Biology subjects

Chai, G.

Publications and source records attributed to Chai, G..

7 recordsLinked to original sources

bioRxiv2026

MtDNA heteroplasmy controls tumor immune reprogramming through mitochondrial translation

Mitochondrial DNA (mtDNA) mutations are among the most frequent genetic alterations in human cancers, yet their molecular mechanisms in shaping tumor progression and metastasis under physiological conditions remain poorly understood. Here, we show that mtDNA heteroplasmy acts as a tumor cell-intrinsic rheostat that orchestrates fate decisions between progression and suppression. Moderate heteroplasmy induces a ribosomal storm of mitochondrial translation and ribosome biogenesis, driven by leucyl-tRNA synthetase 2 (LARS2). This response enhances metabolic fitness and licenses the secretion of S100A8/A9, enabling tumor cells to actively remodel the immune microenvironment through recruitment of myeloid-derived suppressor cells and exclusion of CD8 T cells, thereby promoting immune evasion and metastatic progression. In contrast, high heteroplasmy impairs tumorigenesis due to oxidative phosphorylation collapse. Disruption of LARS2, mitochondrial translation, or S100A9 signalling abrogates tumor progression. Our findings establish mtDNA heteroplasmy as a key regulator of cancer evolution, linking mitochondrial genetic variation to immune modulation, and reveal the LARS2-mitochondrial translation-S100A8/A9 axis as a therapeutically targetable programme within the pro-tumorigenic window of mtDNA heteroplasmy.

cancer biology↗

bioRxiv2024

Comprehensive analysis across mammalian tissues and cells decipher the underlying mechanism of m6A specificity

N6-methyladenine (m6A) stands out as the most prevalent internal chemical modification on mammalian mRNA, playing a vital role in diverse biological processes. Despite considerable advancements in individual cell line studies, the characteristics of m6A sites across distinct cell lines or tissues remain elusive. In this study, we have successfully identified approximately 1.5 million high-confidence m6A sites in human and mouse cell lines or tissues using published m6A-seq data. By categorizing m6A sites into different consistency levels, we observe that those of high consistency are notably enriched near the stop codon. Furthermore, they exhibit a higher likelihood of interaction with known m6A binding proteins such as YTHDF1-3, RBM15, YTHDC1, and IGF2BP1, thereby influencing gene expression homeostasis. Additionally, these sites display a higher CpG density in the promoter region of the genes they mark, with METTL3 demonstrating a preference for binding to the promoter region of its marked genes. m6A sites of low consistency levels, including unique m6A sites, show a significant enrichment near the start codon. These sites are more prone to binding by newly discovered m6A-binding proteins such as DDX3X, PRPF8, and EIF3G. The identification of these distinct features of m6A sites lays a foundational understanding for unraveling the functional roles of m6A.

bioinformatics↗

bioRxiv2022

miR-148a-3p inhibits osteogenesis by targeting Itga11 via PI3K/Akt/GSK3/β-catenin pathway

In previous research, miR-148a-3p deficiency was observed in bone malformation in hemifacial microsomia. Nevertheless, the mechanism of miR-148a regulating osteogenesis remains unclear. Herein, in this article, we probed into the role of miR-148a-3p in bone physiology by utilizing miR-148a knock-out (KO) mice. Compared with wild-type (WT) or heterozygotic (HE) littermates, miR-148a knock-out mice manifested lower body weight, bone dysplasia with increased bone mass. Through in-vitro experiments, in terms of miR-148a-3p overexpression (miRNA mimic transfection) and knockout (primary cells from WT and KO littermates), we found that miR-148a-3p can suppress osteogenesis, either in the ALP activity or bone nodules formation. Afterward, by means of proteomics, combined with RNA-sequencing and prediction databases of microRNA targets (miRDB and TargetScan), nine candidate genes targeted by miR-148a-3p were identified. Among them, only Itga11 was regulated by mRNA degradation, while the others were modulated via post-transcriptional inhibition. Based on several online databases (GenePaint, BioGPS, STRING), Integrin Subunit Alpha 11 (Itga11) was suggested to play an essential role in osteogenesis and it was confirmed as one direct target of miR-148a-3p by dual-luciferase reporter assay. Meanwhile, gene set enrichment analysis (GSEA) indicated activation of PI3K-Akt signaling pathway and WNT signaling pathway in miR-148a KO mice. The thereafter western blot confirmed that PI3K/Akt/GSK3/{beta}-catenin signaling pathway was involved. Finally, with the help of esterase-response bone-affiliative liposome with the Itga11 siRNA delivery system, the enhanced osteogenesis in miR-148a KO mice was partly rescued. Taken together, we demonstrated that miR-148a-3p can inhibit osteogenesis by targeting Itga11 via PI3K/Akt/GSK3/{beta}-catenin pathway.

