Biology subjects

Mariappan, A.

Publications and source records attributed to Mariappan, A..

7 recordsLinked to original sources

bioRxiv2025

CCB79 is a primate-specific cilium initiation factor essential to maintain neural progenitor diversity in developing brain tissue.

Identifying the genes that regulate the accurate spatiotemporal diversity of neural progenitor cells (NPCs) helps to understand the mechanisms of human neocortex expansion. In primate brains, an additional intermediate progenitor layer, the outer subventricular zone (oSVZ), facilitates the expansion of the neocortex. Here, we identify an uncharacterized gene, KIAA0408, and show that its expression is enriched in intermediate progenitors. Removing KIAA0408 in human-induced pluripotent stem cell (iPSC)-derived brain organoids results in an impaired cortical organization characterized by abnormal cell fate and patterning defects, including the depletion of intermediate and ventral progenitors. Molecularly, KIAA0408 codes for a 79-kilodalton centriolar distal appendage protein (DAP) that controls cilium biogenesis (hereafter CCB79). CCB79 forms a complex with other DAP components and specifically localizes in the DAP at the onset of ciliogenesis, and its absence blocks ciliogenesis. Mechanistically, progenitors in 3D brain tissues are unable to form cilia, which induces aberrant hedgehog signaling and causes premature differentiation. Finally, human CCB79, rather than the mouse ortholog, rescues cilia defects, suggesting that CCB79 has undergone rapid evolution from rodents to primates to fine-tune ciliogenesis for proper brain development.

neuroscience↗

bioRxiv2024

High-Resolution Multimodal Profiling of Human Epileptic Brain Activity via Explanted Depth Electrodes

Understanding neurological disorders necessitates systems-level approaches that integrate multimodal data, but progress has been hindered by limited sample availability, and the absence of combined electrophysiological and molecular data from live patients. Here, we demonstrate that intracranial stereoelectroencephalography (SEEG) electrodes used for identifying the seizure focus in epilepsy patients enable the integration of RNA sequencing, genomic variants and epigenome maps with in vivo recordings and brain imaging. Specifically, we report a method, MoPEDE (Multimodal Profiling of Epileptic Brain Activity via Explanted Depth Electrodes) that recovers extensive protein-coding transcripts, DNA methylation and mutation profiles from explanted SEEG electrodes matched with electrophysiological and radiological data allowing for high-resolution reconstructions of brain structure and function in human patients. Our study shows that epilepsies of different aetiologies have distinct molecular landscapes and identify transcripts correlating with neurophysiological signals, including immediate early genes, inflammation markers, and axon guidance molecules. Additionally, we identify DNA methylation profiles indicative of transcriptionally permissive or restrictive chromatin states. While gene expression gradients corresponded with the assigned epileptogenicity index, we found outlier molecular fingerprints in some electrodes, potentially indicating seizure generation or propagation zones not detected during electroclinical assessments. These findings validate that RNA profiles, genetic variation and genome-wide epigenetic data from explanted SEEG electrodes offer high-resolution surrogate molecular landscapes of brain activity. Our transformative MoPEDE approach has the potential to enhance diagnostic decisions and deepen our understanding of epileptogenic network processes in the human brain.

genomics↗

bioRxiv2023

Deciphering the gene regulatory circuitry governing chemoresistance in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, due in part to extensive intratumoral heterogeneity, high rates of metastasis and chemoresistance, leading to poor clinical outcomes. Despite progress, the mechanistic basis of chemotherapy resistance in TNBC patients remains poorly understood. Here, using single-cell transcriptome datasets of matched longitudinal TNBC chemoresponsive and chemoresistant patient cohorts, we discover cell subpopulations associated with chemoresistance and the signature genes defining these populations. Notably, we show that the expression of these chemoresistance genes is driven via a set of TNBC super-enhancers and transcription factor networks across TNBC subtypes. Furthermore, genetic screens reveal that a subset of these transcription factors is essential for the survival of TNBC cells and their loss increases sensitivity to chemotherapeutic agents. Overall, our study has revealed transcriptional regulatory networks underlying chemoresistance and suggests novel avenues to stratify and improve the treatment of patients with a high risk of developing resistance.

