Genomic modules and intramodular network concordance in susceptible and resilient male mice across models of stress

AbstractThe multifactorial etiology of stress-related disorders necessitates a constant interrogation of the molecular convergences in preclinical models of stress that use disparate paradigms as stressors spanning from environmental challenges to genetic predisposition to hormonal signaling. Using RNA-sequencing, we investigated the genomic signatures in the ventral hippocampus common to mouse models of stress. Chronic oral corticosterone (CORT) induced increased anxiety- and depression-like behavior in wild-type male mice and male mice heterozygous for the gene coding for brain-derived neurotrophic factor Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of male mice, chronic social defeat stress (CSDS) led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, namely standard housing or enriched environment. Rank-rank-hypergeometric overlap (RRHO), a threshold-free approach that ranks genes by their p value and effect size direction, was used to identify genes from a continuous gradient of significancy that were concordant across groups. In mice treated with CORT and in standard-housed susceptible mice, differentially expressed genes (DEGs) were concordant for gene networks involved in neurotransmission, cytoskeleton function, and vascularization. Weighted gene co-expression analysis generated 54 gene hub modules and revealed two modules in which both CORT and CSDS-induced enrichment in DEGs, whose function was concordant with the RRHO predictions, and correlated with behavioral resilience or susceptibility. These data showed transcriptional concordance across models in which the stress coping depends upon hormonal, environmental, or genetic factors revealing common genomic drivers that embody the multifaceted nature of stress-related disorders.

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Genomic Modules and Intramodular Network Convergency of Susceptibility and Resilience in Multimodeled Stress in Male Mice

10.1101/2021.06.30.450390 ◽

2021 ◽

Author(s):

Jordan Marrocco ◽

Salvatore G Caradonna ◽

Tie-Yuan Zhang ◽

Nicholas O'Toole ◽

Mo-Jun Shen ◽

...

Keyword(s):

Construct Validity ◽

Gene Networks ◽

Anxiety And Depression ◽

Rna Seq ◽

Data Set ◽

Genomic Signatures ◽

Medical Standards ◽

Gene Coding ◽

Chronic Social Defeat Stress ◽

Response To Stress

The multifactorial etiology of stress-related disorders is a challenge in developing synchronized medical standards for treatment and diagnosis. It is largely unknown whether there exists molecular convergence in preclinical models of stress generated using disparate construct validity. Using RNA-sequencing (RNA-seq), we investigated the genomic signatures in the ventral hippocampus, which mostly regulates affective behavior, in mouse models that recapitulate the hallmarks of anxiety and depression. Chronic oral corticosterone (CORT), a model that causes a blunted endocrine response to stress, induced anxiety- and depression-like behavior in wildtype mice and mice heterozygous for the gene coding for brain-derived neurotrophic factor (BDNF) Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of mice, chronic social defeat stress led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, standard housing or enriched environment. A rank-rank-hypergeometric (RRHO) analysis of the RNA-seq data set across models demonstrated that in mice treated with CORT and susceptible mice raised in standard housing differentially expressed genes (DEGs) converged toward gene networks involved in similar biological functions. Weighted gene co-expression analysis generated 54 unique modules of interconnected gene hubs, two of which included a combination of all experimental groups and were significantly enriched in DEGs, whose function was consistent with that predicted in the RRHO GO analysis. This multimodel approach showed transcriptional synchrony between models of stress with hormonal, environmental or genetic construct validity shedding light on common genomic drivers that embody the multifaceted nature of stress-related disorders.

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Pemafibrate Protects against Fatty Acid-Induced Nephropathy by Maintaining Renal Fatty Acid Metabolism

Metabolites ◽

10.3390/metabo11060372 ◽

2021 ◽

Vol 11 (6) ◽

pp. 372

Author(s):

Daiki Aomura ◽

Makoto Harada ◽

Yosuke Yamada ◽

Takero Nakajima ◽

Koji Hashimoto ◽

...

Keyword(s):

Fatty Acid ◽

Kidney Disease ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Male Mice ◽

Histological Findings ◽

Tubular Injury ◽

Wild Type ◽

Wild Type Male ◽

And Oxidative Stress

As classical agonists for peroxisomal proliferator-activated receptor alpha (PPARα), fibrates activate renal fatty acid metabolism (FAM) and provide renoprotection. However, fibrate prescription is limited in patients with kidney disease, since impaired urinary excretion of the drug causes serious adverse effects. Pemafibrate (PEM), a novel selective PPARα modulator, is mainly excreted in bile, and, thus, may be safe and effective in kidney disease patients. It remains unclear, however, whether PEM actually exhibits renoprotective properties. We investigated this issue using mice with fatty acid overload nephropathy (FAON). PEM (0.5 mg/kg body weight/day) or a vehicle was administered for 20 days to 13-week-old wild-type male mice, which were simultaneously injected with free fatty acid (FFA)-binding bovine serum albumin from day 7 to day 20 to induce FAON. All mice were sacrificed on day 20 for assessment of the renoprotective effect of PEM against FAON. PEM significantly attenuated the histological findings of tubular injury caused by FAON, increased the renal expressions of mRNA and proteins related to FAM, and decreased renal FFA content and oxidative stress. Taken together, PEM exhibits renoprotective effects through the activation and maintenance of renal FAM and represents a promising drug for kidney disease.

