial reprogramming in PH, yet progress in dissecting these processes remains limited. Approach and ResultsLung samples from pulmonary arterial hypertension (PAH) patients and two rodent models of PH were used. Expression of the scaffolding protein ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50, or NHERF1) was downregulated in PAH patient pulmonary arteries and isolated pulmonary arterial endothelial cells (PAECs), and in PH animal lung tissue and mouse isolated PAECs. In human PAECs in vitro, EBP50 was downregulated by PH-relevant stimuli, hypoxia and proinflammatory cytokine interleukin-1 beta (IL-1{beta}). Phenocopy of EBP50 reduction in PAECs time-dependently increased expression and nuclear abundance of EndMT transcription factors Snail and Zeb1, and potentiated hypoxia-driven upregulation of Slug. Loss of EBP50 also drove expression of mesenchymal markers S100A4, fibronectin, N-cadherin, and transgelin (SM22), and inhibited cell proliferation and barrier function. In vivo studies on female EBP50+/- mice demonstrated that downregulation of EBP50 exacerbated the chronic hypoxia-induced rise in RV maximum pressure. ConclusionsThese data identify EBP50 as a key regulator of EndMT in PH whose expression is downregulated in PH patient pulmonary endothelium and whose partial deletion exacerbates PH disease manifestations in rodents, opening doors for future therapeutic strategies to target EBP50 restoration to reverse PH.

cell biology↗

bioRxiv2021

The repertoire of testicular extracellular vesicles cargoes and their involvement in inter-compartmental communication required for spermatogenesis

Extracellular vesicles (EVs) secreted by the epididymis and prostate are involved in sperm functions and epigenetic inheritance. However, the EVs in the testis remains unexplored. Here, we have established a testis dissociation protocol that allows the isolation of testicular EVs by minimizing the disruption of fragile sperm cells. We showed that testicular EVs were specifically and efficiently uptaken by somatic cells and germ cells in both interstitial space and seminiferous tubules compartments, including the spermatozoa. We profiled the proteome of testicular EVs and probed the cell types that release them. Moreover, we sequenced the small RNAs cargos of testicular EVs and identified sets of small non-coding RNAs that were overlooked in the testis transcriptome. Selected miRNA candidates in testicular EVs were found in sperm RNA payload and demonstrated specific resistance towards ribonuclease A independent of the vesicle membrane. Small molecule inhibition of EVs secretion increased the apoptosis of germ cells via inter-compartmental communication. Together, our study has provided valuable resources on the cargoes of testicular EVs and revealed the inter-compartmental communication that regulates spermatogenesis and may implicate in paternal inheritance.

cell biology↗

bioRxiv2019

Loss of CIC promotes mitotic dysregulation and chromosome segregation defects

CIC encodes a transcriptional repressor and MAPK signalling effector that is inactivated by loss-of-function mutations in several cancer types, consistent with a role as a tumour suppressor. Here, we used bioinformatic, genomic, and proteomic approaches to investigate CICs interaction networks. We observed both previously identified and novel candidate interactions between CIC and SWI/SNF complex members, and also observed novel interactions between CIC and cell cycle regulators and RNA processing factors. We found that CIC loss is associated with an increased frequency of mitotic defects in human cell lines and an in vivo mouse model and with dysregulated expression of mitotic regulators. We also observed aberrant splicing in CIC-deficient cell lines predominantly at 3 and 5 untranslated regions of genes, including genes involved in MAPK signalling, DNA repair, and cell cycle regulation. Our study thus characterises the complexity of CICs functional network and describes the effect of its loss on cell cycle regulation, mitotic integrity, and transcriptional splicing, thereby expanding our understanding of CICs potential roles in cancers. In addition, our work exemplifies how multi-omic, network-based analyses can be used to uncover novel insights into the interconnected functions of pleiotropic genes/proteins across cellular contexts. Simple summaryCapicua (CIC) is a gene that is frequently mutated in several cancer types, including stomach cancers and certain subtypes of brain tumours and sarcomas. CIC, the protein encoded by the CIC gene, has been shown to play a multitude of roles in both normal and cancer cell functions; however, most studies exploring these roles focus on a single aspect of CIC function and may therefore overlook complex interconnected activities in which CIC is involved. In this study, we have used multiple complementary approaches to obtain a broader view of CICs complex functional networks. We observed novel interactions (genetic or physical) between CIC and genes/proteins involved in various aspects of cellular function, including regulation of cell division and processing of RNA molecules. Altogether, our work characterises the complexity of CICs functional network and expands our understanding of its potential roles in cancer.

cancer biology↗