Quantitative genomics of voluntary exercise in mice: transcriptional analysis and mapping of expression QTL in muscle

Motivation and ability both underlie voluntary exercise, each with a potentially unique genetic architecture. Muscle structure and function are one of many morphological and physiological systems acting to simultaneously determine exercise ability. We generated a large ( n = 815) advanced intercross line of mice (G4) derived from a line selectively bred for increased wheel running (high runner) and the C57BL/6J inbred strain. We previously mapped quantitative trait loci (QTL) contributing to voluntary exercise, body composition, and changes in body composition as a result of exercise. Using brain tissue in a subset of the G4 ( n = 244), we have also previously reported expression QTL (eQTL) colocalizing with the QTL for the higher-level phenotypes. Here, we examined the transcriptional landscape of hind limb muscle tissue via global mRNA expression profiles. Correlations revealed an ∼1,168% increase in significant relationships between muscle transcript expression levels and the same exercise and body composition phenotypes examined previously in the brain. The exercise trait most often significantly correlated with gene expression in the brain was running duration while in the muscle it was maximum running speed. This difference may indicate that time spent engaging in exercise behavior may be more influenced by central (neurobiological) mechanisms, while intensity of exercise may be largely controlled by peripheral mechanisms. Additionally, we used subsets of cis-acting eQTL, colocalizing with QTL, to identify candidate genes based on both positional and functional evidence. We discuss three plausible candidate genes ( Insig2, Prcp, Sparc) and their potential regulatory role.

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Parent-of-origin effects on voluntary exercise levels and body composition in mice

Physiological Genomics ◽

10.1152/physiolgenomics.00139.2009 ◽

2010 ◽

Vol 40 (2) ◽

pp. 111-120 ◽

Cited By ~ 17

Author(s):

Scott A. Kelly ◽

Derrick L. Nehrenberg ◽

Kunjie Hua ◽

Ryan R. Gordon ◽

Theodore Garland ◽

...

Keyword(s):

Body Composition ◽

Body Fat ◽

Wheel Running ◽

Voluntary Exercise ◽

Phenotypic Variance ◽

In Utero Environment ◽

Dependent Activity ◽

Health Related ◽

Parent Of Origin ◽

Origin Effects

Despite the health-related benefits of exercise, many people do not engage in enough activity to realize the rewards, and little is known regarding the genetic or environmental components that account for this individual variation. We created and phenotyped a large G4 advanced intercross line originating from reciprocal crosses between mice with genetic propensity for increased voluntary exercise (HR line) and the inbred strain C57BL/6J. G4 females (compared to males) ran significantly more when provided access to a running wheel and were smaller with a greater percentage of body fat pre- and postwheel access. Change in body composition resulting from a 6-day exposure to wheels varied between the sexes with females generally regulating energy balance more precisely in the presence of exercise. We observed parent-of-origin effects on most voluntary wheel running and body composition traits, which accounted for 3–13% of the total phenotypic variance pooled across sexes. G4 individuals descended from progenitor (F0) crosses of HR♀ and C57BL/6J♂ ran greater distances, spent more time running, ran at higher maximum speeds/day, and had lower percent body fat and higher percent lean mass than mice descended from reciprocal progenitor crosses (C57BL/6J♀ × HR♂). For some traits, significant interactions between parent of origin and sex were observed. We discuss these results in the context of sex dependent activity and weight loss patterns, the contribution of parent-of-origin effects to predisposition for voluntary exercise, and the genetic (i.e., X-linked or mtDNA variations), epigenetic (i.e., genomic imprinting), and environmental (i.e., in utero environment or maternal care) phenomena potentially modulating these effects.

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Genetics in the Honey Bee: Achievements and Prospects toward the Functional Analysis of Molecular and Neural Mechanisms Underlying Social Behaviors

Insects ◽

10.3390/insects10100348 ◽

2019 ◽

Vol 10 (10) ◽

pp. 348 ◽

Cited By ~ 4

Author(s):

Hiroki Kohno ◽

Takeo Kubo

Keyword(s):

Candidate Genes ◽

Honey Bee ◽

Genetic Manipulation ◽

Expression Profiles ◽

Model Organism ◽

Social Behaviors ◽

Forward Genetics ◽

Mushroom Bodies ◽

Functional Analyses ◽

The Brain

The European honey bee is a model organism for studying social behaviors. Comprehensive analyses focusing on the differential expression profiles of genes between the brains of nurse bees and foragers, or in the mushroom bodies—the brain structure related to learning and memory, and multimodal sensory integration—has identified candidate genes related to honey bee behaviors. Despite accumulating knowledge on the expression profiles of genes related to honey bee behaviors, it remains unclear whether these genes actually regulate social behaviors in the honey bee, in part because of the scarcity of genetic manipulation methods available for application to the honey bee. In this review, we describe the genetic methods applied to studies of the honey bee, ranging from classical forward genetics to recently developed gene modification methods using transposon and CRISPR/Cas9. We then discuss future functional analyses using these genetic methods targeting genes identified by the preceding research. Because no particular genes or neurons unique to social insects have been found yet, further exploration of candidate genes/neurons correlated with sociality through comprehensive analyses of mushroom bodies in the aculeate species can provide intriguing targets for functional analyses, as well as insight into the molecular and neural bases underlying social behaviors.

