Biology subjects

Gupta, A. R.

Publications and source records attributed to Gupta, A. R..

8 recordsLinked to original sources

bioRxiv2026

Task-based functional connectivity in striato-motor-cortical system in autism: Associations with sex and executive function

Previously we found that female autistic youth (Aut-F) showed reduced brain response in dorsal striatum (putamen) when viewing human motion, alongside larger rare copy number variants that included genes expressed in early striatal development. Thus, striatal differences may characterize Aut-F, but broader systems-level and behavioral implications of these differences remain unexplored. We conducted secondary data analysis of the sex-balanced cohort (8-17y) in which we first discovered these patterns, in order to: 1) understand how functional connectivity between putamen and frontal targets might vary from the non-autistic population, and differ by sex; and 2) explore which brain connectivity and phenotypic features best predicted executive function. Using psychophysiological interaction analysis (N=184), we found that Aut-F youth (n=45) showed reduced functional connectivity between left anterior putamen (Pa) and dorsal premotor cortex/pre-supplementary motor area versus matched non-autistic female peers (NAut-F; n=45), suggesting reduced engagement of a typical Pa-frontal pathway for attentional regulation. Best subsets regression (N=200) indicated that left Pa-left dorsolateral prefrontal functional connectivity explained significant variance in executive functioning across all participants, controlling for neurotype. These results suggest that striatal differences in Aut-F may have adaptive consequences in part due to impacts on connectivity between Pa and frontal regions important for attentional control. Lay summaryWe previously found that female autistic people show differences in a part of the brain called the striatum. Some parts of the striatum connect to the frontal lobe of the brain, and may help people control their attention and behavior. We studied how the striatum "talked to" the frontal lobe in autistic girls. We found out that this communication is lower in autistic than non-autistic girls. We also found out that how much striatum "talks to" frontal lobe helps explain differences in how well both autistic and non-autistic youth of both sexes control their attention and behavior.

neuroscience↗

bioRxiv2025

Structural Determinants of Signal Speed: A Multimodal Investigation of Face Processing in Autism Spectrum Disorder

It has not previously been possible to investigate the fundamental relationship between axonal structure - which dictates action potential transmission - and human neuronal function in vivo. Here, we introduce a novel metric of axonal signal speed, estimated axonal latency (EAL), derived from the relationship between axonal diameter, myelination, and length measured via MRI. We validate EAL along two pathways of the face processing network by relating it to N170 latency, an electrophysiological marker of face processing speed measured via EEG. Our results show that EAL along these pathways predicts N170 latency specifically during face processing. Moreover, we demonstrate that individuals with and without autism rely upon different pathways, potentially providing a structural account for autism-related face processing differences. By establishing this relationship between EEG-based electrical function and MRI-based axonal microstructure, we provide a non-invasive, spatially detailed estimate of neuronal processing speed that can inform our understanding of brain function, development, and disorder. TeaserEstimated axonal latency is a non-invasive, spatially detailed measure of neuronal speed to inform brain function and disorder.

neuroscience↗

bioRxiv2024

Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function

Kidney disease is highly heritable; however, the causal genetic variants, the cell types in which these variants function, and the molecular mechanisms underlying kidney disease remain largely unknown. To identify genetic loci affecting kidney function, we performed a GWAS using multiple kidney function biomarkers and identified 462 loci. To begin to investigate how these loci affect kidney function, we generated single-cell chromatin accessibility (scATAC-seq) maps of the human kidney and identified candidate cis-regulatory elements (cCREs) for kidney podocytes, tubule epithelial cells, and kidney endothelial, stromal, and immune cells. Kidney tubule epithelial cCREs explained 58% of kidney function SNP-heritability and kidney podocyte cCREs explained an additional 6.5% of SNP-heritability. In contrast, little kidney function heritability was explained by kidney endothelial, stromal, or immune cell-specific cCREs. Through functionally informed fine-mapping, we identified putative causal kidney function variants and their corresponding cCREs. Using kidney scATAC-seq data, we created a deep learning model (which we named ChromKid) to predict kidney cell type-specific chromatin accessibility from sequence. ChromKid and allele specific kidney scATAC-seq revealed that many fine-mapped kidney function variants locally change chromatin accessibility in tubule epithelial cells. Enhancer assays confirmed that fine-mapped kidney function variants alter tubule epithelial regulatory element function. To map the genes which these regulatory elements control, we used CRISPR interference (CRISPRi) to target these regulatory elements in tubule epithelial cells and assessed changes in gene expression. CRISPRi of enhancers harboring kidney function variants regulated NDRG1 and RBPMS expression. Thus, inherited differences in tubule epithelial NDRG1 and RBPMS expression may predispose to kidney disease in humans. We conclude that genetic variants affecting tubule epithelial regulatory element function account for most SNP-heritability of human kidney function. This work provides an experimental approach to identify the variants, regulatory elements, and genes involved in polygenic disease.

