Biology subjects

Shangguan, S.

Publications and source records attributed to Shangguan, S..

5 recordsLinked to original sources

bioRxiv2025

Multimodal brain cell atlas across the adult macaque lifespan

High-throughput single-cell omics of non-human primate tissues present a remarkable opportunity to study primate brain aging. Here, we introduce a transcriptomic and chromatin accessibility landscape of 1,985,317 cells from eight brain regions of 13 cynomolgus female monkeys spanning adult lifespan including exceptionally old individuals up to 29-years old. This dataset uncovers dynamic molecular changes in critical brain functions such as synaptic communication and axon myelination, exhibiting a high degree of cell type and brain region specificity. We identify the multicellular networks of the pons and medulla as a previously unrecognized hotspot for aging. Furthermore, comparative analyses with human neurodegeneration datasets highlight both shared and distinct mechanisms contributing to aging and disease. In addition, we uncover transcription factors implicated in monkey brain aging and pinpoint aging-regulated loci linked to longevity and neurodegeneration. This spatiotemporal atlas will advance our understanding of primate brain aging and its broader implications for health and disease.

neuroscience↗

bioRxiv2024

Single-cell analyses reveal that monocyte gene expression profiles influence HIV-1 reservoir size in acutely treated cohorts

Elimination of latent HIV-1 is a major goal of AIDS research but the host factors determining the size of these reservoirs are poorly understood. Here, we investigated whether differences in host gene expression modulate the size of the HIV-1 reservoir during suppressive ART. Peripheral blood mononuclear cells (PBMC) from fourteen individuals initiating ART during acute infection who demonstrated effective viral suppression but varying magnitude of total HIV-1 DNA were characterized by single-cell RNA sequencing (scRNA-seq). Differentially expressed genes and enriched pathways demonstrated increased monocyte activity in participants with undetectable HIV-1 reservoirs. IL1B expression in CD14+ monocytes showed the greatest fold difference. The inverse association of IL1B with reservoir size was validated in an independent cohort comprised of 38 participants with different genetic backgrounds and HIV-1 subtype infections, and further confirmed with intact proviral DNA assay (IPDA(R)) measurements of intact HIV-1 proviruses in a subset of the samples. Modeling interactions with cell population frequencies showed that monocyte IL1B expression associated inversely with reservoir size in the context of higher frequencies of central memory CD4+ T cells, implicating an indirect effect of IL1B via the cell type well established to be a reservoir for persistent HIV-1. Signatures consisting of co-expressed genes including IL1B were highly enriched in the "TNF signaling via NF-{kappa}B" geneset. Functional analyses in cell culture revealed that IL1B activates NF-{kappa}B, thereby promoting productive HIV-1 infection while simultaneously suppressing viral spread, suggesting a natural latency reversing activity to deplete the reservoir in ART treated individuals. Altogether, unbiased high throughput scRNA-seq analyses revealed that monocyte IL1B variation could decrease HIV-1 proviral reservoirs in individuals initiating ART during acute infection.

immunology↗

bioRxiv2022

Human iPSC-derived neuron of 16p11.2 deletion reveals haplotype-specific expression of MAPK3 and its contribution to variable NDD phenotypes

Recurrent proximal 16p11.2 deletion (16p11.2del) is risk factor of diverse neurodevelopmental disorders (NDDs) with variable penetrance. Although previous human induced pluripotent stem cell (hiPSC) models of 16p11.2del confirmed disrupted neuron development, it is not known which gene(s) at this interval are mainly responsible for the abnormal cellular phenotypes and how the NDD penetrance is regulated. After haplotype phasing of 16p11.2 region, we generated hiPSCs for two 16p11.2del families with distinct residual haplotypes and variable NDD phenotypes. We also differentiated the hiPSCs to cortical neural cells and demonstrated MAPK3 as a driver signal of 16p11.2 region contributing to the dysfunctions in multiple pathways related to neuron development, which leads to altered morphological or electrophysiological properties in neuron cells. Furthermore, residual haplotype-specific MAPK3 expression was identified in 16p11.2del neuron cells, associating MAPK3 down-expression with the minor allele of the residual haplotype. Ten SNPs of the residual haplotype are mapped as enhancer SNPs (enSNPs) of MAPK3, eight enSNPs were functionally validated by luciferase assays, implying enSNPs contribute to residual haplotype-specific MAPK3 expression via cis-regulation. Finally, the analyses of three different patient cohorts showed that the residual haplotype of 16p11.2del is associated with variable NDD phenotypes.

genetics↗

bioRxiv2021

Cell transcriptomic atlas of the non-human primate Macaca fascicularis

Studying tissue composition and function in non-human primates (NHP) is crucial to understand the nature of our own species. Here, we present a large-scale single-cell and single-nucleus transcriptomic atlas encompassing over one million cells from 43 tissues from the adult NHP Macaca fascicularis. This dataset provides a vast, carefully annotated, resource to study a species phylogenetically close to humans. As proof of principle, we have reconstructed the cell-cell interaction networks driving Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases and intersected our data with human genetic disease orthologous coordinates to identify both expected and unexpected associations. Our Macaca fascicularis cell atlas constitutes an essential reference for future single-cell studies in human and NHP.

cell biology↗

bioRxiv2021

Monocyte-derived transcriptome signature indicates antibody-dependent cellular 1 phagocytosis as the primary mechanism of vaccine-induced protection against HIV-1

A gene signature previously correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus (SIV) and SHIV challenge models in non-human primates (NHP). In this report we investigated presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanism for protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy. Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial, showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with vaccine efficacy represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate development of new vaccine candidates.

systems biology↗