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1.
Nature ; 571(7766): 505-509, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31243369

RESUMO

The evolution of gene expression in mammalian organ development remains largely uncharacterized. Here we report the transcriptomes of seven organs (cerebrum, cerebellum, heart, kidney, liver, ovary and testis) across developmental time points from early organogenesis to adulthood for human, rhesus macaque, mouse, rat, rabbit, opossum and chicken. Comparisons of gene expression patterns identified correspondences of developmental stages across species, and differences in the timing of key events during the development of the gonads. We found that the breadth of gene expression and the extent of purifying selection gradually decrease during development, whereas the amount of positive selection and expression of new genes increase. We identified differences in the temporal trajectories of expression of individual genes across species, with brain tissues showing the smallest percentage of trajectory changes, and the liver and testis showing the largest. Our work provides a resource of developmental transcriptomes of seven organs across seven species, and comparative analyses that characterize the development and evolution of mammalian organs.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Organogênese/genética , Transcriptoma/genética , Animais , Evolução Biológica , Galinhas/genética , Feminino , Humanos , Macaca mulatta/genética , Masculino , Camundongos , Gambás/genética , Coelhos , Ratos
2.
Mol Biol Evol ; 40(2)2023 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-36721950

RESUMO

Genomic imprinting is a parent-of-origin-specific expression phenomenon that plays fundamental roles in many biological processes. In animals, imprinting is only observed in therian mammals, with ∼200 imprinted genes known in humans and mice. The imprinting pattern in marsupials has been minimally investigated by examining orthologs to known eutherian imprinted genes. To identify marsupial-specific imprinting in an unbiased way, we performed RNA-seq studies on samples of fetal brain and placenta from the reciprocal cross progeny of two laboratory opossum stocks. We inferred allele-specific expression for >3,000 expressed genes and discovered/validated 13 imprinted genes, including three previously known imprinted genes, Igf2r, Peg10, and H19. We estimate that marsupials imprint ∼60 autosomal genes, which is a much smaller set compared with eutherians. Among the nine novel imprinted genes, three noncoding RNAs have no known homologs in eutherian mammals, while the remaining genes have important functions in pluripotency, transcription regulation, nucleolar homeostasis, and neural differentiation. Methylation analyses at promoter CpG islands revealed differentially methylated regions in five of these marsupial-specific imprinted genes, suggesting that differential methylation is a common mechanism in the epigenetic regulation of marsupial imprinting. Clustering and co-regulation were observed at marsupial imprinting loci Pou5f3-Npdc1 and Nkrfl-Ipncr2, but eutherian-type multi-gene imprinting clusters were not detected. Also differing from eutherian mammals, the brain and placenta imprinting profiles are remarkably similar in opossums, presumably due to the shared origin of these organs from the trophectoderm. Our results contribute to a fuller understanding of the origin, evolution, and mechanisms of genomic imprinting in therian mammals.


Assuntos
Marsupiais , Gravidez , Humanos , Feminino , Animais , Camundongos , Marsupiais/genética , Metilação de DNA , Epigênese Genética , Duplicação Gênica , Impressão Genômica , Gambás/genética , Mamíferos , Eutérios/genética
3.
Int J Mol Sci ; 23(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36293487

RESUMO

Marsupials have been a powerful comparative model to understand mammalian biology. However, because of the unique characteristics of their embryology, marsupial pluripotency architecture remains to be fully understood, and nobody has succeeded in developing embryonic stem cells (ESCs) from any marsupial species. We have developed an integration-free iPSC reprogramming method and established validated iPSCs from two inbred strains of a marsupial, Monodelphis domestica. The monoiPSCs showed a significant (6181 DE-genes) and highly uniform (r2 [95% CI] = 0.973 ± 0.007) resetting of the cellular transcriptome and were similar to eutherian ESCs and iPSCs in their overall transcriptomic profiles. However, monoiPSCs showed unique regulatory architecture of the core pluripotency transcription factors and were more like marsupial epiblasts. Our results suggest that POU5F1 and the splice-variant-specific expression of POU5F3 synergistically regulate the opossum pluripotency gene network. It is plausible that POU5F1, POU5F3 splice variant XM_016427856.1, and SOX2 form a self-regulatory network. NANOG expression, however, was specific to monoiPSCs and epiblasts. Furthermore, POU5F1 was highly expressed in trophectoderm cells, whereas all other pluripotency transcription factors were significantly downregulated, suggesting that the regulatory architecture of core pluripotency genes of marsupials may be distinct from that of eutherians.


