Prediction of the Sex-Associated Genomic Region in Tunas (Thunnus Fishes)

Fish species have a variety of sex determination systems. Tunas (genus Thunnus) have an XY genetic sex determination system. However, the Y chromosome or responsible locus has not yet been identified in males. In a previous study, a female genome of Pacific bluefin tuna (T. orientalis) was sequenced, and candidates for sex-associated DNA polymorphisms were identified by a genome-wide association study using resequencing data. In the present study, we sequenced a male genome of Pacific bluefin tuna by long-read and linked-read sequencing technologies and explored male-specific loci through a comparison with the female genome. As a result, we found a unique region carrying the male-specific haplotype, where a homolog of estrogen sulfotransferase gene was predicted to be encoded. The genome-wide mapping of previously resequenced data indicated that, among the functionally annotated genes, only this gene, named sult1st6y, was paternally inherited in the males of Pacific bluefin tuna. We reviewed the RNA-seq data of southern bluefin tuna (T. maccoyii) in the public database and found that sult1st6y of southern bluefin tuna was expressed in all male testes, but absent or suppressed in the female ovary. Since estrogen sulfotransferase is responsible for the inactivation of estrogens, it is reasonable to assume that the expression of sult1st6y in gonad cells may inhibit female development, thereby inducing the individuals to become males. Thus, our results raise a promising hypothesis that sult1st6y is the sex determination gene in Thunnus fishes or at least functions at a crucial point in the sex-differentiation cascade.

A candidate for the sex-determination gene in tunas (Thunnus fishes)

Fish species have a variety of sex determination systems. Tunas (genus Thunnus) have an XY genetic sex-determination system. However, the Y chromosome or responsible locus has not yet been identified in males. In a previous study, a female genome of Pacific bluefin tuna (T. orientalis) was sequenced, and candidates for sex-associated DNA polymorphisms were identified by a genome-wide association study using resequencing data. In the present study, we sequenced a male genome of Pacific bluefin tuna by long-read and linked-read sequencing technologies, and explored male-specific loci through a comparison with the female genome. As a result, we found a unique region carrying the male-specific haplotype, where a homolog of estrogen sulfotransferase gene was predicted to be encoded. The genome-wide mapping of previously resequenced data indicated that, among the functionally annotated genes, only this gene, named sult1st6y, was paternally inherited in the males of Pacific bluefin tuna. We reviewed the RNA-seq data of southern bluefin tuna (T. maccoyii) in the public database and found that sult1st6y of southern bluefin tuna was expressed in all male testes, but absent or suppressed in the female ovary. Since estrogen sulfotransferase is responsible for the inactivation of estrogens, it is reasonable to assume that the expression of sult1st6y in gonad cells may inhibit female development, thereby inducing the individuals to become males. Thus, our results raise a promising hypothesis that sult1st6y is the sex-determination gene in Thunnus fishes, or at least functions at a crucial point in the sex-differentiation cascade.

Estrogen Sulfotransferase (SULT1E1): Its Molecular Regulation, Polymorphisms, and Clinical Perspectives

Estrogen sulfotransferase (SULT1E1) is a phase II enzyme that sulfates estrogens to inactivate them and regulate their homeostasis. This enzyme is also involved in the sulfation of thyroid hormones and several marketed medicines. Though the profound action of SULT1E1 in molecular/pathological biology has been extensively studied, its genetic variants and functional studies have been comparatively rarely studied. Genetic variants of this gene are associated with some diseases, especially sex-hormone-related cancers. Comprehending the role and polymorphisms of SULT1E1 is crucial to developing and integrating its clinical relevance; therefore, this study gathered and reviewed various literature studies to outline several aspects of the function, molecular regulation, and polymorphisms of SULT1E1.

RORα phosphorylation by casein kinase 1α as glucose signal to regulate estrogen sulfation in human liver cells

Estrogen sulfotransferase (SULT1E1) metabolically inactivates estrogen and SULT1E1 expression is tightly regulated by multiple nuclear receptors. Human fetal, but not adult, livers express appreciable amounts of SULT1E1 protein, which is mimicked in human hepatoma-derived HepG2 cells cultured in high glucose (450 mg/dl) medium. Here, we have investigated this glucose signal that leads to phosphorylation of nuclear receptor RORα (NR1F1) at Ser100 and the transcription mechanism by which phosphorylated RORα transduces this signal to nuclear receptor HNF4α, activating the SULT1E1 promoter. The promoter is repressed by non-phosphorylated RORα which binds a distal enhancer (−943/−922 bp) and interacts with and represses HNF4α-mediated transcription. In response to high glucose, RORα becomes phosphorylated at Ser100 and reverses its repression of HNF4α promoter activation. Moreover, the casein kinase CK1α, which is identified in an enhancer-bound nuclear protein complex, phosphorylates Ser100 in in vitro kinase assays. During these dynamic processes, both RORα and HNF4α remain on the enhancer. Thus, RORα utilizes phosphorylation to integrate HNF4α and transduces the glucose signal to regulate the SULT1E1 gene in HepG2 cells and this phosphorylation-mediated mechanism may also regulate SULT1E1 expressions in the human liver.

