Publications by authors named "Tristan V de Jong"

8 Publications

  • Page 1 of 1

Human iPSC-Derived Cardiomyocytes of Peripartum Patients With Cardiomyopathy Reveal Aberrant Regulation of Lipid Metabolism.

Circulation 2020 Dec 7;142(23):2288-2291. Epub 2020 Dec 7.

Department of Cardiology (M.F.H., N.B., K.F.A.G., P.v.d.M.), University Medical Center Groningen, University of Groningen, The Netherlands.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846285PMC
December 2020

Gene expression variability: the other dimension in transcriptome analysis.

Physiol Genomics 2019 05 15;51(5):145-158. Epub 2019 Mar 15.

European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen , Groningen , The Netherlands.

Transcriptome sequencing is a powerful technique to study molecular changes that underlie the differences in physiological conditions and disease progression. A typical question that is posed in such studies is finding genes with significant changes between sample groups. In this respect expression variability is regarded as a nuisance factor that is primarily of technical origin and complicates the data analysis. However, it is becoming apparent that the biological variation in gene expression might be an important molecular phenotype that can affect physiological parameters. In this review we explore the recent literature on technical and biological variability in gene expression, sources of expression variability, (epi-)genetic hallmarks, and evolutionary constraints in genes with robust and variable gene expression. We provide an overview of recent findings on effects of external cues, such as diet and aging, on expression variability and on other biological phenomena that can be linked to it. We discuss metrics and tools that were developed for quantification of expression variability and highlight the importance of future studies in this direction. To assist the adoption of expression variability analysis, we also provide a detailed description and computer code, which can easily be utilized by other researchers. We also provide a reanalysis of recently published data to highlight the value of the analysis method.
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http://dx.doi.org/10.1152/physiolgenomics.00128.2018DOI Listing
May 2019

Modeling Human Cardiac Hypertrophy in Stem Cell-Derived Cardiomyocytes.

Stem Cell Reports 2018 03 15;10(3):794-807. Epub 2018 Feb 15.

Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, Groningen, the Netherlands. Electronic address:

Cardiac hypertrophy accompanies many forms of cardiovascular diseases. The mechanisms behind the development and regulation of cardiac hypertrophy in the human setting are poorly understood, which can be partially attributed to the lack of a human cardiomyocyte-based preclinical test system recapitulating features of diseased myocardium. The objective of our study is to determine whether human embryonic stem cell-derived cardiomyocytes (hESC-CMs) subjected to mechanical stretch can be used as an adequate in vitro model for studying molecular mechanisms of cardiac hypertrophy. We show that hESC-CMs subjected to cyclic stretch, which mimics mechanical overload, exhibit essential features of a hypertrophic state on structural, functional, and gene expression levels. The presented hESC-CM stretch approach provides insight into molecular mechanisms behind mechanotransduction and cardiac hypertrophy and lays groundwork for the development of pharmacological approaches as well as for discovering potential circulating biomarkers of cardiac dysfunction.
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http://dx.doi.org/10.1016/j.stemcr.2018.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918264PMC
March 2018

A p300 and SIRT1 Regulated Acetylation Switch of C/EBPα Controls Mitochondrial Function.

Cell Rep 2018 01;22(2):497-511

European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands. Electronic address:

Cellular metabolism is a tightly controlled process in which the cell adapts fluxes through metabolic pathways in response to changes in nutrient supply. Among the transcription factors that regulate gene expression and thereby cause changes in cellular metabolism is the basic leucine-zipper (bZIP) transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα). Protein lysine acetylation is a key post-translational modification (PTM) that integrates cellular metabolic cues with other physiological processes. Here, we show that C/EBPα is acetylated by the lysine acetyl transferase (KAT) p300 and deacetylated by the lysine deacetylase (KDAC) sirtuin1 (SIRT1). SIRT1 is activated in times of energy demand by high levels of nicotinamide adenine dinucleotide (NAD) and controls mitochondrial biogenesis and function. A hypoacetylated mutant of C/EBPα induces the transcription of mitochondrial genes and results in increased mitochondrial respiration. Our study identifies C/EBPα as a key mediator of SIRT1-controlled adaption of energy homeostasis to changes in nutrient supply.
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http://dx.doi.org/10.1016/j.celrep.2017.12.061DOI Listing
January 2018

Lung tissue gene-expression signature for the ageing lung in COPD.

