Biology subjects

McGill, C. J.

Publications and source records attributed to McGill, C. J..

11 recordsLinked to original sources

bioRxiv2026

Reversible, Sexually Dimorphic Sympathetic Aging: Distal Axon Withdrawal Shaped by Prepubertal Gonadal Influences

Peripheral innervation declines with age, but whether this process is sexually dimorphic and whether it reflects neuronal degeneration or deterioration of nerve-target interactions remain unclear. Using mouse skin as a defined neuroeffector system, we show that sympathetic aging is strongly sexually dimorphic, with greater denervation in aged males. Skin-projecting sympathetic neurons remain intact, indicating that denervation reflects distal axon withdrawal rather than neuronal loss. Nerve-target interactions and the arrector pili muscle niche deteriorate with age, predominantly in males. Aged sympathetic neurons retain NGF responsiveness, and restoring NGF within arrector pili muscles promotes sympathetic reinnervation and hair regeneration in aged males. Genetic and endocrine models show that divergent aging trajectories are associated with gonadal rather than chromosomal sex and are attenuated by early gonadectomy. Together, these findings identify sympathetic aging as a reversible, sexually dimorphic distal axonopathy shaped by the target environment and gonadal influences.

developmental biology↗

bioRxiv2026

17α-Estradiol Confers Limited Protection Against APOE4 Phenotypes in Middle-Aged Female Mice

Longevity-promoting interventions represent a promising strategy to mitigate brain aging and reduce Alzheimers disease (AD) risk. The NIA Interventions Testing Program identified the weak estrogen 17-estradiol (17E2) as a compound that extends healthspan and lifespan in mice, with effects observed primarily in males. Our recent work demonstrated that 17E2 healthspan benefits were modulated by human apolipoprotein E (APOE) genotype such that aging phenotypes were improved more strongly in middle-aged male mice with targeted-replacement of the AD-associated APOE4 allele compared to APOE3, the risk neutral and most common APOE allele. Here, we tested whether APOE-dependent, AD-relevant benefits of 17E2 observed in males extend to females. Specifically, we treated 12-month-old APOE3 and APOE4 targeted-replacement female mice for 6 months with chow containing 0 or 14.4ppm 17E2. We find that relative to APOE3, APOE4 genotype largely exhibits more robust systemic phenotypes associated with aging, including increased adiposity, impaired glucose tolerance, and reduced energy expenditure. Further, we observe that treatment with 17E2 yields modest improvements in some outcomes, including decreased adiposity and increased lean mass, glucose tolerance, and energy expenditure, though significant benefits are found only in APOE4 females. In the CNS, we observed mixed effects of APOE genotype on behavioral performance and indices of brain aging, with APOE4 females performing worse in the Barnes Maze and having higher levels of the AD-related peptide soluble {beta}-amyloid, but no APOE genotype differences in cortical lipid raft oxidative damage. In contrast to its systemic effects, 17E2 did not significantly improve neural outcomes in APOE3 or APOE4 females. These findings address the impact of biological sex on established protective effects of a longevity-promoting intervention against APOE4 phenotypes, which have significant relevance to the prevention of age-related conditions including metabolic dysfunction, cognitive impairment and vulnerability to AD.

systems biology↗

bioRxiv2026

Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity

The metabolite acetyl-CoA plays a central role in cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 has been linked to peripheral neuropathy (heterozygous mutations), developmental delay with premature death (homozygous mutations) and intellectual disability with progeria (duplication). These phenotypes can be reproduced in the mouse. Here, we show that AT-1 overexpression in primary neurons impacts diverse phenotypes related to neuronal function and plasticity. At the gene level, AT-1 induces brain aging signatures, and key differences in ribosomal and synaptic processes were identified in both the transcriptome and the proteome. Changes in mitochondria-associated pathways were reflected in an increase in expression of mitochondrial master regulator PGC-1 and its target genes. Functionally, marked differences in mitochondrial membrane potential, architecture, and respiration were detected. Tracing experiments indicated altered glucose utilization in glycogen storage and nucleotide production. Shifts in redox metabolism were linked to differences in levels of NAD-dependent SIRT1 and CtBP2, with consequences for acetylated lysine modification. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization and a major shift in cellular lipid composition. These broad-scale changes in metabolism were coincident with reduced expression of synaptic proteins and reduced activity among synaptic networks, indicating that neuronal electrophysiology and network communication are coordinated at least in part through neuronal acetyl-CoA metabolism.