Assuntos
Células-Tronco Pluripotentes Induzidas , Monodelphis , Animais , Monodelphis/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Embrionárias , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Mamíferos , Reprogramação Celular/genética
4.
Genome Res ; 27(12): 1961-1973, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29079676

RESUMO

Sexual dimorphism depends on sex-biased gene expression, but the contributions of microRNAs (miRNAs) have not been globally assessed. We therefore produced an extensive small RNA sequencing data set to analyze male and female miRNA expression profiles in mouse, opossum, and chicken. Our analyses uncovered numerous cases of somatic sex-biased miRNA expression, with the largest proportion found in the mouse heart and liver. Sex-biased expression is explained by miRNA-specific regulation, including sex-biased chromatin accessibility at promoters, rather than piggybacking of intronic miRNAs on sex-biased protein-coding genes. In mouse, but not opossum and chicken, sex bias is coordinated across tissues such that autosomal testis-biased miRNAs tend to be somatically male-biased, whereas autosomal ovary-biased miRNAs are female-biased, possibly due to broad hormonal control. In chicken, which has a Z/W sex chromosome system, expression output of genes on the Z Chromosome is expected to be male-biased, since there is no global dosage compensation mechanism that restores expression in ZW females after almost all genes on the W Chromosome decayed. Nevertheless, we found that the dominant liver miRNA, miR-122-5p, is Z-linked but expressed in an unbiased manner, due to the unusual retention of a W-linked copy. Another Z-linked miRNA, the male-biased miR-2954-3p, shows conserved preference for dosage-sensitive genes on the Z Chromosome, based on computational and experimental data from chicken and zebra finch, and acts to equalize male-to-female expression ratios of its targets. Unexpectedly, our findings thus establish miRNA regulation as a novel gene-specific dosage compensation mechanism.


Assuntos
Galinhas/genética , Mecanismo Genético de Compensação de Dose/genética , MicroRNAs/genética , Monodelphis/genética , Caracteres Sexuais , Animais , Conjuntos de Dados como Assunto , Feminino , Tentilhões/genética , Perfilação da Expressão Gênica , Masculino , Camundongos , MicroRNAs/biossíntese , Proteínas/genética , Sequências Reguladoras de Ácido Nucleico
5.
Int J Syst Evol Microbiol ; 70(12): 6032-6043, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33079029

RESUMO

In a search for potential causes of increased prolapse incidence in grey short-tailed opossum colonies, samples from the gastrointestinal tracts of 94 clinically normal opossums with rectal prolapses were screened for Helicobacter species by culture and PCR. Forty strains of two novel Helicobacter species which differed from the established Helicobacter taxa were isolated from opossums with and without prolapses. One of the Helicobacter species was spiral-shaped and urease-negative whereas the other Helicobacter strain had fusiform morphology with periplasmic fibres and was urease-positive. 16S rRNA gene sequence analysis revealed that all the isolates had over 99 % sequence identity with each other, and were most closely related to Helicobacter canadensis. Strains from the two novel Helicobacter species were subjected to gyrB and hsp60 gene and whole genome sequence analyses. These two novel Helicobacter species formed separate phylogenetic clades, divergent from other known Helicobacter species. The bacteria were confirmed as novel Helicobacter species based on digital DNA-DNA hybridization and average nucleotide identity analysis of their genomes, for which we propose the names Helicobacter monodelphidis sp. nov. with the type strain MIT 15-1451T (=LMG 29780T=NCTC 14189T) and Helicobacter didelphidarum sp. nov with type strain MIT 17-337T (=LMG 31024T=NCTC 14188T).


