Biology subjects

Saberi, S.

Publications and source records attributed to Saberi, S..

5 recordsLinked to original sources

bioRxiv2025

Spatial genomics of the cardiac sarcomere

Structure-function mapping of proteins has improved our understanding of disease mechanisms and protein domains while human population genetics has provided a window into variational tolerance that can be modeled at a structural level. Here, to reveal novel insight into the cardiac sarcomere, the motor unit of the heart, we develop a novel analytical framework to integrate data from over 17,000 patients with hypertrophic cardiomyopathy (HCM) and combine it with two population-scale genomic databases that incorporate data from more than 800,000 individuals. We integrate in silico genetic predictions of gene variant pathogenicity with 3 dimensional integrative spatial scanning across multiple structural models of cardiac motor proteins. Results reveal both recognized and novel regions of structural variant intolerance across the critical genes of the cardiac sarcomere including novel insights into protein function. We discuss the structural relevance of variant enrichment in the context of sarcomere organization and destabilization of sequestered myosin leading to hypercontractility seen in HCM, by incorporating the recently defined high-resolution structure of human cardiac myosin filament. We extend and validate these findings through pathogenic variant class enrichment and reveal novel associations with the earlier onset of disease in a large clinical cohort. In summary, our study provides a multi-dimensional framework for integrating structural, genomic, and modeling data to reveal novel insight into the cardiac sarcomere.

genomics↗

bioRxiv2025

Biliverdin Reductase A is a major determinant of neuroprotective Nrf2 signaling

Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a novel non-enzymatic role for BVRA in redox regulation. We show that BVRA directly interacts with nuclear factor erythroid-derived factor-like 2 (Nrf2), the master regulator of redox homeostasis, to modulate target signaling pathways. ChIP-seq and RNA-seq analyses reveal that this interaction coordinates the expression of neuroprotective genes that are typically dysregulated in Alzheimers disease and other neurodegenerative conditions. Thus, this previously unknown BVRA-Nrf2 axis controls an essential pathway of redox signaling in neuroprotection. Our findings establish BVRA as a dual-function integrator of antioxidant defenses in both the lipophilic and hydrophilic subcellular compartments, bridging these two distinct and critical cellular protection mechanisms in the brain. This advancement in understanding the endogenous antioxidant system of the brain positions the BVRA-Nrf2 axis as a promising therapeutic target for neurodegenerative disease. Significance StatementWe show a non-canonical role for biliverdin reductase A (BVRA), classically known as the biosynthetic enzyme for bilirubin, in nonenzymatic modulation of antioxidant neuroprotective nuclear factor erythroid-derived factor-like 2 (Nrf2) signaling in the brain. Both BVRA and Nrf2 signaling are compromised in neurodegenerative diseases such as Alzheimers disease, and the BVRA-Nrf2 axis offers a new direction for developing neuroprotective therapies.

neuroscience↗

bioRxiv2020

Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation.

PurposeVariants in MYBPC3 causing loss-of-function are the most common cause of HCM. However, a substantial number of patients carry missense variants of uncertain significance (VUS) in MYBPC3. We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on protein folding, will improve clinical risk stratification of patients with HCM and a MYBPC3 VUS. MethodsAmong 7,963 patients in the multi-center Sarcomeric Human Cardiomyopathy Registry, 120 unique missense VUSs in MYBPC3 were identified. Variants were evaluated for their effect on subdomain folding and a stratified time-to-event analysis for an overall composite endpoint (first occurrence of ventricular arrhythmia, heart failure, all-cause mortality, atrial fibrillation, and stroke) was performed for patients with HCM and a MYBPC3 missense VUS. ResultsWe demonstrated that patients carrying a MYBPC3 VUS predicted to cause subdomain misfolding (STRUM +, {Delta}{Delta}G [≤]-1.2 kcal/mol) exhibited a higher rate of adverse events compared to those with a STRUM-VUS (Hazard Ratio=2.29, P=0.0282). In silico saturation mutagenesis of MYBPC3 identified 4,943/23,427 (21%) missense variants that were predicted to cause subdomain misfolding. ConclusionsSTRUM enables clinical risk stratification of patients with HCM and a MYBPC3 VUS and has the capacity to improve prognostic predictions and clinical decision making.

genetics↗

bioRxiv2020

Robust Tobacco Smoking Self-Report in two Cohorts of Vulnerable Pregnant Women and Adults

BackgroundStigma associated with tobacco smoking, especially during pregnancy, may lead to underreporting and possible bias in studies relying on self-reported smoking data. Cotinine, a nicotine metabolite with a [~]20h half-life in blood, is often used as a biomarker of smoking. The objective of this study was to examine the concordance between self-reported smoking and plasma cotinine concentration among participants enrolled in two related cohorts of vulnerable individuals: human immunodeficiency virus (HIV)-positive and HIV-negative pregnant women enrolled in the CARMA-PREG cohort and HIV-positive and HIV-negative non-pregnant women and men enrolled in the CARMA-CORE cohort. MethodsFor HIV-positive (n=76) and negative (n=24) pregnant women, plasma cotinine was measured by ELISA in specimens collected during the third trimester, between 28 and 38 weeks of gestation. Plasma cotinine was also measured in HIV-positive (n=43) and negative (n=57) women and men enrolled in the CARMA-CORE cohort. ResultsSelf-reported smokers were more likely to have low income (p<0.001) in both cohorts, and to deliver preterm (p=0.007) in CARMA-PREG. In the CARMA-PREG cohort, concordance between plasma cotinine was 95% for self-reported smoking, and 89% for self-reported non-smoking. In the CARMA-CORE cohort we observed similarly high concordances of 96% and 92% for self-reported smoking and non-smoking, respectively. In this sample, the odds of discordance between self-reported smoking status and cotinine levels were not significantly different between self-reported smokers and non-smokers, nor between pregnant women and others. Taken together, the overall concordance between plasma cotinine and self-reported data was 94% with a Cohens kappa coefficient of 0.860 among all participants. ConclusionsGiven the high proportion of vulnerable people in the CARMA-PREG and CARMA-CORE cohorts, our results may not be fully generalizable to the general population. However, they demonstrate that participant surveying in a non-judgemental context can lead to accurate and robust self-report data. ImplicationsReliable self-reported smoking data is necessary to account for smoking status in subsequent studies. Our results suggest that future studies should ensure that study participants feel sale to speak candidly to non-judgemental research staff to obtain reliable self-report data.

pathology↗

bioRxiv2019

Glioblastomas derived from genetically modified pluripotent stem cells recapitulate pathobiology

Many current cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of cancer that underlies treatment resistance. Here we introduce a new cancer modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) that capture authentic cancer pathobiology. Orthotopic engraftment of neural progenitor cells derived from hiPSCs that have been genome-edited to contain tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas project for glioblastoma (GBM) result in formation of high-grade gliomas. As observed in GBM patient samples, these models harbor inter-tumor heterogeneity resembling different GBM molecular subtypes, and intra-tumor heterogeneity. Further, re-engraftment of primary tumor neurospheres generates secondary tumors with features characteristic of patient samples and present mutation-dependent patterns of tumor evolution. Thus, these cancer avatar models provide a platform for a comprehensive longitudinal assessment of human tumor development as governed by molecular subtype mutations and lineage-restricted differentiation.

cancer biology↗