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Inhibition of Soluble Epoxide Hydrolase Is Protective against the Multiomic Effects of a High Glycemic Diet on Brain Microvascular Inflammation and Cognitive Dysfunction

Nutrients ◽

10.3390/nu13113913 ◽

2021 ◽

Vol 13 (11) ◽

pp. 3913

Author(s):

Saivageethi Nuthikattu ◽

Dragan Milenkovic ◽

Jennifer E. Norman ◽

John Rutledge ◽

Amparo Villablanca

Keyword(s):

Gene Expression ◽

Differential Expression ◽

Gene Networks ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Wild Type ◽

Protein Coding ◽

Wild Type Male ◽

Molecular Effects ◽

Microvascular Inflammation

Diet is a modifiable risk factor for cardiovascular disease (CVD) and dementia, yet relatively little is known about the effect of a high glycemic diet (HGD) on the brain’s microvasculature. The objective of our study was to determine the molecular effects of an HGD on hippocampal microvessels and cognitive function and determine if a soluble epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Wild type male mice were fed a low glycemic diet (LGD, 12% sucrose/weight) or an HGD (34% sucrose/weight) with/without the sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks. Brain hippocampal microvascular gene expression was assessed by microarray and data analyzed using a multi-omic approach for differential expression of protein and non-protein-coding genes, gene networks, functional pathways, and transcription factors. Global hippocampal microvascular gene expression was fundamentally different for mice fed the HGD vs. the LGD. The HGD response was characterized by differential expression of 608 genes involved in cell signaling, neurodegeneration, metabolism, and cell adhesion/inflammation/oxidation effects reversible by t-AUCB and hence sEH inhibitor correlated with protection against Alzheimer’s dementia. Ours is the first study to demonstrate that high dietary glycemia contributes to brain hippocampal microvascular inflammation through sEH.

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Gender- and Age-dependent Changes in Kidney Androgen Protein mRNA Expression in a Knockout Mouse Model for Nephrolithiasis

Journal of Histochemistry & Cytochemistry ◽

10.1177/002215540205001211 ◽

2002 ◽

Vol 50 (12) ◽

pp. 1663-1669 ◽

Cited By ~ 2

Author(s):

Eleni G. Tzortzaki ◽

Dayna Glass ◽

Min Yang ◽

Andrew P. Evan ◽

Sharon B. Bledsoe ◽

...

Keyword(s):

Mrna Expression ◽

Kidney Tissue ◽

Mouse Kidney ◽

Male Mice ◽

Wild Type ◽

Rt Pcr ◽

Cytoplasmic Staining ◽

Female Mice ◽

Age Dependent ◽

Wild Type Male

Kidney androgen-regulated protein (Kap) is the most abundant protein in the mouse kidney, but its function is unknown. We previously observed a significant decrease in Kap mRNA expression in whole kidney tissue from male mice with adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadenine (DHA) nephrolithiasis. The disease phenotype is more severe in male mice and is age-dependent. To identify the cellular basis for differential Kap expression, we used in situ hybridization (ISH) and reverse transcription-polymerase chain reaction ISH (RT-PCR ISH) to identify the cell types expressing this mRNA in paraffin-embedded kidney sections. In 1-month-old wild-type male mice, Kap was detected primarily in S3 proximal tubule segments, but expression was very low in female mice. In 1-month-old APRT-deficient male mice, Kap expression was decreased significantly and was undetectable in female mice. Kap mRNA was not detected in 3- or 6-month-old mice using our standard ISH protocol, but we observed intense cytoplasmic staining in S3 proximal tubules in wild-type male mice of these age groups using an improved RT-PCR ISH procedure. Our studies demonstrate age-, gender-, and APRT genotype-dependent changes in Kap mRNA expression in mouse kidney. Kap expression is under multihormonal control, and hormonal changes in DHA-induced nephrolithiasis may account for the decreased Kap expression in APRT-deficient mice.