cell biology↗

bioRxiv2024

Sex-dimorphic gene regulation in murine macrophages across niches

Macrophages are a key cell type of the innate immune system and are involved at all steps of inflammation: (i) they present antigens to initiate inflammation, (ii) they clear up foreign bodies through phagocytosis, and (iii) they resolve inflammation by removing or deactivating mediator cells. Many subtypes of macrophages have been identified, classified by their niche and/or embryonic origin. In order to better develop therapies for conditions with macrophage dysfunction, it is crucial to decipher potential sex-differences in key physiological mediators of inflammation so that treatment efficacy can be ensured regardless of biological sex. Here, we conduct a meta-analysis approach of transcriptomics datasets for male vs. female mouse macrophages across 8 niches to characterize conserved sex-dimorphic pathways in macrophages across origins and niches. For this purpose, we leveraged new and publicly available RNA-sequencing datasets from murine macrophages, preprocessed these datasets and filtered them based on objective QC criteria, and performed differential gene expression analysis using sex as the covariate of interest. Differentially expressed (DE) genes were compared across datasets and macrophage subsets, and functional enrichment analysis was performed to identify sex-specific functional differences. Consistent with their presence on the sex chromosomes, three genes were found to be differentially expressed across all datasets (i.e. Xist, Eif2s3y, and Ddx3y). More broadly, we found that female-biased pathways across macrophage niches are more consistent than male-biased pathways, specifically relating to components of the extracellular matrix. Our findings increase our understanding of transcriptional similarities across macrophage niches and underscore the importance of including sex as a biological variable in immune-related studies. HighlightsO_LIAcross 17 independently transcriptomic macrophage datasets, three genes are always differentially expressed between males and females: Ddx3y, Eif2s3y, and Xist. C_LIO_LIJaccard analysis reveals female macrophages have more stereotypical transcriptional profile than male macrophages across niches. C_LIO_LIFunctional enrichment analyses show that female-biased pathways across macrophage subtypes are enriched for extracellular matrix-related genes. C_LI

immunology↗

bioRxiv2024

Protection against APOE4-associated aging phenotypes with the longevity-promoting intervention 17α-estradiol in male mice

The apolipoprotein {varepsilon}4 allele (APOE4) is associated with decreased longevity, increased vulnerability to age-related declines, and disorders across multiple systems. Interventions that promote healthspan and lifespan represent a promising strategy to attenuate the development of APOE4-associated aging phenotypes. Here we studied the ability of the longevity-promoting intervention 17-estradiol (17E2) to protect against age-related impairments in APOE4 versus the predominant APOE3 genotype using early middle-aged mice with knock-in of human APOE alleles. Beginning at age 10 months, male APOE3 or APOE4 mice were treated for 20 weeks with 17E2 or vehicle then compared for indices of aging phenotypes body-wide. Across peripheral and neural measures, APOE4 was associated with poorer outcomes. Notably, 17E2 treatment improved outcomes in a genotype-dependent manner favoring APOE4 mice. These data demonstrate a positive APOE4 bias in 17E2-mediated healthspan actions, suggesting that longevity-promoting interventions may be useful in mitigating deleterious age-related risks associated with APOE4 genotype.

systems biology↗

bioRxiv2023

The ENCODE4 long-read RNA-seq collection reveals distinct classes of transcript structure diversity