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Functional Genomic Architecture of Predisposition to Voluntary Exercise in Mice: Expression QTL in the Brain

Genetics ◽

10.1534/genetics.112.140509 ◽

2012 ◽

Vol 191 (2) ◽

pp. 643-654 ◽

Cited By ~ 25

Author(s):

Scott A. Kelly ◽

Derrick L. Nehrenberg ◽

Kunjie Hua ◽

Theodore Garland ◽

Daniel Pomp

Keyword(s):

Voluntary Exercise ◽

Functional Genomic ◽

Expression Qtl ◽

Genomic Architecture ◽

The Brain

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Transcriptional analysis of insect extreme freeze tolerance

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2019.2019 ◽

2019 ◽

Vol 286 (1913) ◽

pp. 20192019 ◽

Cited By ~ 2

Author(s):

Lauren E. Des Marteaux ◽

Petr Hůla ◽

Vladimír Koštál

Keyword(s):

Candidate Genes ◽

Expression Profiles ◽

Freeze Tolerance ◽

Transcriptional Analysis ◽

Central Theme ◽

Mrna Transcripts ◽

Fundamental Understanding ◽

Application Potential ◽

Freeze Tolerant ◽

High Application

Few invertebrates can survive cryopreservation in liquid nitrogen, and the mechanisms by which some species do survive are underexplored, despite high application potential. Here, we turn to the drosophilid Chymomyza costata to strengthen our fundamental understanding of extreme freeze tolerance and gain insights about potential avenues for cryopreservation of biological materials. We first use RNAseq to generate transcriptomes of three C. costata larval phenotypic variants: those warm-acclimated in early or late diapause (weak capacity to survive cryopreservation), and those undergoing cold acclimation after diapause entry (extremely freeze tolerant, surviving cryopreservation). We identify mRNA transcripts representing genes and processes that accompany the physiological transition to extreme freeze tolerance and relate cryopreservation survival to the transcriptional profiles of select candidate genes using extended sampling of phenotypic variants. Enhanced capacity for protein folding, refolding and processing appears to be a central theme of extreme freeze tolerance and may allow cold-acclimated larvae to repair or eliminate proteins damaged by freezing (thus mitigating the toxicity of denatured proteins, endoplasmic reticulum stress and subsequent apoptosis). We also find a number of candidate genes (including both known and potentially novel, unannotated sequences) whose expression profiles tightly mirror the change in extreme freeze tolerance status among phenotypic variants.

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MicroRNA profiling of the pig periaqueductal grey (PAG) region reveals candidates potentially related to sex-dependent differences

Biology of Sex Differences ◽

10.1186/s13293-020-00343-2 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Klaudia Pawlina-Tyszko ◽

Maria Oczkowicz ◽

Artur Gurgul ◽

Tomasz Szmatoła ◽

Monika Bugno-Poniewierska

Keyword(s):

Expression Profiles ◽

Differential Expression Analysis ◽

Mirna Profile ◽

Human Model ◽

Periaqueductal Grey ◽

Neurological Research ◽

Downstream Analysis ◽

Neuron Growth ◽

Human Brains ◽

The Brain

Abstract Background MicroRNAs indirectly orchestrate myriads of essential biological processes. A wide diversity of miRNAs of the neurodevelopmental importance characterizes the brain tissue, which, however, exhibits region-specific miRNA profile differences. One of the most conservative regions of the brain is periaqueductal grey (PAG) playing vital roles in significant functions of this organ, also those observed to be sex-influenced. The domestic pig is an important livestock species but is also believed to be an excellent human model. This is of particular importance for neurological research because of the similarity of pig and human brains as well as difficult access to human samples. However, the pig PAG profile has not been characterized so far. Moreover, molecular bases of sex differences connected with brain functioning, including miRNA expression profiles, have not been fully deciphered yet. Methods Thus, in this study, we applied next-generation sequencing to characterize pig PAG expressed microRNAs. Furthermore, we performed differential expression analysis between females and males to identify changes of the miRNA profile and reveal candidates underlying sex-related differences. Results As a result, known brain-enriched, and new miRNAs which will expand the available profile, were identified. The downstream analysis revealed 38 miRNAs being differentially expressed (DE) between female and male samples. Subsequent pathway analysis showed that they enrich processes vital for neuron growth and functioning, such as long-term depression and axon guidance. Among the identified sex-influenced miRNAs were also those associated with the PAG physiology and diseases related to this region. Conclusions The obtained results broaden the knowledge on the porcine PAG miRNAome, along with its dynamism reflected in different isomiR signatures. Moreover, they indicate possible mechanisms associated with sex-influenced differences mediated via miRNAs in the PAG functioning. They also provide candidate miRNAs for further research concerning, i.e., sex-related bases of physiological and pathological processes occurring in the nervous system. Graphical abstract