Inhibition of Estrogen Sulfotransferase (SULT1E1/EST) Ameliorates Ischemic Acute Kidney Injury in Mice

BackgroundStudies have suggested that estrogens may protect mice from AKI. Estrogen sulfotransferase (SULT1E1, or EST) plays an important role in estrogen homeostasis by sulfonating and deactivating estrogens, but studies on the role of SULT1E1 in AKI are lacking.MethodsWe used the renal ischemia-reperfusion model to investigate the role of SULT1E1 in AKI. We subjected wild-type mice, Sult1e1 knockout mice, and Sult1e1 knockout mice with liver-specific reconstitution of SULT1E1 expression to bilateral renal ischemia-reperfusion or sham surgery, either in the absence or presence of gonadectomy. We assessed relevant biochemical, histologic, and gene expression markers of kidney injury. We also used wild-type mice treated with the SULT1E1 inhibitor triclosan to determine the effect of pharmacologic inhibition of SULT1E1 on AKI.ResultsAKI induced the expression of Sult1e1 in a tissue-specific and sex-specific manner. It induced expression of Sult1e1 in the liver in both male and female mice, but Sult1e1 induction in the kidney occurred only in male mice. Genetic knockout or pharmacologic inhibition of Sult1e1 protected mice of both sexes from AKI, independent of the presence of sex hormones. Instead, a gene profiling analysis indicated that the renoprotective effect was associated with increased vitamin D receptor signaling. Liver-specific transgenic reconstitution of SULT1E1 in Sult1e1 knockout mice abolished the protection in male mice but not in female mice, indicating that Sult1e1’s effect on AKI was also tissue-specific and sex-specific.ConclusionsSULT1E1 appears to have a novel function in the pathogenesis of AKI. Our findings suggest that inhibitors of SULT1E1 might have therapeutic utility in the clinical management of AKI.

Triad entanglement of estrogen-sulfotransferase (SULT1E1), NFκβ and Nrf-2 confers matrix-metalloprotease (MMP 2/9) action in breast carcinogenesis

ABSTRACTEstrogen (E2) is one of the most important signaling molecules that control cell-differentiation/early-embryogenesis/organogenesis in gender-independent manner. Nevertheless, during adolescence/adulthood it influences female reproductive-functions by delicate cellular proliferative-events via nongenomic (cellular-signaling)/genomic (transcriptional-signaling) pathways to recruit a number of genes/proteins. In case of post-menopausal-women high E2 may initiates tumors in breast/gynaecological-tissues. Impired estrogenic signaling may be the results from abnormal redox-regulations of estrogen-metabolizing-enzyme estrogen-sulfotransferase(SULT1E1), transcriptional-factors NFκβ, Nrf-2 and Matrixmetalloproteases (specially MMP 2/9) in the breast-tumor. Here, tumor and its surrounding tissues were obtained from the district-hospital. Intracellular redox-environment of tumors was screened with some in vitro-studies. RT-PCR for SULT1E1 expression and MMP 2/9-zymogram were conducted in lasoprazole (Nrf-2 inducer) or dexamethasone (SULT1E1 inducer) treted rat liver tissues. Immunohistochemistry was performed to analyze SULT1E1/NFκβ localization and MMP 2/9-zymogram in human breast-cancer versus its surrounding tissues. It can be hypothesized that transcription-factors (NFκβ/Nrf-2) imposes effect on MMPs expressions resulting in significant impacts on metastatic transition of breast-cancer. Breast tumor reveals higher (vs surrounding-tissue) expression/immunolocalization of NFκB/SULT1E1 paralleling to our previous finding of Nrf-2 induction. The relation between Nrf2/NFκB is determined by oxidative-stress and by CBP recruitment of HDAC3. Further, this relation is a determinant of MMP-regulations and SULT1E1-mediated E2 levels. Adaptively, augmented Nrf-2 may induce SULT1E1 resulting in lower active-estrogen. The triad regulations of NFκβ, SULT1E1 and Nrf2 are proposed here to execute MMPs function in the severity of human breast-carcinogenesis. Therapeutically this triad system may be effectively targeted for breast cancer treatment. Further studies are necessary in this regard.