Assuntos
Cloaca/patologia , Helicobacter/classificação , Monodelphis/microbiologia , Filogenia , Animais , Técnicas de Tipagem Bacteriana , Composição de Bases , Cloaca/microbiologia , DNA Bacteriano/genética , Ácidos Graxos/química , Trato Gastrointestinal/microbiologia , Genes Bacterianos , Helicobacter/isolamento & purificação , Hibridização de Ácido Nucleico , Prolapso , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Texas
6.
J Med Primatol ; 49(1): 3-9, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31709573

RESUMO

INTRODUCTION: The baboon is a well-characterized model of human early stage atherosclerosis. However, histological and morphological changes involved in atherogenesis in baboons are not known. Previously, we challenged baboons with a high-cholesterol, high-fat diet for two years and observed fatty streak and plaque lesions in iliac arteries (RCIA). METHODS: We evaluated histological and morphological changes of baboon arterial lesions and control arteries. In addition, we evaluated the vascular expression of CD68 and SMαA markers with progression of atherosclerosis. RESULTS: We observed changes that correlated with extent of atherosclerosis, including increased maximum intimal thickness. We demonstrated at molecular level the infiltration of smooth muscle cells and macrophages into the intimal layer. Further, we observed histological and morphological discordancy between the affected and adjacent areas of the same RCIA. CONCLUSION: Atherogenesis in baboons is accompanied by histological, morphological, and molecular changes, as in humans, providing insights to evaluate the mechanisms underlying early stage atherosclerosis in target tissues.


Assuntos
Aterosclerose/patologia , Colesterol/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Artéria Ilíaca/patologia , Animais , Aterosclerose/etiologia , Papio hamadryas
7.
J Lipid Res ; 60(9): 1630-1639, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31227640

RESUMO

The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry-specific rare functional variant, L175Q, in delta 4-desaturase, sphingolipid 1 (DEGS1), a key enzyme in the pathway that converts dihydroceramide to ceramide. This amino acid change was significantly associated with large increases in plasma dihydroceramides. Indexes of DEGS1 enzymatic activity were dramatically reduced in heterozygotes. CRISPR/Cas9 genome editing of HepG2 cells confirmed that the L175Q variant results in a partial loss of function for the DEGS1 enzyme. Understanding the biological role of DEGS1 variants, such as L175Q, in ceramide synthesis may improve the understanding of metabolic-related disorders and spur ongoing research of drug targets along this pathway.


Assuntos
Ceramidas/biossíntese , Ácidos Graxos Dessaturases/genética , Western Blotting , Sistemas CRISPR-Cas/genética , Ceramidas/metabolismo , Feminino , Genótipo , Células Hep G2 , Humanos , Masculino , Americanos Mexicanos
8.
Hum Genet ; 137(1): 45-53, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29181734

RESUMO

Over two billion adults are overweight or obese and therefore at an increased risk of cardiometabolic syndrome (CMS). Obesity-related anthropometric traits genetically correlated with CMS may provide insight into CMS aetiology. The aim of this study was to utilise an empirically derived genetic relatedness matrix to calculate heritabilities and genetic correlations between CMS and anthropometric traits to determine whether they share genetic risk factors (pleiotropy). We used genome-wide single nucleotide polymorphism (SNP) data on 4671 Busselton Health Study participants. Exploiting both known and unknown relatedness, empirical kinship probabilities were estimated using these SNP data. General linear mixed models implemented in SOLAR were used to estimate narrow-sense heritabilities (h 2) and genetic correlations (r g) between 15 anthropometric and 9 CMS traits. Anthropometric traits were adjusted by body mass index (BMI) to determine whether the observed genetic correlation was independent of obesity. After adjustment for multiple testing, all CMS and anthropometric traits were significantly heritable (h 2 range 0.18-0.57). We identified 50 significant genetic correlations (r g range: - 0.37 to 0.75) between CMS and anthropometric traits. Five genetic correlations remained significant after adjustment for BMI [high density lipoprotein cholesterol (HDL-C) and waist-hip ratio; triglycerides and waist-hip ratio; triglycerides and waist-height ratio; non-HDL-C and waist-height ratio; insulin and iliac skinfold thickness]. This study provides evidence for the presence of potentially pleiotropic genes that affect both anthropometric and CMS traits, independently of obesity.


