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GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism.

ABSTRACT: Developmental-regulatory networks often include large gene families encoding mechanistically-related proteins like G-protein-coupled receptors, zinc finger transcription factors and solute carrier (SLC) transporters. In principle, a common mechanism may confer expression of multiple members integral to a developmental process, or diverse mechanisms may be deployed. Using genetic complementation and enhancer-mutant systems, we analyzed the 456 member SLC family that establishes the small molecule constitution of cells. This analysis identified SLC gene cohorts regulated by GATA1 and/or GATA2 during erythroid differentiation. As >50 SLC genes shared GATA factor regulation, a common mechanism established multiple members of this family. These genes included Slc29a1 encoding an equilibrative nucleoside transporter (Slc29a1/ENT1) that utilizes adenosine as a preferred substrate. Slc29a1 promoted erythroblast survival and differentiation ex vivo. Targeted ablation of murine Slc29a1 in erythroblasts attenuated erythropoiesis and erythrocyte regeneration in response to acute anemia. Our results reveal a GATA factor-regulated SLC ensemble, with a nucleoside transporter component that promotes erythropoiesis and prevents anemia, and establish a mechanistic link between GATA factor and adenosine mechanisms. We propose that integration of the GATA factor-adenosine circuit with other components of the GATA factor-regulated SLC ensemble establishes the small molecule repertoire required for progenitor cells to efficiently generate erythrocytes.

SUBMITTER: Zwifelhofer NM

PROVIDER: S-EPMC7793295 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism.

Zwifelhofer Nicole M NM Cai Xiaoli X Liao Ruiqi R Mao Bin B Conn Daniel J DJ Mehta Charu C Keles Sunduz S Xia Yang Y Bresnick Emery H EH

PLoS genetics 20201228 12

Developmental-regulatory networks often include large gene families encoding mechanistically-related proteins like G-protein-coupled receptors, zinc finger transcription factors and solute carrier (SLC) transporters. In principle, a common mechanism may confer expression of multiple members integral to a developmental process, or diverse mechanisms may be deployed. Using genetic complementation and enhancer-mutant systems, we analyzed the 456 member SLC family that establishes the small molecule ...[more]

PMID: 33370779

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Project description:The human solute carrier (SLC) superfamily of transporters is comprised of over 400 membrane-bound proteins, and plays essential roles in a multitude of physiological and pharmacological processes. In addition, perturbation of SLC transporter function underlies numerous human diseases, which renders SLC transporters attractive drug targets. Common genetic polymorphisms in SLC genes have been associated with inter-individual differences in drug efficacy and toxicity. However, despite their tremendous clinical relevance, epidemiological data of these variants are mostly derived from heterogeneous cohorts of small sample size and the genetic SLC landscape beyond these common variants has not been comprehensively assessed. In this study, we analyzed Next-Generation Sequencing data from 141,456 individuals from seven major human populations to evaluate genetic variability, its functional consequences, and ethnogeographic patterns across the entire SLC superfamily of transporters. Importantly, of the 204,287 exonic single-nucleotide variants (SNVs) which we identified, 99.8% were present in less than 1% of analyzed alleles. Comprehensive computational analyses using 13 partially orthogonal algorithms that predict the functional impact of genetic variations based on sequence information, evolutionary conservation, structural considerations, and functional genomics data revealed that each individual genome harbors 29.7 variants with putative functional effects, of which rare variants account for 18%. Inter-ethnic variability was found to be extensive, and 83% of deleterious SLC variants were only identified in a single population. Interestingly, population-specific carrier frequencies of loss-of-function variants in SLC genes associated with recessive Mendelian disease recapitulated the ethnogeographic variation of the corresponding disorders, including cystinuria in Jewish individuals, type II citrullinemia in East Asians, and lysinuric protein intolerance in Finns, thus providing a powerful resource for clinical geneticists to inform about population-specific prevalence and allelic composition of Mendelian SLC diseases. In summary, we present the most comprehensive data set of SLC variability published to date, which can provide insights into inter-individual differences in SLC transporter function and guide the optimization of population-specific genotyping strategies in the bourgeoning fields of personalized medicine and precision public health.

