Biology subjects

Lu, R. J.

Publications and source records attributed to Lu, R. J..

6 recordsLinked to original sources

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

Estropausal gut microbiota transplant improves ovarian function in adult mice

Decline in ovarian function with age not only affects fertility but is also linked to a higher risk of age-related diseases in women (e.g. osteoporosis, dementia). Intriguingly, earlier menopause is linked to shorter lifespan; however, the underlying molecular mechanisms of ovarian aging are not well understood. Recent evidence suggests the gut microbiota may influence ovarian health. In this study, we characterized ovarian aging associated microbial profiles in mice and investigated the effect of the gut microbiome from young and estropausal female mice on ovarian health through fecal microbiota transplantation. We demonstrate that the ovarian transcriptome can be broadly remodeled after heterochronic microbiota transplantation, with a reduction in inflammation-related gene expression and trends consistent with transcriptional rejuvenation. Consistently, these mice exhibited enhanced ovarian health and increased fertility. Using metagenomics-based causal mediation analyses and serum untargeted metabolomics, we identified candidate microbial species and metabolites that may contribute to the observed effects of fecal microbiota transplantation. Our findings reveal a direct link between the gut microbiota and ovarian health.

physiology↗

bioRxiv2023

Transcriptional profiling of aging tissues from female and male African turquoise killifish

The African turquoise killifish is an emerging vertebrate model organism with great potential for aging research due to its naturally short lifespan. Thus far, turquoise killifish aging omic studies using RNA-seq have examined a single organ, single sex and/or evaluated samples from non-reference strains. Here, we describe a resource dataset of ribosomal RNA depleted RNA-seq libraries generated from the brain, heart, muscle, and spleen from both sexes, as well as young and old animals, in the reference GRZ turquoise killifish strain. We provide basic quality control steps and demonstrate the utility of our dataset by performing differential gene expression and gene ontology analyses by age and sex. Importantly, we show that age has a greater impact than sex on transcriptional landscapes across probed tissues. Finally, we confirm transcription of transposable elements (TEs), which are highly abundant and increase in expression with age in brain tissue. This dataset will be a useful resource for exploring gene and TE expression as a function of both age and sex in a powerful naturally short-lived vertebrate model.

genomics↗

bioRxiv2023

Age-maintained human neurons demonstrate a developmental loss of intrinsic neurite growth ability

Injury to adult mammalian central nervous system (CNS) axons results in limited regeneration. Rodent studies have revealed a developmental switch in CNS axon regenerative ability, yet whether this is conserved in humans is unknown. Using human fibroblasts from 8 gestational-weeks to 72 years-old, we performed direct reprogramming to transdifferentiate fibroblasts into induced neurons (Fib-iNs), avoiding pluripotency which restores cells to an embryonic state. We found that early gestational Fib-iNs grew longer neurites than all other ages, mirroring the developmental switch in regenerative ability in rodents. RNA-sequencing and screening revealed ARID1A as a developmentally-regulated modifier of neurite growth in human neurons. These data suggest that age-specific epigenetic changes may drive the intrinsic loss of neurite growth ability in human CNS neurons during development. One-Sentence Summary: Directly-reprogrammed human neurons demonstrate a developmental decrease in neurite growth ability.

neuroscience↗

bioRxiv2023

The Human Mitochondrial Genome Encodes for an Interferon-Responsive Host Defense Peptide

The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode for active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a mitochondrial-encoded host defense peptide (HDP) that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the twelve S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targeted E. coli and methicillin-resistant S. aureus (MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In monocytes, IFN{gamma}, LPS, and differentiation signals each induced the expression of endogenous MOTS-c. Notably, MOTS-c translocated to the nucleus to regulate gene expression during monocyte differentiation and programmed them into macrophages with unique transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicates that our immune system is not only encoded by the nuclear genome, but also by the co-evolved mitochondrial genome.

immunology↗

bioRxiv2022

Lack of accelerated ovarian aging in a follicle-stimulating hormone receptor haploinsufficiency model

Follicle-stimulation hormone (FSH) and FSH receptor (FSHR) signaling is essential for lifelong ovarian and endocrine functions in females. Previous studies have reported that Fshr haploinsufficiency in female mice led to accelerated ovarian aging, including anticipated progressive fertility decline, irregular estrus cycles, increased follicular atresia and premature ovarian failure at 7 to 9 months of age. Interestingly, these phenotypes resemble key characteristics of human menopause and thus Fshr haploinsufficiency was proposed as a promising research mouse model of menopause. However, the Fshr haploinsufficiency model had not been fully explored, especially at the molecular level. In this study, we characterized the ovarian and endocrine functions of a Fshr heterozygous knockout allele that was generated on the C57BL/6 genetic background as part of the Knockout Mouse Project (KOMP). Based on our analyses of these mice using a breeding assay, ovarian tissue histology and serum hormone quantifications (i.e. FSH, AMH, INHA) analyses, the KOMP Fshr heterozygous knockout female mice do not show the anticipated phenotypes of ovarian aging in terms of fertility and endocrine function. We further confirmed that the expression of Fshr is unaltered in the ovaries of the KOMP Fshr heterozygous knockout animals compared to wild-type. Together, our data suggests that the KOMP Fshr heterozygous knockout strain does not recapitulate the previously reported ovarian aging phenotypes associated to another model of Fshr haploinsufficiency.

genetics↗