Assuntos
Antropometria , Doenças Cardiovasculares/genética , Pleiotropia Genética , Síndrome Metabólica/genética , Obesidade/genética , Adulto , Idoso , Glicemia/metabolismo , Doenças Cardiovasculares/sangue , HDL-Colesterol/sangue , Estudos Transversais , Pesquisa Empírica , Feminino , Humanos , Artéria Ilíaca/metabolismo , Insulina/sangue , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Obesidade/sangue , Fenótipo , Fatores de Risco , Dobras Cutâneas , Triglicerídeos/sangue , Relação Cintura-Quadril , Austrália Ocidental
9.
J Med Primatol ; 47(1): 3-17, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28620920

RESUMO

BACKGROUND: The purpose of this study was to determine whether dietary manipulation can reliably induce early-stage atherosclerosis and clinically relevant changes in vascular function in an established, well-characterized non-human primate model. METHODS: We fed 112 baboons a high-cholesterol, high-fat challenge diet for two years. We assayed circulating biomarkers of cardiovascular disease (CVD) risk, at 0, 7, and 104 weeks into the challenge; assessed arterial compliance noninvasively at 104 weeks; and measured atherosclerotic lesions in three major arteries at necropsy. RESULTS: We observed evidence of atherosclerosis in all but one baboon fed the two-year challenge diet. CVD risk biomarkers, the prevalence, size, and complexity of arterial lesions, plus consequent arterial stiffness, were increased in comparison with dietary control animals. CONCLUSIONS: Feeding baboons a high-cholesterol, high-fat diet for two years reliably induces atherosclerosis, with risk factor profiles, arterial lesions, and changes in vascular function also seen in humans.


Assuntos
Aterosclerose/etiologia , Dieta Aterogênica/efeitos adversos , Modelos Animais de Doenças , Papio anubis , Papio cynocephalus , Animais , Artérias/fisiologia , Artérias/fisiopatologia , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Feminino , Lipoproteínas/metabolismo , Masculino
10.
Nature ; 487(7406): 254-8, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22722828

RESUMO

In female (XX) mammals, one of the two X chromosomes is inactivated to ensure an equal dose of X-linked genes with males (XY). X-chromosome inactivation in eutherian mammals is mediated by the non-coding RNA Xist. Xist is not found in metatherians (marsupials), and how X-chromosome inactivation is initiated in these mammals has been the subject of speculation for decades. Using the marsupial Monodelphis domestica, here we identify Rsx (RNA-on-the-silent X), an RNA that has properties consistent with a role in X-chromosome inactivation. Rsx is a large, repeat-rich RNA that is expressed only in females and is transcribed from, and coats, the inactive X chromosome. In female germ cells, in which both X chromosomes are active, Rsx is silenced, linking Rsx expression to X-chromosome inactivation and reactivation. Integration of an Rsx transgene on an autosome in mouse embryonic stem cells leads to gene silencing in cis. Our findings permit comparative studies of X-chromosome inactivation in mammals and pose questions about the mechanisms by which X-chromosome inactivation is achieved in eutherians.