The majority of mammalian genes encode multiple transcript isoforms that result from differential promoter use, changes in exonic splicing, and alternative 3 end choice. Detecting and quantifying transcript isoforms across tissues, cell types, and species has been extremely challenging because transcripts are much longer than the short reads normally used for RNA-seq. By contrast, long-read RNA-seq (LR-RNA-seq) gives the complete structure of most transcripts. We sequenced 264 LR-RNA-seq PacBio libraries totaling over 1 billion circular consensus reads (CCS) for 81 unique human and mouse samples. We detect at least one full-length transcript from 87.7% of annotated human protein coding genes and a total of 200,000 full-length transcripts, 40% of which have novel exon junction chains. To capture and compute on the three sources of transcript structure diversity, we introduce a gene and transcript annotation framework that uses triplets representing the transcript start site, exon junction chain, and transcript end site of each transcript. Using triplets in a simplex representation demonstrates how promoter selection, splice pattern, and 3 processing are deployed across human tissues, with nearly half of multitranscript protein coding genes showing a clear bias toward one of the three diversity mechanisms. Evaluated across samples, the predominantly expressed transcript changes for 74% of protein coding genes. In evolution, the human and mouse transcriptomes are globally similar in types of transcript structure diversity, yet among individual orthologous gene pairs, more than half (57.8%) show substantial differences in mechanism of diversification in matching tissues. This initial large-scale survey of human and mouse long-read transcriptomes provides a foundation for further analyses of alternative transcript usage, and is complemented by short-read and microRNA data on the same samples and by epigenome data elsewhere in the ENCODE4 collection.

genomics↗

bioRxiv2023

Sex-dimorphic regulation of extracellular matrix genes in mouse bone marrow neutrophils

The mammalian innate immune system is sex-dimorphic. Neutrophils are the most abundant leukocyte in humans and represent innate immunitys first line of defense. We previously found that primary mouse bone marrow neutrophils show widespread sex-dimorphism throughout life, including at the transcriptional level. Extracellular matrix [ECM]-related terms were observed among the top sex-dimorphic genes. Since the ECM is emerging as an important regulator of innate immune responses, we sought to further investigate the transcriptomic profile of primary mouse bone marrow neutrophils at both the bulk and single-cell level to understand how biological sex may influence ECM component expression in neutrophils throughout life. Here, using curated gene lists of ECM components and unbiased weighted gene co-expression network analysis [WGCNA], we find that multiple ECM-related gene sets show widespread female-bias in expression in primary mouse neutrophils. Since many immune-related diseases (e.g., rheumatoid arthritis) are more prevalent in females, our work may provide insights into the pathogenesis of sex-dimorphic inflammatory diseases.

immunology↗

bioRxiv2021

Uncovering the Gene Regulatory Networks Underlying Macrophage Polarization Through Comparative Analysis of Bulk and Single-Cell Data

Gene regulatory networks (GRNs) provide a powerful framework for studying cellular differentiation. However, it is less clear how GRNs encode cellular responses to everyday microenvironmental cues. Macrophages can be polarized and potentially repolarized based on environmental signaling. In order to identify the GRNs that drive macrophage polarization and the heterogeneous single-cell subpopulations that are present in the process, we used a high-resolution time course of bulk and single-cell RNA-seq and ATAC-seq assays of HL-60-derived macrophages polarized towards M1 or M2 over 24 hours. We identified transient M1 and M2 markers, including the main transcription factors that underlie polarization, and subpopulations of naive, transitional, and terminally polarized macrophages. We built bulk and single-cell polarization GRNs to compare the recovered interactions and found that each technology recovered only a subset of known interactions. Our data provide a resource to study the GRN of cellular maturation in response to microenvironmental stimuli in a variety of contexts in homeostasis and disease.

genomics↗

bioRxiv2020

Comparative Transcriptomics of heads and tails between Steinernema carpocapsae and Caenorhabditis elegans