genetics↗

bioRxiv2021

Single-Cell Multiomics Defines Tolerogenic Extrathymic Aire-Expressing Populations with Unique Homology to Thymic Epithelium

The Autoimmune Regulator (Aire) gene, well defined for its role in medullary thymic epithelial cells (mTECs) and immune self-tolerance, is also expressed in extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs. eTACs have been shown to be hematopoietic antigen presenting cells (APCs) and potent inducers of immune tolerance (1-3). However, the precise identity and function of these cells remain unclear. Here, we use high-dimensional single-cell multiomics and functional approaches to define eTACs at the transcriptional, genomic, and proteomic level. We find that eTACs consist of two similar cell types: CCR7+ Aire-expressing migratory dendritic cells (AmDCs) and a unique Aire-hi population co-expressing Aire and RAR-related orphan receptor gamma-t (ROR{gamma}t). The latter, which have significant transcriptional and genomic homology to migratory dendritic cells (migDCs) and mTECs, we term Janus cells (JCs). All eTACs, and JCs in particular, have a highly accessible chromatin structure and high levels of broad gene expression, including tissue-specific antigens, as well as remarkable transcriptional and genomic homology to thymic medullary epithelium. As in the thymus, Aire expression in eTACs is also dependent on RANK-RANK-ligand interactions. Furthermore, lineage-tracing shows that JCs are not precursors to the majority of AmDCs. Finally, self-antigen expression by eTACs is sufficient to mediate negative selection of T cells escaping thymic selection and can prevent autoimmune diabetes in non-obese diabetic mice. This transcriptional, genomic, and functional symmetry between a hematopoietic Aire-expressing population in the periphery and an epithelial Aire-expressing population in the thymus suggests that a core biological program may influence self-tolerance and self-representation across the spectrum of immune development.

immunology↗

bioRxiv2021

A mitochondrial electron transport chain with atypical subunit composition confers oxygen sensitivity to a mammalian chemoreceptor

The carotid body (CB) is the major chemoreceptor for blood oxygen in the control of ventilation in mammals, contributing to physiological adaptation to high altitude, pregnancy, and exercise, and its hyperactivity is linked to chronic conditions such as sleep-disorder breathing, hypertension, chronic heart failure, airway constriction, and metabolic syndrome (1-3). Upon acute hypoxia (PO2=100 mmHg to <80 mmHg), K+ channels on CB glomus cells are inhibited, causing membrane depolarization to trigger Ca+2 influx and neurotransmitter release that stimulates afferent nerves (1-3). A longstanding model proposes that the CB senses hypoxia through atypical mitochondrial electron transport chain (ETC) metabolism that is more sensitive to decreases in oxygen than other tissues. This model is supported by observations that ETC inhibition by pharmacology and gene knockout activates CB sensory activity and that smaller decreases in oxygen concentration inhibit ETC activity in CB cells compared to other cells (1-5). Determining the composition of atypical ETC subunits in the CB and their specific activities is essential to delineate molecular mechanisms underlying the mitochondrial hypothesis of oxygen sensing. Here, we identify HIGD1C, a novel hypoxia inducible gene domain factor isoform, as an ETC Complex IV (CIV) protein highly and selectively expressed in glomus cells that mediates acute oxygen sensing by the CB. We demonstrate that HIGD1C negatively regulates oxygen consumption by CIV and acts with the hypoxia-induced CIV subunit COX4I2 to enhance the sensitivity of CIV to hypoxia, constituting an important component of mitochondrial oxygen sensing in the CB. Determining how HIGD1C and other atypical CIV proteins expressed in the CB work together to confer exquisite oxygen sensing to the ETC will help us better understand how tissue- and condition-specific CIV subunits contribute to physiological function and disease (6) and allow us to potentially target these proteins to treat chronic diseases characterized by CB dysfunction (7).

physiology↗

bioRxiv2019

Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify candidate risk genes and biological pathways