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Aging Cartilage in Wild-Type Mice: An Observational Study

Cartilage ◽

10.1177/1947603520926713 ◽

2020 ◽

pp. 194760352092671

Author(s):

Joulnar Akoum ◽

Khadija Tahiri ◽

Marie-Thérèse Corvol ◽

Didier Borderie ◽

François Étienne ◽

...

Keyword(s):

Walking Speed ◽

Articular Surface ◽

Type Ii Collagen ◽

Research Society ◽

Male Mice ◽

Wild Type ◽

Calcified Cartilage ◽

Age Related ◽

Wild Type Male ◽

Osteoarthritis Research Society

Objective To describe the spontaneous evolution of age-related changes affecting knee joint articular cartilage, walking speed and a serum biomarker of cartilage remodeling in C57BL/6-JRj wild-type male mice. Design Histological changes were assessed by the Osteoarthritis Research Society International (OARSI) score (0=normal, 6=vertical clefts/erosion to the calcified cartilage extending >75% of the articular surface) in newborn, 1-week- and 1-, 3-, 6-, 9- and 12-month-old C57BL/6-JRj wild-type male mice, walking speed by the Locotronic system, and serum C-terminal telopeptide of type II collagen (CTX-II) content by ELISA in 1-, 3-, 6-, and 9-month-old C57BL/6-JRj wild-type male mice. Results Mean (SD) OARSI score significantly increased from 0.2 (0.3) to 1.3 (0.6) ( p=0.03) between 1 and 3 months of age and from 1.3 (0.6) to 3.3 (0.6) ( p=0.04) between 3 and 6 months of age. Mean walking speed was stable between 1 and 6 months of age but significantly decreased from 11.4 (1.8) to 3.2 (0.8) cm.s-1 ( p=0.03) between 6 and 9 months of age. Serum CTX-II content was maximal at 1 month of age, then decreased from 12.2 (8.5) to 2.4 (8.4) pg/ml ( p=0.02) between 1 and 3 months of age, remaining low and stable thereafter. Conclusions C57BL/6-JRj wild-type male mice showed continuously increasing osteoarthritic changes but delayed decreasing walking speed with age. These variations were maximal between 3 and 9 months of age. Maximal serum CTX-II content preceded these changes.

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Soluble syndecan-1 and glycosaminoglycans in preeclamptic and normotensive pregnancies

Scientific Reports ◽

10.1038/s41598-021-82972-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

H. Hassani Lahsinoui ◽

F. Amraoui ◽

L. J. A. Spijkers ◽

G. J. M. Veenboer ◽

S. L. M. Peters ◽

...

Keyword(s):

Blood Pressure ◽

Heparan Sulphate ◽

Activated Partial Thromboplastin Time ◽

Male Mice ◽

Wild Type ◽

Dermatan Sulphate ◽

Keratan Sulphate ◽

Blood Pressure Elevation ◽

Wild Type Male ◽

Deficient Mice

AbstractPreeclampsia, an important cause of maternal and fetal morbidity and mortality, is associated with increased sFLT1 levels and with structural and functional damage to the glycocalyx contributing to endothelial dysfunction. We investigated glycocalyx components in relation to preeclampsia in human samples. While soluble syndecan-1 and heparan sulphate were similar in plasma of preeclamptic and normotensive pregnant women, dermatan sulphate was increased and keratan sulphate decreased in preeclamptic women. Dermatan sulphate was correlated with soluble syndecan-1, and inversely correlated with blood pressure and activated partial thromboplastin time. To determine if syndecan-1 was a prerequisite for the sFlt1 induced increase in blood pressure in mice we studied the effect of sFlt1 on blood pressure and vascular contractile responses in syndecan-1 deficient and wild type male mice. The classical sFlt1 induced rise in blood pressure was absent in syndecan-1 deficient mice indicating that syndecan-1 is a prerequisite for sFlt1 induced increase in blood pressure central to preeclampsia. The results show that an interplay between syndecan-1 and dermatan sulphate contributes to sFlt1 induced blood pressure elevation in pre-eclampsia.

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Synaptonemal Complex Length Variation in Wild-Type Male Mice

Genes ◽

10.3390/genes1030505 ◽

2010 ◽

Vol 1 (3) ◽

pp. 505-520 ◽

Cited By ~ 5

Author(s):

Neil M. Vranis ◽

Godfried W. Van der Heijden ◽

Safia Malki ◽

Alex Bortvin

Keyword(s):

Synaptonemal Complex ◽

Length Variation ◽

Male Mice ◽

Wild Type ◽

Wild Type Male ◽

Complex Length

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Transient Reduction of DNA Methylation at the Onset of Meiosis in Male Mice

10.1101/177535 ◽

2017 ◽

Author(s):