Thorax 2017 Dec 6. Epub 2017 Dec 6.

University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands.

Introduction: COPD is a chronic, progressive, inflammatory disease of the lungs and the third leading cause of death worldwide. The current knowledge of the pathophysiology of COPD is limited and novel insights in underlying disease mechanisms are urgently needed. Since there are clear parallels between ageing and COPD, we investigated genes underlying lung ageing in general and abnormal lung ageing in COPD.

Methods: Whole genome mRNA profiling was performed on lung tissue samples (n=1197) and differential gene expression with increasing age was analysed using an adjusted linear regression model. Subsequent pathway analysis was performed using GeneNetwork and the gene-expression signature was compared with lung ageing in the Genotype-Tissue Expression (GTEx) project. In a subset of patients with COPD (n=311) and non-COPD controls (n=270), we performed an interaction analysis between age and COPD to identify genes differentially expressed with age in COPD compared with controls, followed by gene set enrichment pathway analysis.

Results: We identified a strong gene-expression signature for lung ageing with 3509 differentially expressed genes, of which 33.5% were found nominal significant in the GTEx project. Interestingly, we found as a strong candidate gene for lung ageing. The age*COPD interaction analysis revealed 69 genes significantly differentially expressed with age between COPD and controls.

Conclusions: Our study indicates that processes related to lung development, cell-cell contacts, calcium signalling and immune responses are involved in lung ageing in general. Pathways related to extracellular matrix, mammalian target of rapamycin signalling, splicing of introns and exons and the ribosome complex are proposed to be involved in abnormal lung ageing in COPD.
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http://dx.doi.org/10.1136/thoraxjnl-2017-210074DOI Listing
December 2017

Unmasking Transcriptional Heterogeneity in Senescent Cells.

Curr Biol 2017 Sep 30;27(17):2652-2660.e4. Epub 2017 Aug 30.

European Research Institute for the Biology of Aging, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands. Electronic address:

Cellular senescence is a state of irreversibly arrested proliferation, often induced by genotoxic stress [1]. Senescent cells participate in a variety of physiological and pathological conditions, including tumor suppression [2], embryonic development [3, 4], tissue repair [5-8], and organismal aging [9]. The senescence program is variably characterized by several non-exclusive markers, including constitutive DNA damage response (DDR) signaling, senescence-associated β-galactosidase (SA-βgal) activity, increased expression of the cyclin-dependent kinase (CDK) inhibitors p16INK4A (CDKN2A) and p21CIP1 (CDKN1A), increased secretion of many bio-active factors (the senescence-associated secretory phenotype, or SASP), and reduced expression of the nuclear lamina protein LaminB1 (LMNB1) [1]. Many senescence-associated markers result from altered transcription, but the senescent phenotype is variable, and methods for clearly identifying senescent cells are lacking [10]. Here, we characterize the heterogeneity of the senescence program using numerous whole-transcriptome datasets generated by us or publicly available. We identify transcriptome signatures associated with specific senescence-inducing stresses or senescent cell types and identify and validate genes that are commonly differentially regulated. We also show that the senescent phenotype is dynamic, changing at varying intervals after senescence induction. Identifying novel transcriptome signatures to detect any type of senescent cell or to discriminate among diverse senescence programs is an attractive strategy for determining the diverse biological roles of senescent cells and developing specific drug targets.
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http://dx.doi.org/10.1016/j.cub.2017.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788810PMC
September 2017

Combating a Global Threat to a Clonal Crop: Banana Black Sigatoka Pathogen Pseudocercospora fijiensis (Synonym Mycosphaerella fijiensis) Genomes Reveal Clues for Disease Control.