Motor stereotypies are common in children with autism spectrum disorder (ASD), intellectual disability, or sensory deprivation, as well as in typically developing children (\"primary\" stereotypies, CMS). The precise pathophysiological mechanism for motor stereotypies is unknown, although genetic etiologies have been suggested. In this study, we perform whole-exome DNA sequencing in 129 parent-child trios with CMS and 853 control trios (118 cases and 750 controls after quality control). We report an increased rate of de novo predicted-damaging variants in CMS versus controls, identifying KDM5B as a high-confidence risk gene and estimating 184 genes conferring risk. Genes harboring de novo damaging variants in CMS probands show significant overlap with those in Tourette syndrome, ASD candidate genes, and those in ASD probands with high stereotypy scores. Furthermore, exploratory biological pathway and gene ontology analysis highlight histone demethylation, organism development, cell motility, glucocorticoid receptor pathway, and ion channel transport. Continued sequencing of CMS trios will identify more risk genes and allow greater insights into biological mechanisms of stereotypies across diagnostic boundaries.

genomics↗

bioRxiv2019

CHD8 regulates the balance between proliferation and differentiation of human iPSCs in neural development

BackgroundChromodomain helicase DNA-binding protein 8 (CHD8), which encodes a chromatin remodeling protein that regulates Wnt/{beta}-catenin mediated gene expression, is one of the most strongly associated genes with autism spectrum disorder (ASD). Characterization of ASD patients with CHD8 disrupting mutations and animal and stem cell models of CHD8 deficiency suggest that CHD8 plays a role in neurodevelopment.\n\nMethodsWe generated iPSCs from the T-lymphocytes of a healthy, typically-developing human male and iPSC lines from the same source which were subjected to CRISPR/Cas9-mediated knockdown (KD) of CHD8. We subsequently derived neural progenitor cells (NPCs) and neural cells and examined the effects of CHD8 deficiency on cell proliferation and neural differentiation.\n\nResultsWe observed that, compared to WT, CHD8 KD: (1) increased the number of iPSC colonies formed, (2) suppressed spontaneous differentiation along the edges of iPSC colonies, (3) increased the proliferation of NPCs, (4) delayed the formation of neural rosettes, (5) delayed neurite outgrowth, (6) decreased the percentage of cells in the G0/G1 phase of the cell cycle, (7) increased the percentage of cells in the G2/M phase of the cell cycle, (8) decreased presence of the neuronal marker MAP2 although not the glial marker GFAP, (9) decreased presence for the excitatory neuronal marker VGLUT1, and (10) decreased presence of the synaptic marker SYN1.\n\nConclusionsOur results suggest that CHD8 deficiency causes alterations in the cell cycle. More specifically, CHD8 KD appears to increase cell proliferation and delay neural differentiation. This may contribute to the pathophysiology of ASD.

neuroscience↗

bioRxiv2017

De novo damaging coding mutations are strongly associated with obsessive-compulsive disorder and overlap with autism

Obsessive-compulsive disorder (OCD) is a debilitating developmental neuropsychiatric disorder with a genetic risk component, yet identification of high-confidence risk genes has been challenging. We performed whole-exome sequencing in 222 OCD parent-child trios (184 trios after quality control), finding strong evidence that de novo likely gene disrupting and predicted damaging missense variants contribute to OCD risk. Together, these de novo damaging variants are enriched in OCD probands (RR 1.52, p=0.0005). We identified two high-confidence risk genes, each containing two de novo damaging variants in unrelated probands: CHD8 (Chromodomain Helicase DNA Binding Protein 8) and SCUBE1 (Signal Peptide, CUB Domain And EGF Like Domain Containing 1). Based on our data, we estimate that 34% of de novo damaging variants seen in OCD contribute to risk, and that de novo damaging variants in approximately 335 genes contribute to risk in 22% of OCD cases. Furthermore, genes harboring de novo damaging variants in OCD are enriched for those reported in neurodevelopmental disorders, particularly autism spectrum disorders. An exploratory network analysis reveals significant functional connectivity and enrichment in canonical pathways related to immune response.\n\nSIGNIFICANCE STATEMENTDecades of genetic studies in obsessive-compulsive disorder (OCD) have yet to provide reproducible, statistically significant findings. Following an approach that has led to tremendous success in gene discovery for several neuropsychiatric disorders, here we report findings from DNA whole-exome sequencing of patients with OCD and their parents. We find strong evidence for the contribution of spontaneous, or de novo, predicted-damaging genetic variants to OCD risk, identify two high-confidence risk genes, and detect significant overlap with genes previously identified in autism. These results change the status quo of OCD genetics by identifying novel OCD risk genes, clarifying the genetic landscape of OCD with respect to de novo variation, and suggesting underlying biological pathways that will improve our understanding of OCD biology.

genetics↗