Valeriya Gaysinskaya ◽

Brendan F. Miller ◽

Godfried W. van der Heijden ◽

Kasper D. Hansen ◽

Alex Bortvin

Keyword(s):

Dna Methylation ◽

Quality Control ◽

Germ Cells ◽

Extended Period ◽

S Phase ◽

Male Mice ◽

Wild Type ◽

Genome Wide ◽

Wild Type Male

AbstractThe quality of germ cells depends on successful chromatin organization in meiotic prophase I (MPI). To better understand the epigenetic context of MPI we studied the dynamics of DNA methylation in wild-type male mice. We discovered an extended period of genome-wide transient reduction of DNA methylation (TRDM) during early MPI. Our data show that TRDM arises by passive demethylation in the premeiotic S phase highlighting the abundance of hemimethylated DNA in MPI. Importantly, TRDM unmasks a deficit in retrotransposon LINE-1 DNA methylation contributing to its expression in early MPI. We propose that TRDM facilitates meiosis and gamete quality control.

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180 EFFECT OF Dnmt1p mRNA KNOCK DOWN ON Dnmt1 PROTEIN TRANSLATION IN MOUSE TESTIS

Reproduction Fertility and Development ◽

10.1071/rdv24n1ab180 ◽

2012 ◽

Vol 24 (1) ◽

pp. 202

Author(s):

H. Kato ◽

R. Kitamura ◽

H. Yamaguchi ◽

Y. Numata ◽

T. Kijima ◽

...

Keyword(s):

Male Mouse ◽

Expression Vector ◽

Expression Level ◽

Male Mice ◽

Wild Type ◽

Shrna Expression ◽

Gene Construct ◽

Shrna Expression Vector ◽

Wild Type Male ◽

F2 Generation

We have reported that there was a significant reduction (P < 0.05) in the relative amount of Dnmt1p mRNA in spermatozoa from aged male mice (Kato et al. 2007 Reprod. Fertil. Dev. 19, 277 abst.). The reduction of mRNA levels of Dnmt1p in spermatozoa would lead to altered epigenetic modification of the genome. Dnmt1p is one of 5′ exon alternative isoforms of Dnmt1 and its mRNA is specifically expressed in the pachytene spermatocyte. However, the function of Dnmt1p still has not been elucidated. In this study, we tried to elucidate the function of Dnmt1p in the male mouse reproductive system. This was accomplished by suppressing the expression level of Dnmt1p in the whole testis by short hairpin RNA (shRNA) expression, which was specifically designed from mouse Dnmt1p mRNA. Dnmt1p cDNA was cloned from total RNA extracted from a piece of testis from a C57BL/6J male mouse. Four shRNA expression vectors were constructed and the knock-down efficiency of each shRNA expression vector was evaluated by flow cytometry. From these results, the 589 shRNA expression vector was picked out for further experimentation. The 589 shRNA expression vector was linearized and injected into the pronuclei of C57BL/6J mouse embryos. After injection, the embryos were cultured for 24 h and cleavage was evaluated. Cleaved embryos were transferred into oviducts of recipient ICR mice. After 18 to 19 days, fetuses were delivered by C-section. Two weeks after the birth, the existence of the 589 shRNA expression gene construct in its genome was evaluated by PCR. From founders with 589 shRNA expression gene construct in its genome, finally 1 TG strain was established and used for further experimentation. Two F2 -generation male mice with the 589 shRNA expression gene construct, 2 F2-generation male mice without the 589 shRNA expression gene construct and 1 C57BL/6J wild-type male mouse were used for evaluating the expression level of Dnmt1p mRNA in the whole testis by quantitative PCR. Then, thin sections of testis derived from the F2-generation mouse, which showed a suppressed expression level of Dnmt1p, was evaluated by immunostaining for Dnmt1 protein. The survival rate of mouse embryos after gene injection was 76.8% (202/263) and the cleavage rate of gene-injected embryos was 69.8% (141/202). The developmental rate of transferred embryos to the birth was 19% (27/139). The rate of newborn mice with the 589 shRNA expression gene construct was 37% (10/27). The fertility of established TG strain mouse was normal and there was no abnormality in the thin section figure of testis stained with hematoxylin-eosin double staining method. The relative expression level of Dnmt1p mRNA in the whole testis of the F2 TG mouse was ∼25% of C57BL/6J wild-type male mouse (P < 0.05, Student's t-test). There was Dnmt1 protein in seminiferous tubules, especially in spermatids of C57BL/6J wild-type male mouse. However, there was no Dnmt1 protein in seminiferous tubules of the F2 TG mouse. From these results, it was concluded that the expression of Dnmt1p mRNA was associated in some way with the translation of the Dnmt1 protein in the mouse testis.

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