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Voluntary exercise and cardiac remodeling in a myocardial infarction model

Open Medicine ◽

10.1515/med-2020-0109 ◽

2020 ◽

Vol 15 (1) ◽

pp. 545-555

Author(s):

Hamad Al Shahi ◽

Tomoyasu Kadoguchi ◽

Kazunori Shimada ◽

Kosuke Fukao ◽

Satoshi Matsushita ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Cardiac Remodeling ◽

Skeletal Muscles ◽

Wheel Running ◽

Voluntary Exercise ◽

Fibroblast Growth Factor 21 ◽

Expression Levels ◽

Factor Α ◽

Necrosis Factor

AbstractWe investigated the effects of voluntary exercise after myocardial infarction (MI) on cardiac function, remodeling, and inflammation. Male C57BL/6J mice were divided into the following four groups: sedentary + sham (Sed-Sh), sedentary + MI (Sed-MI), exercise + sham (Ex-Sh), and exercise + MI (Ex-MI). MI induction was performed by ligation of the left coronary artery. Exercise consisting of voluntary wheel running started after the operation and continued for 4 weeks. The Ex-MI mice had significantly increased cardiac function compared with the Sed-MI mice. The Ex-MI mice showed significantly reduced expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 in the infarcted area of the left ventricle compared with the Sed-MI mice. In the Ex-MI mice, the expression levels of fibrosis-related genes including collagen I and III were decreased compared to the Sed-MI mice, and the expression levels of IL-1β, IL-6, follistatin-like 1, fibroblast growth factor 21, and mitochondrial function-related genes were significantly elevated in skeletal muscle compared with the Sed mice. The plasma levels of IL-6 were also significantly elevated in the Ex-MI group compared with the Sed-MI groups. These findings suggest that voluntary exercise after MI may improve in cardiac remodeling associated with anti-inflammatory effects in the myocardium and myokine production in the skeletal muscles.

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Gene Expression Profiles Associated with Radio-Responsiveness in Locally Advanced Rectal Cancer

Biology ◽

10.3390/biology10060500 ◽

2021 ◽

Vol 10 (6) ◽

pp. 500

Author(s):

Jeeyong Lee ◽

Junhye Kwon ◽

DaYeon Kim ◽

Misun Park ◽

KwangSeok Kim ◽

...

Keyword(s):

Candidate Genes ◽

Expression Profiles ◽

Cell Cycle Control ◽

Methylation Status ◽

Locally Advanced ◽

Gene Expression Profiles ◽

Advanced Rectal Cancer ◽

Bioinformatic Analysis ◽

Locally Advanced Rectal Cancer ◽

Genes Encoding

LARC patients were sorted according to their radio-responsiveness and patient-derived organoids were established from the respective cancer tissues. Expression profiles for each group were obtained using RNA-seq. Biological and bioinformatic analysis approaches were used in deciphering genes and pathways that participate in the radio-resistance of LARC. Thirty candidate genes encoding proteins involved in radio-responsiveness–related pathways, including the immune system, DNA repair and cell-cycle control, were identified. Interestingly, one of the candidate genes, cathepsin E (CTSE), exhibited differential methylation at the promoter region that was inversely correlated with the radio-resistance of patient-derived organoids, suggesting that methylation status could contribute to radio-responsiveness. On the basis of these results, we plan to pursue development of a gene chip for diagnosing the radio-responsiveness of LARC patients, with the hope that our efforts will ultimately improve the prognosis of LARC patients.

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Macrophages and microglia: the cerberus of glioblastoma

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01156-z ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Alice Buonfiglioli ◽

Dolores Hambardzumyan

Keyword(s):

Tumor Cells ◽

Innate Immune System ◽

Tumor Heterogeneity ◽

Expression Profiles ◽

Brain Parenchyma ◽

Innate Immune ◽

Malignant Growth ◽

Neoplastic Cells ◽

Functional Roles ◽

The Brain

AbstractGlioblastoma (GBM) is the most aggressive and deadliest of the primary brain tumors, characterized by malignant growth, invasion into the brain parenchyma, and resistance to therapy. GBM is a heterogeneous disease characterized by high degrees of both inter- and intra-tumor heterogeneity. Another layer of complexity arises from the unique brain microenvironment in which GBM develops and grows. The GBM microenvironment consists of neoplastic and non-neoplastic cells. The most abundant non-neoplastic cells are those of the innate immune system, called tumor-associated macrophages (TAMs). TAMs constitute up to 40% of the tumor mass and consist of both brain-resident microglia and bone marrow-derived myeloid cells from the periphery. Although genetically stable, TAMs can change their expression profiles based upon the signals that they receive from tumor cells; therefore, heterogeneity in GBM creates heterogeneity in TAMs. By interacting with tumor cells and with the other non-neoplastic cells in the tumor microenvironment, TAMs promote tumor progression. Here, we review the origin, heterogeneity, and functional roles of TAMs. In addition, we discuss the prospects of therapeutically targeting TAMs alone or in combination with standard or newly-emerging GBM targeting therapies.

