Biology subjects

Kaphle, P.

Publications and source records attributed to Kaphle, P..

3 recordsLinked to original sources

bioRxiv2025

Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth

The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated [~]100-fold in HGGs relative to controls, which was caused by imbalanced activities of enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an unexpected function. GAA accumulates in GAMT deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABAA receptors and causing depolarizing GABA currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a new mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.

cancer biology↗

bioRxiv2025

Mutant IDH silences GSX2 to reprogram neural progenitor cell fate and promote gliomagenesis

Isocitrate dehydrogenase (IDH) mutations arise early in gliomas and are associated with a defined neurodevelopmental cancer cell hierarchy. However, how mutant IDH contributes to this hierarchy and whether this interaction promotes gliomagenesis remain unclear. We captured the dynamics of IDH-mutant glioma initiation in genetically engineered mice through time-resolved, single-cell genomics. Mutant IDH activates and induces lineage switching of neural progenitor cells (NPCs). These actions expand oligodendrocyte precursor cells, the predominant cell-of-origin for these tumors, at the expense of interneurons. Lineage switching is mediated by promoter hypermethylation and silencing of Gsx2, a homeobox gene required for neurogenesis. Critically, Gsx2 ablation recapitulates NPC fate reprogramming by mutant IDH. We provide a new model of neural cell fate control by IDH oncogenes and insights into the developmental origins of glioma.

cancer biology↗

bioRxiv2019

Interrogation of Enhancer Function by Enhanced CRISPR Epigenetic Editing

Tissue-specific gene expression requires coordinated control of gene-proximal and -distal cis-regulatory elements (CREs), yet functional analysis of gene-distal CREs such as enhancers remains challenging. Here we describe enhanced CRISPR/dCas9-based epigenetic editing systems, enCRISPRa and enCRISPRi, for multiplexed analysis of enhancer function in situ and in vivo. Using dual effectors capable of re-writing enhancer-associated chromatin modifications, we show that enCRISPRa and enCRISPRi modulate gene transcription by remodeling local epigenetic landscapes at sgRNA-targeted enhancers and associated genes. Comparing with existing methods, the new systems display more robust perturbation of enhancer activity and gene transcription with minimal off-targets. Allele-specific targeting of enCRISPRa to oncogenic TAL1 super-enhancer modulates TAL1 expression and cancer progression in xenotransplants. Multiplexed perturbations of lineage-specific enhancers using an enCRISPRi knock-in mouse establish in vivo evidence for lineage-restricted essentiality of developmental enhancers during hematopoietic lineage specification. Hence, enhanced CRSIPR epigenetic editing provides opportunities for interrogating enhancer function in native biological contexts.

molecular biology↗