cancer biology↗

bioRxiv2022

Inhibition of Centrosome Clustering Reduces Cystogenesis and Improves Kidney Function in Autosomal Dominant Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inherited monogenic disorder accounting for [~]5% of patients with renal failure. Yet, therapeutics for the treatment of ADPKD remain limited. ADPKD tissues display defects in the biogenesis of the centrosome which causes genome instability, aberrant ciliary signaling, and secretion of pro-inflammatory factors that drive cyst growth and fibrosis. Cystic cells form excess centrosomes via a process termed centrosome amplification (CA), which often causes abnormal multipolar spindle configurations, mitotic catastrophe, and reduced cell viability. However, cells with CA can suppress multipolarity via "centrosome clustering", a key mechanism by which cells circumvent apoptosis. Here, we demonstrate that inhibiting centrosome clustering can counteract the proliferation of renal cystic cells with high incidences of CA. Using ADPKD human cells and mouse models, we show that blocking centrosome clustering with two inhibitors, CCB02 and PJ34, blocks cyst initiation and growth in vitro and in vivo. Inhibition of centrosome clustering activates a p53-mediated mitotic surveillance mechanism leading to apoptosis, reduced cyst expansion, interstitial fibrosis, and improved kidney function. Transcriptional analysis of kidneys from treated mice identified pro-inflammatory signaling pathways implicated in CA-mediated cystogenesis and fibrosis. Our results provide the first evidence that centrosome clustering is a cyst-selective target for the improvement of renal morphology and function in ADPKD.

developmental biology↗

bioRxiv2021

Human brain organoids assemble functionally integrated bilateral optic vesicles

During embryogenesis, optic vesicles develop from the diencephalon via a complex process of organogenesis. Using iPSC-derived human brain organoids, we attempted to simplify the complexities and demonstrate the formation of forebrain-associated bilateral optic vesicles, cellular diversity, and functionality. Around day thirty, brain organoids could assemble optic vesicles, which progressively develop as visible structures within sixty days. These optic vesicle-containing brain organoids (OVB-Organoids) constitute a developing optic vesicles cellular components, including the primitive cornea and lens-like cells, developing photoreceptors, retinal pigment epithelia, axon-like projections, and electrically active neuronal networks. Besides, OVB-Organoids also display synapsin-1, CTIP-positive, myelinated cortical neurons, and microglia. Interestingly, various light intensities could trigger photoreceptor activity of OVB-Organoids, and light sensitivities could be reset after a transient photo bleach blinding. Thus, brain organoids have the intrinsic ability to self-organize forebrain-associated primitive sensory structures in a topographically restricted manner and can allow conducting interorgan interaction studies within a single organoid.

developmental biology↗

bioRxiv2020

Cilium induction triggers differentiation of glioma stem cells

Glioblastoma multiforme (GBM) possesses glioma stem cells (GSCs) that promote self-renewal, tumor propagation, and relapse. GBM has a poor prognosis, and currently, there are no curative options exist. Understanding the mechanisms of GSCs self-renewal can offer targeted therapeutic interventions. However, insufficient knowledge of the fundamental biology of GSCs is a significant bottleneck hindering these efforts. Here, we show that patient-derived GSCs recruit an elevated level of proteins that ensure the temporal cilium disassembly, leading to suppressed ciliogenesis. Depleting the cilia disassembly complex components at the ciliary base is sufficient to induce ciliogenesis in a subset of GSCs. Importantly, restoring ciliogenesis caused GSCs to behave like healthy NPCs switching from self-renewal to differentiation. Finally, using an organoid-based glioma invasion assay and brain xenografts in mice, we establish that ciliogenesis-induced differentiation can prevent the infiltration of GSCs into the brain. Our findings illustrate a crucial role for cilium as a molecular switch in determining GSCs fate and suggest that cilium induction is an attractive strategy to intervene in GSCs proliferation.

cell biology↗

bioRxiv2020

SARS-CoV-2 targets cortical neurons of 3D human brain organoids and shows neurodegeneration-like effects

COVID-19 pandemic caused by SARS-CoV-2 infection is a public health emergency. COVID-19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS-CoV-2 on the central nervous system (CNS). Here, we show that a Dusseldorf isolate of SARS-CoV-2 enters 3D human brain organoids within two days of exposure. Using COVID-19 convalescent serum, we identified that SARS-CoV-2 preferably targets soma of cortical neurons but not neural stem cells, the target cell type of ZIKA virus. Imaging cortical neurons of organoids reveal that SARS-CoV-2 exposure is associated with missorted Tau from axons to soma, hyperphosphorylation, and apparent neuronal death. Surprisingly, SARS-CoV-2 co-localizes specifically with Tau phosphorylated at Threonine-231 in the soma, indicative of early neurodegeneration-like effects. Our studies, therefore, provide initial insights into the impact of SARS-CoV-2 as a neurotropic virus and emphasize that brain organoids could model CNS pathologies of COVID-19. One sentence summaryCOVID-19 modeling in human brain organoids

cell biology↗