Steinernema nematodes have been widely studied for insect infection and mutualism, but little is known about the patterns of gene expression along the body of these worms or how these compare to the model organism Caenorhabditis elegans. Here we perform the first comparative analysis between the heads and tail regions of Steinernema carpocapsae and C. elegans Infective Juveniles (IJs)/dauers and young adults using single-worm RNA-seq. While we find overall agreement in gene expression there were several sets of genes with substantial differences between the two species. Gene expression in the S. carpocapsae female compared to the C. elegans hermaphrodite heads and tails revealed differences in metabolism, aging, and determination of lifespan. Young adult male heads and tails showed major differences in developmental related processes such as morphogenesis as well as neuronal development and signaling. We also found head- and tail-specific gene expression differences between S. carpocapsae IJs and C. elegans dauers for genes related to growth and development as well as neuronal signaling and activity. This study is one of the first comparative transcriptomic analyses of body parts between distantly related species of nematodes and provides insight into both the highly conserved and genetically distinctive characteristics of both species.

genomics↗

bioRxiv2020

Long-TUC-seq is a robust method for quantification of metabolically labeled full-length isoforms

The steady state expression of each gene is the result of a dynamic transcription and degradation of that gene. While regular RNA-seq methods only measure steady state expression levels, RNA-seq of metabolically labeled RNA identifies transcripts that were transcribed during the window of metabolic labeling. Whereas short-read RNA sequencing can identify metabolically labeled RNA at the gene level, long-read sequencing provides much better resolution of isoform-level transcription. Here we combine thiouridine-to-cytosine conversion (TUC) with PacBio long-read sequencing to study the dynamics of mRNA transcription in the GM12878 cell line. We show that using long-TUC-seq, we can detect metabolically labeled mRNA of distinct isoforms more reliably than using short reads. Long-TUC-seq holds the promise of capturing isoform dynamics robustly and without the need for enrichment.

genomics↗

bioRxiv2019

Hybrid assembly of the genome of the entomopathogenic nematode Steinernema carpocapsae identifies the X-chromosome

Entomopathogenic nematodes from the genus Steinernema are lethal insect parasites that quickly kill their insect hosts with the help of their symbiotic bacteria. Steinernema carpocapsae is one of the most studied entomopathogens due to its broad lethality to diverse insect species and its effective commercial use as a biological control agent for insect pests, as well as a genetic model for studying parasitism, pathogenesis, and symbiosis. In this study, we used long-reads from the Pacific Biosciences platform and BioNano Genomics Irys system to assemble the best genome of S. carpocapsae ALL strain to date, comprising 84.5 Mb in 16 scaffolds, with an N50 of 7.36Mb. The largest scaffold, with 20.9Mb, was identified as chromosome X based on sex-specific genome sequencing. The high level of contiguity allowed us to characterize gene density, repeat content, and GC content. RNA-seq data from 17 developmental stages, spanning from embryo to adult, were used to predict 30,957 gene models. Using this new genome, we performed a macrosyntenic analysis to Caenorhabditis elegans and Pristionchus pacificus and found S. carpocapsaes chromosome X to be primarily orthologous to C. elegans and P. pacificus chromosome II and IV. We also investigated the expansion of protein families and gene expression differences between male and female stage nematodes. This new genome and more accurate set of annotations provide a foundation for new comparative genomic and gene expression studies within the Steinernema clade and across the Nematoda phylum.\n\nArticle SummaryThe insect killing worms Steinernema carpocapsae is a model organism for parasitism and symbiosis. The authors have used long reads and optical mapping to generate substantially contiguous assembly and a new set of gene annotations. They have identified the X chromosome as well as expansions in specific family proteases found in the venom of this worm. A macrosyntenic analysis with C. elegans shows a broad conservation of ancestral chromosomes with the exception of chromosome X. This new assembly will be useful to the Steinernema community and the broader nematode genomics community.

genomics↗