Biology subjects

Chetty, S.

Publications and source records attributed to Chetty, S..

4 recordsLinked to original sources

bioRxiv2025

Cellular mechanisms of early brain overgrowth in autistic children: elevated levels of GPX4 and resistance to ferroptosis

Autistic individuals with disproportionate megalencephaly (ASD-DM), characterized by enlarged brains relative to body height, have higher rates of intellectual disability and face more severe cognitive challenges than autistic children with average brain sizes. The cellular and molecular mechanisms underlying this neurophenotype remain poorly understood. To investigate these mechanisms, we generated human induced pluripotent stem cells from non-autistic typically developing children and autistic children with and without disproportionate megalencephaly. We assessed these children longitudinally from ages two to twelve years using magnetic resonance imaging and comprehensive cognitive and medical evaluations. We show that neural progenitor cells (NPCs) derived from ASD-DM children exhibit increased rates of cell survival and suppressed cell death, accompanied by heightened oxidative stress and ferrous iron accumulation. Despite these stressors, ASD-DM NPCs actively suppress apoptosis and ferroptosis by regulating proteins such as caspase-3 (CASP3), poly(ADP-ribose) polymerase 1 (PARP1), and glutathione peroxidase 4 (GPX4). Cellular ferroptotic signatures are further supported by elevated expression of selenocysteine genes, including GPX4, in the blood of ASD-DM children and their mothers, suggesting potential hereditary or environmental influences. Furthermore, we show that peripheral expression of GPX4 and other selenocysteine genes correlate with cognitive outcomes (IQ). These findings underscore the role of ferroptosis in autism, pointing to potential diagnostic biomarkers and targets for intervention.

neuroscience↗

bioRxiv2019

Overexpression of CD47 is associated with brain overgrowth in 16p11.2 deletion syndrome

One of the most common genetic linkages associated with neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, occurs at the 16p11.2 locus. Copy number variants (CNVs) of the 16p gene can manifest in opposing head sizes. 16p11.2 deletion carriers tend to have macrocephaly (or brain enlargement), while those with 16p11.2 duplication frequently have microcephaly. Increases in both gray and white matter volume have been observed in brain imaging studies in 16p11.2 deletion carriers with macrocephaly. Here, we use human induced pluripotent stem cells (hiPSCs) derived from controls and subjects with 16p11.2 deletion and 16p11.2 duplication to understand the underlying mechanisms regulating brain overgrowth. To model both gray and white matter, we differentiated patient-derived iPSCs into neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). In both NPCs and OPCs, we show that CD47 (a dont eat me signal) is overexpressed in the 16p11.2 deletion carriers contributing to reduced phagocytosis both in vitro and in vivo. Treatment of 16p11.2 deletion NPCs and OPCs with an anti-CD47 antibody to block CD47 restores phagocytosis to control levels. Furthermore, 16p11.2 deletion NPCs and OPCs upregulate cell surface expression of calreticulin (a pro-phagocytic eat me signal) and its binding sites, indicating that these cells should be phagocytosed but fail to be eliminated due to elevations in CD47. While the CD47 pathway is commonly implicated in cancer progression, we document a novel role for CD47 in regulating brain overgrowth in psychiatric disorders and identify new targets for therapeutic intervention.

neuroscience↗

bioRxiv2019

Variations and expression features of CYP2D6 contribute to schizophrenia risk

ObjectiveGenome-wide association studies (GWAS) have successfully identified 145 loci implicated in schizophrenia (SCZ). However, the underlying mechanisms remain largely unknown.\n\nMethodsHere, we analyze 1,479 RNA-seq data from 13 postmortem brain regions in combination with their genotype data and identify SNPs that are associated with expression throughout the genome by dissecting expression features to genes (eGene) and exon-exon junctions (eJunction). Then, we co-localize eGene and eJunction with SCZ GWAS using SMR and mapping. Multiple ChIP-seq data and DNA methylation data generated from brain were used for identifying the causative variants. Finally, we used a hypothesis-free (no SCZ risk loci considered) enrichment analysis to determine implicated pathways.\n\nResultsWe identified 171 genes and eight splicing junctions located within four genes (SNX19, ARL6IP4, APOPT1 and CYP2D6) that potentially contribute to SCZ susceptibility. Among the genes, CYP2D6 is significantly associated with SCZ SNPs in both eGene and eJunction across the 13 brain regions. In-depth examination of the CYP2D6 region revealed that a non-synonymous single nucleotide variant (SNV) rs16947 is strongly associated with a higher abundance of CYP2D6 exon 3 skipping junctions. While we found rs133377 and two other SNPs in high linkage disequilibrium (LD) with rs16947 (r2 = 0.9539), histone acetylation analysis showed they are located within active transcription start sites. Furthermore, our data-driven enrichment analysis showed CYP2D6 is significantly involved in drug metabolism of tamoxifen, codeine and citalopram.\n\nConclusionsOur study facilitates an understanding of the genetic architecture of SCZ and provides new drug targets.

genetics↗

bioRxiv2019

Cell cycle dynamics of human pluripotent stem cells primed for differentiation

Understanding the molecular properties of the cell cycle of human pluripotent stem cells (hPSCs) is critical for effectively promoting differentiation. Here, we use the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) system adapted into hPSCs and perform RNA-sequencing on cell cycle sorted hPSCs primed and unprimed for differentiation. Gene expression patterns of signaling factors and developmental regulators change in a cell cycle-specific manner in cells primed for differentiation without altering genes associated with pluripotency. Furthermore, we identify an important role for PI3K signaling in regulating the early transitory states of hPSCs towards differentiation.

genetics↗