Biology subjects

Vuong, C. K.

Publications and source records attributed to Vuong, C. K..

4 recordsLinked to original sources

bioRxiv2026

scRBP infers cell-specific RNA-binding protein regulons from single-cell transcriptomes at gene and isoform resolution

Single-cell regulatory network inference remains dominated by transcription factors, despite RNA-binding proteins (RBPs) orchestrating major aspects of transcriptional regulation. We present scRBP, a framework that infers motif-supported RBP regulons from short- and long-read single-cell transcriptomes at gene and isoform resolution, resolves targets by transcript region (5'UTR, CDS, intron, 3'UTR), scores regulon activity in individual cells, and tests common- and rare-variant association against matched empirical nulls. From 20,746 motifs for 616 RBPs, scRBP recovered experimentally defined targets across 223 ENCODE eCLIP datasets at gene and isoform level. Across 30 tissues, transcript-region preferences separated 3'UTR-associated stability factors from intron-dominant splicing regulators. In published genome-scale CRISPRi Perturb-seq data, scRBP-inferred targets were over-represented among genes responding to RBP knockdown (1.4-2.5-fold across 161 RBPs; FDR<2x10-4). Across 6.2 million cells and 50 traits, scRBP prioritized cell-specific post-transcriptional programs linking human genetic risk to development and disease.

genetics↗

bioRxiv2025

A single cell multi-omic analysis identifies molecular and gene-regulatory mechanisms dysregulated in the developing Down syndrome neocortex

Down syndrome is the most common genetic cause of intellectual disability, presenting with cognitive, learning, memory, and language deficits. The cellular and molecular mechanisms driving this disorder remain unclear, limited by a lack of systematic studies in the developing human brain. Here, we leveraged single-nucleus multi-omics to profile the mid-gestation neocortex in a cohort of 26 donors. We observed a reduction in neural progenitors and corticothalamic neurons and concomitant increase of intratelencephalic neurons, accompanied by accelerated time to neuronal specification. We uncovered widespread changes in gene expression, chromatin accessibility and cell interaction networks impacting neurogenesis, specification and maturation and gene-regulatory networks directing these processes, including those downstream of transcription factors encoded in chromosome 21. Finally, we identified cell-specific molecular pathways shared with other neurodevelopmental disorders as well as heritability enrichment of GWAS signals in altered chromatin. Together, our data revealed a cascade of molecular dysregulation outlining the earliest steps in Down syndrome, providing a foundation for future therapeutic targets.

genomics↗

bioRxiv2023

KAT6A mutations drive transcriptional dysregulation of cell cycle and Autism risk genes in an Arboleda-Tham Syndrome cerebral organoid model

Arboleda-Tham Syndrome (ARTHS, OMIM#616268) is a rare neurodevelopmental disorder caused by de novo mutations in KAT6A. Individuals with ARTHS typically exhibit varying degrees of intellectual disability, speech and language deficits and clinical manifestations across multiple systems that lead to abnormal: vision, craniofacial features, cardiac morphology, and gastrointestinal function. To gain insight into the potential neuropathological mechanisms underlying ARTHS, we investigate how KAT6A mutations disrupt in vitro brain development using induced pluripotent stem cells (iPSCs) and cerebral organoids (COs) derived from ARTHS patients harboring KAT6A nonsense mutations. In this study, we conducted comprehensive transcriptomic profiling by performing time-course experiments and generating short-read and long-read RNA sequencing (RNA-seq) data from undifferentiated iPSCs and COs at 15 and 25 days of neural differentiation. Our analysis revealed abnormal expression of 235 genes in ARTHS across all three timepoints examined. Notably, we observed persistent dysregulation of genes such as CTSF, ZNF229, PCDHB12, and PAK3. Additionally, we found a consistent enrichment of PTBP1-target genes among the upregulated genes in ARTHS at all three stages assessed by RNA-seq. During neural differentiation, we identified 980 genes that consistently display aberrant transcription in ARTHS at both CO stages. These genes are enriched for genes involved in cell fate determination through modulation of cell-cycle dynamics (e.g. E2F family) and cell-adhesion molecules (e.g. PCDH genes). Our findings indicate that ARTHS COs exhibit slower downregulation of pluripotency and cell cycle genes compared to controls and that this delay led to an overrepresentation of cycling human neural progenitor markers during neural differentiation in ARTHS. Finally, matching the variable neurodevelopment phenotypes in ARTHS, we discovered that the aberrantly expressed genes in ARTHS are enriched for genes associated with Autism Spectrum Disorder and Epilepsy, with a subset showing isoform-specific dysregulation. Strikingly, the same PTBP1-target genes were enriched amongst the genes that display differential isoform usage in ARTHS. For the first time, we demonstrate that KAT6A mutations lead to a delay in repressing pluripotency and cell cycle genes during neural differentiation, suggesting that prolonged activation of these gene networks disrupts the temporal dynamics of human brain development in ARTHS.

genetics↗

bioRxiv2018

A single cell transcriptomic analysis of human neocortical development

Defining the number, proportion, or lineage of distinct cell types in the developing human brain is an important goal of modern brain research. We defined single cell transcriptomic profiles for 40,000 cells at mid-gestation to identify cell types in the developing human neocortex. We define expression profiles corresponding to all known major cell types at this developmental period and identify multiple transcription factors and co-factors expressed in specific cell types, providing an unprecedented resource for understanding human neocortical development including the first single-cell characterization of human subplate neurons. We characterize major developmental trajectories during early neurogenesis, showing that cell type differentiation occurs on a continuum that involves transitions that tie cell cycle progression with early cell fate decisions. We use these data to deconvolute regulatory networks and map neuropsychiatric disease genes to specific cell types, implicating dysregulation of specific cell types, as the mechanistic underpinnings of several neurodevelopmental disorders. Together these results provide an extensive catalog of cell types in human neocortex and extend our understanding of early cortical development, human brain evolution and the cellular basis of neuropsychiatric disease.\n\nOne Sentence SummaryComprehensive single cell transcriptomes in developing human cortex inform models of cell diversity, differentiation and disease risk.

neuroscience↗