Assuntos
Monodelphis/genética , Monodelphis/metabolismo , RNA/genética , RNA/metabolismo , Inativação do Cromossomo X , Cromossomo X/genética , Cromossomo X/metabolismo , Animais , Feminino , Regulação da Expressão Gênica , Inativação Gênica , Camundongos , Transgenes
11.
Genome Res ; 24(1): 70-83, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24065774

RESUMO

Evidence from a few genes in diverse species suggests that X-chromosome inactivation (XCI) in marsupials is characterized by exclusive, but leaky inactivation of the paternally derived X chromosome. To study the phenomenon of marsupial XCI more comprehensively, we profiled parent-of-origin allele-specific expression, DNA methylation, and histone modifications in fetal brain and extra-embryonic membranes in the gray, short-tailed opossum (Monodelphis domestica). The majority of X-linked genes (152 of 176 genes with trackable SNP variants) exhibited paternally imprinted expression, with nearly 100% of transcripts derived from the maternal allele; whereas 24 loci (14%) escaped inactivation, showing varying levels of biallelic expression. In addition to recently reported evidence of marsupial XCI regulation by the noncoding Rsx transcript, strong depletion of H3K27me3 at escaper gene loci in the present study suggests that histone state modifications also correlate strongly with opossum XCI. In contrast to mouse, the opossum did not show an association between X-linked gene expression and promoter DNA methylation, with one notable exception. Unlike all other X-linked genes examined, Rsx was differentially methylated on the maternal and paternal X chromosomes, and expression was exclusively from the inactive (paternal) X chromosome. Our study provides the first comprehensive catalog of parent-of-origin expression status for X-linked genes in a marsupial and sheds light on the regulation and evolution of imprinted XCI in mammals.


Assuntos
Encéfalo/embriologia , Genes Ligados ao Cromossomo X , Monodelphis/embriologia , Monodelphis/genética , Placenta/metabolismo , RNA não Traduzido/genética , Inativação do Cromossomo X , Cromossomo X/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular , Metilação de DNA , Embrião de Mamíferos , Epigênese Genética , Evolução Molecular , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Variação Genética , Histonas , Masculino , Camundongos , Polimorfismo de Nucleotídeo Único , Gravidez , RNA Longo não Codificante/genética , Análise de Sequência de RNA , Cromossomo X/genética
12.
BMC Genomics ; 15: 89, 2014 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-24484454

RESUMO

BACKGROUND: Imprinted genes have been extensively documented in eutherian mammals and found to exhibit significant interspecific variation in the suites of genes that are imprinted and in their regulation between tissues and developmental stages. Much less is known about imprinted loci in metatherian (marsupial) mammals, wherein studies have been limited to a small number of genes previously known to be imprinted in eutherians. We describe the first ab initio search for imprinted marsupial genes, in fibroblasts from the opossum, Monodelphis domestica, based on a genome-wide ChIP-seq strategy to identify promoters that are simultaneously marked by mutually exclusive, transcriptionally opposing histone modifications. RESULTS: We identified a novel imprinted gene (Meis1) and two additional monoallelically expressed genes, one of which (Cstb) showed allele-specific, but non-imprinted expression. Imprinted vs. allele-specific expression could not be resolved for the third monoallelically expressed gene (Rpl17). Transcriptionally opposing histone modifications H3K4me3, H3K9Ac, and H3K9me3 were found at the promoters of all three genes, but differential DNA methylation was not detected at CpG islands at any of these promoters. CONCLUSIONS: In generating the first genome-wide histone modification profiles for a marsupial, we identified the first gene that is imprinted in a marsupial but not in eutherian mammals. This outcome demonstrates the practicality of an ab initio discovery strategy and implicates histone modification, but not differential DNA methylation, as a conserved mechanism for marking imprinted genes in all therian mammals. Our findings suggest that marsupials use multiple epigenetic mechanisms for imprinting and support the concept that lineage-specific selective forces can produce sets of imprinted genes that differ between metatherian and eutherian lines.