cell biology↗

bioRxiv2022

Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer's disease

The pathology of Alzheimers disease (AD) is associated with the extracellular amyloid-{beta} (A{beta}) plaques that perturb the mechanical properties of brain tissue. Microglia sense and integrate biochemical cues in their local microenvironment, intimate linking with AD progress. However, neither the microglial mechanosensing pathway nor its impact on AD pathogenesis is well studied. Here, we showed that the mechanosensitive ion channel Piezo1 is increased in microglia upon stiffness stimuli of A{beta} fibrils. The upregulation of Piezo1 in A{beta} plaque-associated microglia was observed in AD mouse models and human patients. Microglia lacking Piezo1 disturbed microglial clustering, phagocytosis, and compaction of A{beta} plaques, resulting in the exacerbation of A{beta} and neurodegenerative pathologies in AD. Conversely, pharmacological activation of Piezo1 ameliorated brain A{beta} burden and cognitive impairment in the 5xFAD mouse. Together, our results reveal Piezo1, as a mechanosensor of A{beta} fibrils stiffness in microglia, could represent a promising therapeutic target for AD.

neuroscience↗

bioRxiv2020

Temporal stability of human sperm mosaic mutations results in life-long threat of transmission to offspring

Every newborn harbors scores of new single nucleotide variants (SNVs) that may impact health and disease1-4; the majority of these are contributed by the paternal germ cells5. In some cases, these mutations are identifiable in a subset of the parents cells--a phenomenon called mosaicism, which is capable of producing disease recurrence6-8. Here, we provide a comprehensive analysis of male gonadal mosaic mutations, employing 300x whole genome sequencing (WGS) of blood and sperm in 17 healthy individuals, including assessment across multiple samples and age groups. Approximately 1 in 15 healthy males is predicted to harbor a transmissible, likely pathogenic exonic variant that is mosaic in his sperm. In general, only a third of sperm mosaic mutations were detectable in blood cells, all were remarkably stable over the course of months to years, and 23% were present in 5% or more of sperm cells. There was no evidence of age-dependent clonal expansion or collapse, as seen in hematopoiesis. Thus, despite the observed increase of mutations in offspring of men with advanced paternal age, detectable sperm mosaicism remains stable, represents a life-long transmission risk to offspring, and suggests a testis stem cell niche that prevents widespread clonality.

genomics↗

bioRxiv2020

Somatic mosaicism in the mature brain reveals clonal cellular distributions during cortical development

The structure of the human neocortex underlies species-specific features and is a reflection of intricate developmental programs. Here we analyzed neocortical cellular lineages through a comprehensive assessment of brain somatic mosaicism--which acts as a neutral recorder of lineage history. We employed deep whole genome and variant sequencing in a single postmortem neurotypical human brain across 25 anatomic regions and three distinct modalities: bulk geographies, sorted cell types, and single nuclei. We identified 259 mosaic variants, revealing remarkable differences in localization, clonal abundance, cell type specificity, and clade distribution. We identified a set of hierarchical cellular diffusion barriers, whereby the left-right axis separation of the neocortex occurs prior to anterior-posterior and dorsal-ventral axis separation. We also found that stochastic distribution is a driver of clonal dispersion, and that rules regarding cellular lineages and anatomical boundaries are often ignored. Our data provides a comprehensive analysis of brain somatic mosaicism across the human cerebral cortex, deconvolving clonal distributions and migration patterns in the human embryo. One Sentence SummaryComprehensive evaluation of brain somatic mosaicism in the adult human identifies rules governing cellular distribution during embryogenesis.

genomics↗

bioRxiv2018

Genome-wide identification and expression analysis of the FAR gene family in hexaploid wheat (Triticum aestivum L.)

Fatty acyl-CoA reductase (FAR) is involved in the biosynthesis of primary alcohols, which are waxy constituents that play an important role in plant stress. Previous studies have shown that primary alcohol is the most important component in the wheat seeding stage and accounts for more than 80% of the total composition. To date, eight FAR genes have been identified in wheat, but there has not been a systematic analysis. In this study, a comprehensive overview of the TaFAR gene family was performed, including analyses of the phylogenetic relationship, the multiple sequence alignment, the conserved motif distribution and the expression pattern. The result showed that a total of 41 wheat FAR genes were identified and designated TaFAR1-A-TaFAR22-D; all FAR genes were divided into six classes according to their phylogenetic relationship, and most of the FAR genes might be related to wheat cuticular wax synthesis. The analysis of the promoter binding site showed that TaFAR genes could be regulated by the MYB transcription factor and could be used as target genes for hormone regulation under adverse conditions, especially during a drought. This study provides a basis for further analyses of the TaFAR gene function and of upstream regulatory genes.

plant biology↗