Gene Expression Analysis Reveals Age and Ethnicity Signatures Between Young and Old Adults in Human PBMC

Yang, Huanming; Xu, Yuewen; Mao, Lipeng; Wen, Lu; Xiang, Jian; Gao, Lijuan; Jiang, Jie; Huang, Li'an; Luo, Oscar Junhong; Duan, Jinhai; Chen, Guobing

doi:10.3389/fragi.2021.797040

Cited by 8 publications

(2 citation statements)

References 40 publications

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“…This is in line with our recently published investigation where we showed a strong correlation between Hispanic and NHW transcriptome profiles [59] , ultimately confirming that the brain region used to extract RNA was more relevant than the ethnic group the brain belonged to. Additional proofs of the optimal transferability across ethnicities comes from a recent publication showing that gene expression signatures of aging in peripheral blood are shared between East Asian and NHW populations, with specific hub genes like NUDT7 and OXNAD1, decreasing in expression with age [60] . This finding reinforces the universality of aging biomarkers across ethnicities, which further validates our study.…”

Section: Discussionmentioning

confidence: 99%

MU-BRAIN: MUltiethnic Brain Rna-seq for Alzheimer INitiative

Yang,

Cieza,

Reyes-Dumeyer

et al. 2024

Preprint

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BackgroundsAlzheimer’s Disease (AD) exhibits a complex molecular and phenotypic profile. Investigating gene expression plays a crucial role in unraveling the disease’s etiology and progression. Transcriptome data across ethnic groups lack, negatively impacting equity in intervention and research.MethodsWe employed 565 brains across six U.S. brain banks (N=399 non-Hispanic Whites, N=113 Hispanics, N=12 African Americans) to generated bulk RNA sequencing from prefrontal cortex. We sought to identify cross-ancestry and ancestry-specific differentially expressed genes (DEG) across Braak stages, adjusting for sex, age at death, and RNA quality metrics. We further validated our findings using the Religious Orders Study/Memory Aging Project brains (ROS/MAP; N=1,095). We conducted Gene Set and Variation and Enrichment analysis (GSVA; GSEA). We employed a machine-learning approach for phenotype prediction and gene prioritization to construct a polytranscriptomics risk score (PTRS) splitting our sample into training and testing sub-samples, either randomly or by ethnicity (“ancestry-agnostic” and “ancestry-aware”, respectively). Lastly, we validated top DEG using single-nucleus RNA sequencing (snRNAseq) data.ResultsWe identified DEG associated with Braak staging: AD-known genesVGF(padj=3.78E-07) andADAMTS2(padj=1.21E-04) were consistently differentially expressed across statistical models, ethnicities, and replicated in ROS/MAP. Genes from the heat shock protein (HSP) family, e.g.HSPB7(padj=3.78E-07), were the top differentially expressed genes and replicated in ROS/MAP. Ethnic-stratified analyses prioritizedTNFSF14andSPOCD1as top Hispanics DEG. GSEA highlighted “Alzheimer disease” (padj=4.24E-06) and “TYROBP causal network in microglia” (padj=1.68E-08) pathways. Up- and down-regulated genes were enriched in several pathways (e.g. “Immune response activation signal pathways”, “Vesicle-mediated transport in synapse”, “cognition”). Ancestry-agnostic and ancestry-aware PTRS effectively classified brains (AUC=0.77 and 0.73 respectively) and replicated in ROS/MAP. snRNAseq validated prioritized genes, includingVGF (downregulated in neurons; padj=1.1 E-07).ConclusionsThis is the largest diverse transcriptome for AD in post-mortem tissue to our knowledge. We identified perturbated genes, pathways and network expressions in AD brains resulting in cross-ethnic and ethnic-specific findings, ultimately highlighting the diversity within AD pathogenesis. The latter underscores the need for an integrative and personalized approach in AD studies.

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Section: Discussionmentioning

confidence: 99%

MU-BRAIN: MUltiethnic Brain Rna-seq for Alzheimer INitiative

Yang,

Cieza,

Reyes-Dumeyer

et al. 2024

Preprint

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“…Remarkably, PURPL transcript levels were higher than p16 and p21 mRNA levels, so it could serve as a new, more robust transcript biomarker correlated with age and cellular senescence [185]. Distinctive transcriptomic profiles of senescent cells have been described for different types of fibroblasts, but scRNAseq data for senescent immune cells are lacking, despite a large number of bulk RNA-seq studies of PBMC from donors of different age groups [191][192][193].…”

Section: Multi-omics Changes 281 Transcriptomementioning

confidence: 99%

Reliable Hallmarks and Biomarkers of Senescent Lymphocytes

Martyshkina,

Tereshchenko,

Bogdanova

et al. 2023

IJMS

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The phenomenon of accumulation of senescent adaptive immunity cells in the elderly is attracting attention due to the increasing risk of global epidemics and aging of the global population. Elderly people are predisposed to various infectious and age-related diseases and are at higher risk of vaccination failure. The accumulation of senescent cells increases age-related background inflammation, “Inflammaging”, causing lymphocyte exhaustion and cardiovascular, neurodegenerative, autoimmune and cancer diseases. Here, we present a comprehensive contemporary review of the mechanisms and phenotype of senescence in the adaptive immune system. Although modern research has not yet identified specific markers of aging lymphocytes, several sets of markers facilitate the separation of the aging population based on normal memory and exhausted cells for further genetic and functional analysis. The reasons for the higher predisposition of CD8+ T-lymphocytes to senescence compared to the CD4+ population are also discussed. We point out approaches for senescent-lymphocyte-targeting markers using small molecules (senolytics), antibodies and immunization against senescent cells. The suppression of immune senescence is the most relevant area of research aimed at developing anti-aging and anti-cancer therapy for prolonging the lifespan of the global population.

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Decoding Skd3 (Human CLPB): a Mitochondrial Protein Disaggregase Critical for Human Health

Cupo,

Shorter

2024

Israel Journal of Chemistry

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Protein folding is important for all life. Indeed, protein misfolding can result in catastrophic protein aggregation and toxicity. The pathways involved in reversing protein aggregation within human mitochondria had long been unknown. We recently discovered that Skd3 (human CLPB) is a potent mitochondrial protein disaggregase, which is regulated by the rhomboid protease PARL, and maintains the solubility of many important mitochondrial proteins. Skd3 variants underlie several debilitating human diseases, including 3‐methylglutaconic aciduria, severe congenital neutropenia, and premature ovarian insufficiency. Here, we describe advances in understanding Skd3 function, mechanism, and structure and place these discoveries in the context of physiology and disease.

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Gene Expression Analysis Reveals Age and Ethnicity Signatures Between Young and Old Adults in Human PBMC

Cited by 8 publications

References 40 publications

MU-BRAIN: MUltiethnic Brain Rna-seq for Alzheimer INitiative

MU-BRAIN: MUltiethnic Brain Rna-seq for Alzheimer INitiative

Reliable Hallmarks and Biomarkers of Senescent Lymphocytes

Decoding Skd3 (Human CLPB): a Mitochondrial Protein Disaggregase Critical for Human Health

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