Assuntos
Fibroblastos/metabolismo , Genoma , Impressão Genômica , Histonas/genética , Monodelphis/genética , Animais , Imunoprecipitação da Cromatina , Ilhas de CpG , Metilação de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Masculino , Proteína Meis1 , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
13.
J Hum Evol ; 68: 14-31, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24508352

RESUMO

Recently proposed ancestral locomotor and morphological 'stages' leading to the evolution of primates have emphasized small body size, and a transition from a clawed non-grasping stage, to a clawed, grasping stage with clawless opposable hallux, to a fully-nailed primate with grasping extremities. This evolutionary transition was presumably associated with frequent use of the small branch niche. To model elements of these evolutionary transitions, we investigate how body size, substrate size, substrate orientation and grasping morphology interact to influence quadrupedal kinematics within and between ontogenetic samples of two small-bodied marsupials, one arboreal (Petaurus breviceps) and the other mainly terrestrial (Monodelphis domestica). Longitudinal morphometric and kinematic data were collected from four juvenile P. breviceps (33-75 g) and two juvenile M. domestica (18-95 g) walking across poles of three diameters (2.5, 1.0, and 0.5 cm) and three orientations (horizontal, 30° incline, 30° decline). The two species responded similarly to some substrate conditions, but diverged in response to others. Kinematic divergence between the two species reflects Monodelphis' relatively shorter digits, reduced grasping ability and greater need for stabilizing mechanisms on narrow substrates. At a given relative body size or pole orientation, Monodelphis used higher limb duty factors, more limbs in support per stride, lower limb phases, and in some conditions, faster speeds compared with Petaurus. Interspecific differences were the least distinct on declined poles, highlighting the particular challenge of this substrate condition, even for arboreally adapted species. Small-bodied, arboreal primate ancestors would likely have employed the kinematic mechanisms common to our model taxa, but those with enhanced grasping adaptations would most likely not have required the increased level of stabilizing mechanisms exhibited by Monodelphis. Thus, using these two species as locomotor models has underscored the functional importance of grasping extremities in primate origins, even if ancestral primates were very small in body size.


Assuntos
Tamanho Corporal/fisiologia , Locomoção/fisiologia , Marsupiais/anatomia & histologia , Marsupiais/fisiologia , Animais , Evolução Biológica , Fenômenos Biomecânicos , Feminino , Pé/anatomia & histologia , Pé/fisiologia , Masculino , Monodelphis
14.
Cell Genom ; 4(3): 100509, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38430910

RESUMO

Steady-state expression quantitative trait loci (eQTLs) explain only a fraction of disease-associated loci identified through genome-wide association studies (GWASs), while eQTLs involved in gene-by-environment (GxE) interactions have rarely been characterized in humans due to experimental challenges. Using a baboon model, we found hundreds of eQTLs that emerge in adipose, liver, and muscle after prolonged exposure to high dietary fat and cholesterol. Diet-responsive eQTLs exhibit genomic localization and genic features that are distinct from steady-state eQTLs. Furthermore, the human orthologs associated with diet-responsive eQTLs are enriched for GWAS genes associated with human metabolic traits, suggesting that context-responsive eQTLs with more complex regulatory effects are likely to explain GWAS hits that do not seem to overlap with standard eQTLs. Our results highlight the complexity of genetic regulatory effects and the potential of eQTLs with disease-relevant GxE interactions in enhancing the understanding of GWAS signals for human complex disease using non-human primate models.


Assuntos
Dieta Hiperlipídica , Estudo de Associação Genômica Ampla , Estudo de Associação Genômica Ampla/métodos , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica , Locos de Características Quantitativas/genética , Fenótipo
15.
J Comp Neurol ; 532(7): e25655, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38980080

