Biology subjects

Indralingam, H. S.

Publications and source records attributed to Indralingam, H. S..

4 recordsLinked to original sources

bioRxiv2026

Single-cell Multiome Analysis of Chromatin State and Transcriptome in the Human Basal Ganglia

The basal ganglia play essential roles in motor control, emotion, learning and reward processing. Their dysfunction contributes to many neurological and psychiatric disorders. However, the gene regulatory programs defining basal ganglia cell-type identity and function remain poorly understood, limiting interpretation of disease-associated non-coding variants. Here, we present the first single-cell multiome atlas of histone modifications and transcriptomes across eight basal ganglia regions from neurotypical adult human donors. Joint profiling reveals cell-type-specific deployment of active and repressive cis-regulatory elements and gene regulatory networks, and suggests a combinatorial homeobox transcription factor code underlying cell identity. Integration with matched spatial transcriptomic MERFISH data uncovers regional heterogeneity of epigenomic landscapes. Comparative analysis between human and mouse medium spiny neurons uncovers conservation of core gene regulatory features. This atlas interprets non-coding risk variants of neuropsychiatric disorders and supports the development of a deep learning model to predict gene regulation and functional effects of disease-associated variants. HIGHLIGHTSO_LIJoint single-cell profiling of transcriptomes and three histone modifications across eight human basal ganglia regions characterizes active and repressive chromatin states at cell-type resolution. C_LIO_LICell-type-specific gene regulatory programs decode combinatorial homeobox TF grammar governing the identity and diversification of basal ganglia neurons. C_LIO_LIIntergrative analyses link noncoding neuropsychiatric risk variants to specific cell types, regulatory elements, and candidate target genes. C_LIO_LIA sequence-to-function deep-learning model predicts gene regulation from DNA sequence and prioritizes functional disease-associated variants. C_LI

genomics↗

bioRxiv2026

Single-Cell Atlas of Transcription and Chromatin States Reveals Regulatory Programs in the Human Brain

Directly measuring chromatin states alongside transcription is essential for understanding how cell-type-specific regulatory programs are established and maintained in the adult human brain. We present a large-scale single-cell multimodal atlas generated by jointly profiling transcriptome with active (H3K27ac) and repressive (H3K27me3) histone modifications across 18 brain regions. We profile >750,000 nuclei spanning 160 cell types and integrate these data with chromatin accessibility, DNA methylation, 3D genome architecture, and spatial transcriptome. This framework annotates >500,000 regulatory elements and resolves cell-type-specific chromatin states. We link enhancers to target genes, infer gene regulatory networks, and classify chromatin interactions, revealing neuron-enriched long-range Polycomb repression of developmental genes. Integrating these maps with GWAS data and sequence-based model prioritizes noncoding variants, effector genes, and vulnerable cell types for neuropsychiatric disorders. Finally, cross-species comparisons show conserved activation but more divergent repression. Together, this study provides a functional reference for interpreting noncoding variants, epigenetic memory, and brain organization. HIGHLIGHTSO_LIJoint single-cell profiling of transcriptomes with active or repressive histone modification in >750,000 nuclei across adult human brain. C_LIO_LIChromatin state annotation of >500,000 candidate cis-regulatory elements distinguishes active enhancers from accessible and Polycomb-repressed regions. C_LIO_LICell-type-resolved regulatory networks and sequence-based deep learning model prioritize functional neuropsychiatric risk variants. C_LIO_LISpatial epigenomic imputation reveals laminar layer-specific Polycomb repression programs. C_LIO_LIIntegration with 3D genome architecture reveals neuron-specific super long-range chromatin loops silencing early developmental genes. C_LIO_LIEvolutionary analysis uncovers conserved active regulatory grammar but divergent repressive landscape. C_LI

genomics↗

bioRxiv2025

Single-cell multiomic human brain atlas reveals regulatory drivers of cortical regionality