PLoS Genet 2016 08 11;12(8):e1005876. Epub 2016 Aug 11.

Plant Research International, Wageningen University and Research, Wageningen, The Netherlands.

Black Sigatoka or black leaf streak disease, caused by the Dothideomycete fungus Pseudocercospora fijiensis (previously: Mycosphaerella fijiensis), is the most significant foliar disease of banana worldwide. Due to the lack of effective host resistance, management of this disease requires frequent fungicide applications, which greatly increase the economic and environmental costs to produce banana. Weekly applications in most banana plantations lead to rapid evolution of fungicide-resistant strains within populations causing disease-control failures throughout the world. Given its extremely high economic importance, two strains of P. fijiensis were sequenced and assembled with the aid of a new genetic linkage map. The 74-Mb genome of P. fijiensis is massively expanded by LTR retrotransposons, making it the largest genome within the Dothideomycetes. Melting-curve assays suggest that the genomes of two closely related members of the Sigatoka disease complex, P. eumusae and P. musae, also are expanded. Electrophoretic karyotyping and analyses of molecular markers in P. fijiensis field populations showed chromosome-length polymorphisms and high genetic diversity. Genetic differentiation was also detected using neutral markers, suggesting strong selection with limited gene flow at the studied geographic scale. Frequencies of fungicide resistance in fungicide-treated plantations were much higher than those in untreated wild-type P. fijiensis populations. A homologue of the Cladosporium fulvum Avr4 effector, PfAvr4, was identified in the P. fijiensis genome. Infiltration of the purified PfAVR4 protein into leaves of the resistant banana variety Calcutta 4 resulted in a hypersensitive-like response. This result suggests that Calcutta 4 could carry an unknown resistance gene recognizing PfAVR4. Besides adding to our understanding of the overall Dothideomycete genome structures, the P. fijiensis genome will aid in developing fungicide treatment schedules to combat this pathogen and in improving the efficiency of banana breeding programs.
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http://dx.doi.org/10.1371/journal.pgen.1005876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981457PMC
August 2016

Single-cell sequencing reveals karyotype heterogeneity in murine and human malignancies.

Genome Biol 2016 05 31;17(1):115. Epub 2016 May 31.

European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.

Background: Chromosome instability leads to aneuploidy, a state in which cells have abnormal numbers of chromosomes, and is found in two out of three cancers. In a chromosomal instable p53 deficient mouse model with accelerated lymphomagenesis, we previously observed whole chromosome copy number changes affecting all lymphoma cells. This suggests that chromosome instability is somehow suppressed in the aneuploid lymphomas or that selection for frequently lost/gained chromosomes out-competes the CIN-imposed mis-segregation.

Results: To distinguish between these explanations and to examine karyotype dynamics in chromosome instable lymphoma, we use a newly developed single-cell whole genome sequencing (scWGS) platform that provides a complete and unbiased overview of copy number variations (CNV) in individual cells. To analyse these scWGS data, we develop AneuFinder, which allows annotation of copy number changes in a fully automated fashion and quantification of CNV heterogeneity between cells. Single-cell sequencing and AneuFinder analysis reveals high levels of copy number heterogeneity in chromosome instability-driven murine T-cell lymphoma samples, indicating ongoing chromosome instability. Application of this technology to human B cell leukaemias reveals different levels of karyotype heterogeneity in these cancers.

Conclusion: Our data show that even though aneuploid tumours select for particular and recurring chromosome combinations, single-cell analysis using AneuFinder reveals copy number heterogeneity. This suggests ongoing chromosome instability that other platforms fail to detect. As chromosome instability might drive tumour evolution, karyotype analysis using single-cell sequencing technology could become an essential tool for cancer treatment stratification.
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http://dx.doi.org/10.1186/s13059-016-0971-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888588PMC
May 2016