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Dynamic genome-wide association analysis and identification of candidate genes involved in anaerobic germination tolerance in rice

Rice ◽

10.1186/s12284-020-00444-x ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Ling Su ◽

Jing Yang ◽

Dandan Li ◽

Ziai Peng ◽

Aoyun Xia ◽

...

Keyword(s):

Candidate Genes ◽

Genome Wide Association Study ◽

Expression Profiles ◽

Oxygen Deficiency ◽

Direct Seeding ◽

Genome Wide Association ◽

Genome Wide ◽

Anaerobic Germination ◽

Dynamic Genome ◽

Rice Seeds

Abstract Background In Asian rice production, an increasing number of countries now choose the direct seeding mode because of rising costs, labour shortages and water shortages. The ability of rice seeds to undergo anaerobic germination (AG) plays an important role in the success of direct seeding. Results In this study, we used 2,123,725 single nucleotide polymorphism (SNP) markers based on resequencing to conduct a dynamic genome-wide association study (GWAS) of coleoptile length (CL) and coleoptile diameter (CD) in 209 natural rice populations. A total of 26 SNP loci were detected in these two phenotypes, of which 5 overlapped with previously reported loci (S1_ 39674301, S6_ 20797781, S7_ 18722403, S8_ 9946213, S11_ 19165397), and two sites were detected repeatedly at different time points (S3_ 24689629 and S5_ 27918754). We suggest that these 7 loci (−log10 (P) value > 7.3271) are the key sites that affect AG tolerance. To screen the candidate genes more effectively, we sequenced the transcriptome of the flooding-tolerant variety R151 in six key stages, including anaerobic (AN) and the oxygen conversion point (AN-A), and obtained high-quality differential expression profiles. Four reliable candidate genes were identified: Os01g0911700 (OsVP1), Os05g0560900 (OsGA2ox8), Os05g0562200 (OsDi19–1) and Os06g0548200. Then qRT-PCR and LC-MS/ MS targeting metabolite detection technology were used to further verify that the up-regulated expression of these four candidate genes was closely related to AG. Conclusion The four novel candidate genes were associated with gibberellin (GA) and abscisic acid (ABA) regulation and cell wall metabolism under oxygen-deficiency conditions and promoted coleoptile elongation while avoiding adverse effects, allowing the coleoptile to obtain oxygen, escape the low-oxygen environment and germinate rapidly. The results of this study improve our understanding of the genetic basis of AG in rice seeds, which is conducive to the selection of flooding-tolerant varieties suitable for direct seeding.

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Identification of Key Candidate Genes Involved in the Progression of Idiopathic Pulmonary Fibrosis

Molecules ◽

10.3390/molecules26041123 ◽

2021 ◽

Vol 26 (4) ◽

pp. 1123

Author(s):

Yu Cui ◽

Jie Ji ◽

Jiwei Hou ◽

Yi Tan ◽

Xiaodong Han

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Candidate Genes ◽

Expression Profiles ◽

Biological Processes ◽

Protein Protein Interaction ◽

Novel Treatments ◽

Kegg Pathway Analysis ◽

Cell Components ◽

Upregulated Genes

Idiopathic pulmonary fibrosis (IPF) is a lethal, agnogenic interstitial lung disease with limited therapeutic options. To investigate vital genes involved in the development of IPF, we integrated and compared four expression profiles (GSE110147, GSE53845, GSE24206, and GSE10667), including 87 IPF samples and 40 normal samples. By reanalyzing these datasets, we managed to identify 62 upregulated genes and 20 downregulated genes in IPF samples compared with normal samples. Differentially expressed genes (DEGs) were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to illustrate relevant pathways of IPF, biological processes, molecular function, and cell components. The DEGs were then subjected to protein–protein interaction (PPI) for network analysis, serving to find 11 key candidate genes (ANXA3, STX11, THBS2, MMP1, MMP9, MMP7, MMP10, SPP1, COL1A1, ITGB8, IGF1). The result of RT-qPCR and immunohistochemical staining verified our finding as well. In summary, we identified 11 key candidate genes related to the process of IPF, which may contribute to novel treatments of IPF.

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