Distinct regional functionality of the human cortex is orchestrated by diverse cellular and molecular processes, yet the underlying regulatory mechanisms remain poorly understood. We performed multiomic single-cell and spatial characterization of nine regions of the human cortex to define the gene regulatory networks and transcription factors that govern cell-type and region specificity. With the combined data of over three million cells, two striking patterns of cortical neuron specialization were uncovered: a rostral-caudal gradient of calcium regulatory machinery, and subunit switching of multiple signaling receptor families across the transmodal-sensory axis. Gene regulatory network analysis revealed putative transcriptional regulators of cortical neuron specialization with cell-type- and region-specific gene regulation patterns. While regionalization was observed in gene expression, chromatin accessibility, and spatial distributions, these modalities exhibited distinct cortical patterns. Our findings illuminate critical neuronal pathways that vary throughout the cortex and the gene regulatory networks that establish cortical regionalization in the human brain.

neuroscience↗

bioRxiv2025

Persistent Activation of Endothelial Cells is Linked to Thrombosis and Inflammation in Cerebral Cavernous Malformation Disease

AbstractO_ST_ABSBACKGROUNDC_ST_ABSCerebral cavernous malformations (CCM) are neurovascular lesions that affect both children and adults, and morbidity often results from thrombosis, bleeding, and neurological dysfunction. Studies indicate that inflammation-related activation of endothelial cells contributes significantly to the worsening of CCM disease. This suggests that ongoing vascular inflammation and endothelial dysfunction are key factors associated with thrombosis and bleeding in CCM disease. However, the inflammatory mechanisms leading to altered brain endothelial cell function with a high propensity for thrombosis, inflammation, and dysfunction are not fully understood. METHODSMulti-omic analyses was conducted by performing simultaneous high-throughput single-nucleus RNA sequencing (snRNA-seq) and single-nucleus transposase-accessible chromatin sequencing (snATAC-seq) with the 10x Genomics multiome platform in combination with immunofluorescence to study CCM pathogenesis in both female and male mice with CCM (Slco1c1-CreERT2; Pdcd10fl/fl) disease. The analysis was complemented with bulk RNA-seq, bulk ATAC-seq, and ChIP-seq (Chromatin immunoprecipitation sequencing) using an in vitro human CCM model. An AAV-BR1 viral system selectively upregulates the activator protein-1 (AP-1) transcription factor JUNB in brain endothelial cells was used to evaluate its effectiveness in maintaining a persistent activated cell state during the pathogenesis of CCM. RESULTSWe found that epigenetics significantly influences the subtype identity and function of brain endothelial cells within the arteriovenous axis. Through multi-omic analyses, specific regulatory elements and enhancers (cis-Regulatory Elements, cCREs) in mouse brain endothelial cells were identified that influence subtype-specific transcriptional programs and the transcription factors responsible for establishing the various subtypes of brain endothelial cells. Additionally, large-scale epigenomic reprogramming of brain endothelial cell subtypes was observed during the pathogenesis of CCM disease. Among the most significant changes were alterations in the chromatin state of endothelial cells, along with transcriptional processes associated with a persistently activated endothelial cell state, which renders them susceptible to inflammation and thrombosis. The activator AP-1 transcription factor JUNB was identified as a key regulator of the persistently activated endothelial state during chronic neuroinflammation. Moreover, both trans- and cis-regulatory factors conserved between mice and humans were discovered and contribute to the progression of chronic CCM disease. CONCLUSIONSEpigenetics plays a crucial role in determining the transcription patterns and functions of brain arteriovenous endothelial cells. The activator JUNB is identified as a driver of chronic brain vascular inflammation by inducing a persistent activated endothelial cell state from epigenome reprogramming. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/662238v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1297edforg.highwire.dtl.DTLVardef@1488e27org.highwire.dtl.DTLVardef@6cae62org.highwire.dtl.DTLVardef@12cb282_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