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Spatial characterization of sex differential regulations in kidney across lifespan

ABSTRACT: There is a clear sex bias in the incident rates and progressions of many kidney diseases and kidney cancers. To obtain a comprehensive understanding of the genetic and epigenetic regulation of kidney sexual dimorphism, we integrated single nucleus RNA and ATAC sequencing (snRNA-Seq and snATAC-Seq) and Visium spatial transcriptomics (ST) data to build a spatially resolved cell-type-specific molecular atlas for the mouse kidney throughout the lifespan, from embryo, newborn, youth, adolescence, adult to old age, of both sexes. We demonstrate that proximal tubules (PT) have the most sex-biased differentially expressed genes (DEGs) (164 and 227 for male and female respectively), which appear after 3 weeks of age and are associated with hormonal regulations. Notably, we reveal the potential mechanism of indirect and direct involvement of estrogen and androgen, respectively, in sex-biased gene expression regulations in the kidney. Specifically, regulon analysis shows that a set of female-biased DEGs, including Socs2, might be indirectly regulated by estrogen through prolactin-induced Jak2/Stat5 activation. On the other hand, chromatin accessibility investigation identifies androgen receptor motifs as significantly enriched in males, might be directly involved in regulating male-biased DEGs, such as Slco3a1, Serpinf2, Slc7a13, Slc22a30, Cyp4b1, and Acsm2. Sex-biased DEGs identified from mice, including several not previously highlighted, were validated by immunofluorescence and multiplex imaging data in human kidneys. Moreover, older male mice (92 weeks) display more aging-related gene alterations in loops of Henle and PTs, while older females have more aging-related gene alterations in fibroblasts. Our results provide the community with rich resources and better understanding of spatially resolved gene expression and hormone regulation for sexual dimorphism in the kidney across the lifespan.

ORGANISM(S): Mus musculus

PROVIDER: GSE252772 | GEO | 2025/01/13

REPOSITORIES: GEO

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Project description:Background: Stalk-eyed flies (family Diopsidae) are a model system for studying sexual selection due to the presence of elongated and sexually dimorphic eye-stalks in many species. Recent genomic studies on these flies have revealed a neo-X chromosome and evidence of gene movement onto or off of this X chromosome. To determine if sex linkage and gene movement are related to sexual dimorphism and sexual conflict, we compared gene expression between males and females using oligonucleotide microarrays and RNA from either developing eyestalk tissue or adult heads from a dimorphic species, Teleopsis dalmanni, or from developing eyestalk tissue in a congeneric monomorphic species, T. quinqueguttata. Results: Comparison of gene expression between the sexes for 3,748 genes indicates that dosage compensation is present due to elevated expression of X-linked genes in males. However, sex-biased expression was detected in 26% of the genes present in eye-antennal imaginal discs of larval T. dalmanni. Functional annotation reveals that female-biased genes are associated with transcription, anatomical development and cell communication in the nucleus, while male-biased genes are associated with metabolism and the mitochondria. Comparison of gene expression between experiments identified 140 genes with concordant sex-biased expression in the larval and adult tissues of T. dalmanni and 17 genes with identical sex-biased expression between species. There were only five reversals of sex-biased expression across experiments. In T. dalmanni, male-biased genes are more common on autosomes than on the X while female-biased genes are more common on the X in T. quinqueguttata. Female-biased expression is especially common among genes that moved onto the ancestral X while male-biased expression is more common among genes that moved onto an autosome. Conclusions: Genes with sex-biased expression exhibit different functions in each sex as expected if sexual conflict has influenced their evolution. The strong relationship between sex-biased expression and gene movement found in this study is consistent with resolution of sexual conflict by an RNA- or DNA-mediated process that moves genes between chromosomes. Measurement of gene expression in additional species should provide a more complete picture of how gene expression change occurs over evolutionary time in these extraordinary flies. Two-condition experiment, female vs. male RNA using larval eye discs for two species (Teleopsis dalmanni, Teleopsis quinqueguttata), and adult heads for one species (Teleopsis dalmanni).

Project description:Sexually dimorphic traits are by definition exaggerated in one sex, which may arise from a history of sex-specific selection â in males, females, or both. If this exaggeration comes at a cost, exaggeration is expected to be greater in higher condition individuals (condition-dependent). Although studies using small numbers of morphological traits are generally supportive, this prediction has not been examined at a larger scale. We test this prediction across the trancriptome by determining the condition-dependence of sex-biased (dimorphic) gene expression. We find that high-condition populations are more sexually dimorphic in transcription than low-condition populations. High condition populations have more male-biased genes and more female-biased genes, and a greater degree of sexually dimorphic expression in these genes. Also, condition-dependence in male-biased genes was greater than in a set of unbiased genes. Interestingly, male-biased genes expressed in the testes were not more condition-dependent than those in the soma. By contrast, increased female-biased expression under high condition may be have occurred because of the greater contribution of the ovary-specific transcripts to the entire mRNA pool. We did not find any genomic signatures distinguishing the condition-dependent sex-biased genes. The degree of condition-dependent sexual dimorphism (CDSD) did not differ between the autosomes and the X-chromosome. There was only weak evidence that rates of evolution correlated with CDSD. We suggest that the sensitivity of both female-biased genes and male-biased genes to condition may be akin to the overall heightened sensitivity to condition that life-history and sexually selected traits tend to exhibit. Our results demonstrate that through condition-dependence, early life experience has dramatic effects on sexual dimorphism in the adult transcriptome. There were 8 biologically distinct samples. Each was replicated 6 times for a total of 48 biological samples on 24 arrays. There was no reference or control sample as a loop design was used. Each of the 48 samples are represented separately.

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Spatial characterization of sex differential regulations in kidney across lifespan

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