RESUMO

This study used a marsupial Monodelphis domestica, which is born very immature and most of its development is postnatal without placental protection. RNA-sequencing (RNA-Seq) was used to identify the expression of influx and efflux transporters (ATP-binding cassettes [ABCs] and solute carriers [SLCs]) and metabolizing enzymes in brains of newborn to juvenile Monodelphis. Results were compared to published data in the developing eutherian rat. To test the functionality of these transporters at similar ages, the entry of paracetamol (acetaminophen) into the brain and cerebrospinal fluid (CSF) was measured using liquid scintillation counting following a single administration of the drug along with its radiolabelled tracer [3H]. Drug permeability studies found that in Monodelphis, brain entry of paracetamol was already restricted at P5; it decreased further in the first week of life and then remained stable until the oldest age group tested (P110). Transcriptomic analysis of Monodelphis brain showed that expression of transporters and their metabolizing enzymes in early postnatal (P) pups (P0, P5, and P8) was relatively similar, but by P109, many more transcripts were identified. When transcriptomes of newborn Monodelphis brain and E19 rat brain and placenta were compared, several transporters present in the rat placenta were also found in the newborn Monodelphis brain. These were absent from E19 rat brain but were present in the adult rat brain. These data indicate that despite its extreme immaturity, the newborn Monodelphis brain may compensate for the lack of placental protection during early brain development by upregulating protective mechanisms, which in eutherian animals are instead present in the placenta.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Encéfalo , Monodelphis , Animais , Encéfalo/metabolismo , Encéfalo/crescimento & desenvolvimento , Monodelphis/crescimento & desenvolvimento , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Animais Recém-Nascidos , Acetaminofen , Proteínas Carreadoras de Solutos/metabolismo , Feminino , Ratos
16.
J Lipid Res ; 54(7): 1776-85, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23596326

RESUMO

Cardiovascular disease (CVD) is the leading cause of death in developed countries, and dyslipidemia is a major risk factor for CVD. We previously identified a cluster of quantitative trait loci (QTL) on baboon chromosome 11 for multiple, related quantitative traits for serum LDL-cholesterol (LDL-C). Here we report differentially regulated hepatic genes encoding an LDL-C QTL that influences LDL-C levels in baboons. We performed hepatic whole-genome expression profiling for LDL-C-discordant baboons fed a high-cholesterol, high-fat (HCHF) diet for seven weeks. We detected expression of 117 genes within the QTL 2-LOD support interval. Three genes were differentially expressed in low LDL-C responders and 8 in high LDL-C responders in response to a HCHF diet. Seven genes (ACVR1B, CALCOCO1, DGKA, ERBB3, KRT73, MYL6B, TENC1) showed discordant expression between low and high LDL-C responders. To prioritize candidate genes, we integrated miRNA and mRNA expression profiles using network tools and found that four candidates (ACVR1B, DGKA, ERBB3, TENC1) were miRNA targets and that the miRNAs were inversely expressed to the target genes. Candidate gene expression was validated using QRT-PCR and Western blotting. This study reveals candidate genes that influence variation in LDL-C in baboons and potential genetic mechanisms for further investigation.


Assuntos
LDL-Colesterol/genética , Locos de Características Quantitativas/genética , Animais , Western Blotting , LDL-Colesterol/sangue , Perfilação da Expressão Gênica , Papio/genética , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
J Cell Mol Med ; 17(2): 242-51, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23301772

RESUMO

In this study, we used a large non-human primate model, the baboon, to establish a step-wise protocol to generate CD34+ endothelial progenitor cells (EPCs) from embryonic stem cells (ESCs) and to demonstrate their reparative effects. Baboon ESCs were sequentially differentiated from embryoid body cultures for 9 days and then were specified into EPCs by culturing them in monolayer for 12 days. The resulting EPCs expressed CD34, CXCR4 and UEA-1, but neither CD31 nor CD117. The EPCs were able to form intact lumen structures when seeded on Matrigel, took up Dil-LDL, and responded to TNF-α. Angioblasts specified in EGM-2 medium and ECGS medium had 6.41 ± 1.16% (n = 3) and 9.32 ± 3.73% CD34+ cells (n = 3). The efficiency of generating CD34+ EPCs did not differ significantly from ECGS to EGM-2 culture media, however, angioblasts specified in ECGS medium expressed a higher percentage of CD34+/CXCR4+ cells (3.49 ± 1.32%, n = 3) than those specified in EGM-2 medium (0.49 ± 0.52%, n = 3). To observe their reparative capacity, we purified CD34+ progenitors after specification by EGM-2 medium; inoculated fluorescently labelled CD34+ EPCs into an arterial segment denuded of endothelium in an ex vivo system. After 14 days of ex vivo culture, the grafted cells had attached and integrated to the denuded surface; in addition, they had matured further and expressed terminally differentiated endothelial markers including CD31 and CD146. In conclusion, we have proved that specified CD34+ EPCs are promising therapeutic agents for repairing damaged vasculature.


