Direct androgen receptor regulation of sexually dimorphic gene expression in the mammalian kidney
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE225566 | GEO | 2023/08/02
REPOSITORIES: GEO
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Project description:Prostate organogenesis is regulated by interactions between mesenchymal and epithelial cells, and via androgen signalling though androgen receptors (AR) expressed in mesenchymal cells. However, there is little knowledge of AR target genes and we have used high resolution genomic methods to examine AR function in subsets of mesenchyme during prostate development. Using ChIP-seq, we defined genomic AR binding sites (ARBS) in microdissected mesenchymal tissues of neonatal male and female rats during prostate growth. By comparing female tissue subsets (ventral mesenchymal pad and urethral smooth muscle) with male tissues (ventral prostate and dorsolateral prostate), we were able to identify sexually dimorphic ARBS. Females had a distinct AR binding profile from males with enrichment of ARBS proximal to gene transcriptional start sites as well as binding to non-classical AR binding sequence motifs. Using both tissue RNA-sequencing and single-cell RNA-sequencing of the same mesenchymal subsets, we identified 128 differentially expressed transcripts between males and females. Comparison of these to ChIP-seq ARBS allowed us to define sexually dimorphic AR target genes. Selected candidates were validated as sexually dimorphic at both the mRNA and protein level in both rat and human developing prostate tissues by qPCR and western blot. Response to testosterone stimulation was examined using ex vivo rat tissue organ cultures and qPCR. In single cell RNAseq data we observed subpopulations of mesenchymal cells in males and females as well as subpopulations common to both. The distribution of AR and target genes did not follow the subpopulation distribution, suggesting that AR action is not restricted by subset identity.Our study is the first to apply multiple transcriptomic approaches to prostate mesenchyme, and we have identified unique AR targets. We have identified sexually dimorphic, androgen responsive mesenchymal target genes that may underlie sexually dimorphic development of the prostate. We suggest that the analysis of transcription factor binding and transcriptomes in cell subsets will be informative when applied to tumour cells and stroma – since these show similar cellular heterogeneity and subset specific activity.
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Project description:Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveals that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic capacity. Tumor microarray and gene expression analyses demonstrate that AR-FUT4-L1CAM-AJs signaling correlates with pathological staging in melanoma patients. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help to explain sex-associated clinical outcome disparities and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma.
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Project description:Identification of midgut genes with sex-biased transcription and/or splicing under cell-autonomous control of transformer in adult intestinal stem cells Sex differences in physiology are commonly attributed to developmental and/or hormonal factors, but there is increasing realisation that cell-intrinsic mechanisms play important and persistent roles. Here we use the Drosophila melanogaster intestine to investigate the activity and significance of intrinsic sex in an adult somatic organ in vivo. We find that the adult intestinal epithelium is a cellular mosaic of different sex differentiation pathways, and displays extensive sex differences in expression of genes with roles in growth and metabolism. Cell-specific reversals of the sexual identity of adult intestinal stem cells uncover its key roles in controlling organ size, its reproductive plasticity and susceptibility to tumours. Unlike previous examples of sexually dimorphic somatic stem cell activity, the sex differences in intestinal stem cell behaviour arise from intrinsic mechanisms, which control cell cycle duration and involve a new doublesex- and fruitless-independent branch of the sex differentiation pathway downstream of transformer. Together, our findings indicate that the plasticity of an adult somatic organ is reversibly controlled by its intrinsic sexual identity, imparted by a new mechanism that may be active in more tissues than previously recognised.
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Project description:Identification of midgut genes with sex-biased transcription and/or splicing under cell-autonomous control of transformer in adult intestinal stem cells Sex differences in physiology are commonly attributed to developmental and/or hormonal factors, but there is increasing realisation that cell-intrinsic mechanisms play important and persistent roles. Here we use the Drosophila melanogaster intestine to investigate the activity and significance of intrinsic sex in an adult somatic organ in vivo. We find that the adult intestinal epithelium is a cellular mosaic of different sex differentiation pathways, and displays extensive sex differences in expression of genes with roles in growth and metabolism. Cell-specific reversals of the sexual identity of adult intestinal stem cells uncover its key roles in controlling organ size, its reproductive plasticity and susceptibility to tumours. Unlike previous examples of sexually dimorphic somatic stem cell activity, the sex differences in intestinal stem cell behaviour arise from intrinsic mechanisms, which control cell cycle duration and involve a new doublesex- and fruitless-independent branch of the sex differentiation pathway downstream of transformer. Together, our findings indicate that the plasticity of an adult somatic organ is reversibly controlled by its intrinsic sexual identity, imparted by a new mechanism that may be active in more tissues than previously recognised. Adult midgut transcriptomes of 15-day-old virgin females were generated by deep sequencing, in triplicate using a Hiseq2000 using paired end 100bp reads. Genotypes were: control, transformer mutant and transformer mutant female in which transformer was re-introduced in adult intestinal stem cells.
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