Project description:Background & aimsBile acid transporters maintain bile acid homeostasis. Little is known about the functions of some transporters in cholestasis or their regulatory mechanism. We investigated the hepatic expression of solute carrier organic anion transporter family member 3A1 (SLCO3A1, also called OATP3A1) and assessed its functions during development of cholestasis.MethodsWe measured levels of OATP3A1 protein and messenger RNA and localized the protein in liver tissues from 22 patients with cholestasis and 21 patients without cholestasis, using real-time quantitative polymerase chain reaction, immunoblot, and immunofluorescence analyses. We performed experiments with Slco3a1-knockout and C57BL/6J (control) mice. Mice and Sprague-Dawley rats underwent bile duct ligation (BDL) or a sham operation. Some mice were placed on a 1% cholic acid (CA) diet to induce cholestasis or on a control diet. Serum and liver tissues were collected and analyzed; hepatic levels of bile acids and 7-α-C4 were measured using liquid chromatography/mass spectrometry. Human primary hepatocytes and hepatoma (PLC/PRF/5) cell lines were used to study mechanisms that regulate OATP3A1 expression and transport.ResultsHepatic levels of OATP3A1 messenger RNA and protein were significantly increased in liver tissues from patients with cholestasis and from rodents with BDL or 1% CA diet-induced cholestasis. Levels of fibroblast growth factor 19 (FGF19, FGF15 in rodents) were also increased in liver tissues from patients and rodents with cholestasis. FGF19 signaling activated the Sp1 transcription factor and nuclear factor κB to increase expression of OATP3A1 in hepatocytes; we found binding sites for these factors in the SLCO3A1 promoter. Slco3a1-knockout mice had shorter survival times and increased hepatic levels of bile acid, and they developed more liver injury after the 1% CA diet or BDL than control mice. In hepatoma cell lines, we found OATP3A1 to take prostaglandin E2 and thyroxine into cells and efflux bile acids.ConclusionsWe found levels of OATP3A1 to be increased in cholestatic liver tissues from patients and rodents compared with healthy liver tissues. We show that OATP3A1 functions as a bile acid efflux transporter that is up-regulated as an adaptive response to cholestasis.

Project description:Aim: To identify potential key candidate genes, whose expression and clinical significance was further assessed in colorectal cancer (CRC). Methods: Three original microarray datasets (GSE41328, GSE22598, and GSE23878) from NCBI-GEO were used to analyze differentially expressed genes (DEGs) in CRC. Online database analyses through Oncomine and GEIPA were performed to evaluate SLC4A4 expression and explore the prognostic merit of SLC4A4 expression, which was further confirmed by analyses from QPCR based cDNA array and IHC based tissue microarray (TMA). STRING website was used to explore the interaction between SLC4A4 with other DEGs based on the protein-protein interaction (PPI) networks. Results: Analysis of three original microarray datasets from GEO identified 82 shared, differentially expressed genes (28 upregulated and 54 down-regulated) in CRC tissues. Online analyses from Oncomine and GEIPA revealed lower SLC4A4 mRNA expression in CRC tissues compared to adjacent normal tissues, which were further confirmed by QPCR based cDNA array and IHC based TMA analyses on both mRNA and protein levels. Survival analyses through GEIPA and from TMA demonstrated that low SLC4A4 expression is correlated with worse overall survival among patients with CRC. Survival analysis from Kaplan-meier plotter demonstrated that low SLC4A4 expression is significantly associated with poor progression (including relapse-free survival, overall survival, distant metastasis-free survival, post-progression survival) of patients with breast cancer, lung cancer, gastric cancer, and ovarian cancer. PPI analysis found that SLC4A4 is highly correlated with various genes, including SLC9A3, SLC26A6, ENSG00000214921, SLC26A4, SLC9A3R1, and SLC9A1. Conclusion: The mRNA and protein levels of SLC4A4 were decreased in CRC tissues, and low expression of SLC4A4 significantly correlated with shorter survival of CRC patients and poorer progression of patients with breast cancer, lung cancer, gastric cancer and ovarian cancer, suggesting potential role of SLC4A4 on tumor suppression and prognostic prediction in multiple malignancies including CRC.

Dataset Information

GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism.

Publications

GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism.

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