Assuntos
Antígenos CD34/metabolismo , Diferenciação Celular , Células-Tronco Embrionárias/citologia , Endotélio Vascular/citologia , Neovascularização Fisiológica , Células-Tronco/citologia , Animais , Western Blotting , Proliferação de Células , Células Cultivadas , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Citometria de Fluxo , Imunofluorescência , Humanos , Papio , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
18.
Hum Genet ; 132(9): 1059-71, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23736306

RESUMO

Pediatric metabolic syndrome (MS) and its cardiometabolic components (MSCs) have become increasingly prevalent, yet little is known about the genetics underlying MS risk in children. We examined the prevalence and genetics of MS-related traits among 670 non-diabetic Mexican American (MA) children and adolescents, aged 6-17 years (49 % female), who were participants in the San Antonio Family Assessment of Metabolic Risk Indicators in Youth study. These children are offspring or biological relatives of adult participants from three well-established Mexican American family studies in San Antonio, TX, at increased risk of type 2 diabetes. MS was defined as ≥3 abnormalities among 6 MSC measures: waist circumference, systolic and/or diastolic blood pressure, fasting insulin, triglycerides, HDL-cholesterol, and fasting and/or 2-h OGTT glucose. Genetic analyses of MS, number of MSCs (MSC-N), MS factors, and bivariate MS traits were performed. Overweight/obesity (53 %), pre-diabetes (13 %), acanthosis nigricans (33 %), and MS (19 %) were strikingly prevalent, as were MS components, including abdominal adiposity (32 %) and low HDL-cholesterol (32 %). Factor analysis of MS traits yielded three constructs: adipo-insulin-lipid, blood pressure, and glucose factors, and their factor scores were highly heritable. MS itself exhibited 68 % heritability. MSC-N showed strong positive genetic correlations with obesity, insulin resistance, inflammation, and acanthosis nigricans, and negative genetic correlation with physical fitness. MS trait pairs exhibited strong genetic and/or environmental correlations. These findings highlight the complex genetic architecture of MS/MSCs in MA children, and underscore the need for early screening and intervention to prevent chronic sequelae in this vulnerable pediatric population.


Assuntos
Predisposição Genética para Doença/genética , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Americanos Mexicanos/genética , Gordura Abdominal/patologia , Acantose Nigricans/patologia , Adolescente , Glicemia , Pressão Sanguínea , Criança , HDL-Colesterol/sangue , Análise por Conglomerados , Análise Fatorial , Feminino , Humanos , Masculino , Síndrome Metabólica/patologia , Epidemiologia Molecular , Sobrepeso/patologia , Fatores de Risco , Texas/epidemiologia
19.
J Med Primatol ; 42(5): 225-8, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24025076

RESUMO

A reclassification of captive chimpanzees as endangered by the US Fish and Wildlife Service (FWS) would have devastating consequences on critical areas of basic biomedical research for which chimpanzees are uniquely suitable as animal models. It also would have a negative impact on the survival of wild chimpanzees and the preservation of the species.


Assuntos
Pesquisa Biomédica/tendências , Espécies em Perigo de Extinção/legislação & jurisprudência , Pan troglodytes , Animais , Pesquisa Biomédica/legislação & jurisprudência , Hepatite/etiologia , Hepatite/mortalidade , Humanos , Modelos Animais , Qualidade de Vida
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