Epigenetic State Changes Underlie Metabolic Switch in Mouse Post-Infarction Border Zone Cardiomyocytes

Myocardial infarction causes ventricular muscle loss and formation of scar tissue. The surviving myocardium in the border zone, located adjacent to the infarct, undergoes profound changes in function, structure and composition. How and to what extent these changes of border zone cardiomyocytes are regulated epigenetically is not fully understood. Here, we obtained transcriptomes of PCM-1-sorted mouse cardiomyocyte nuclei of healthy left ventricle and 7 days post myocardial infarction border zone tissue. We validated previously observed downregulation of genes involved in fatty acid metabolism, oxidative phosphorylation and mitochondrial function in border zone-derived cardiomyocytes, and observed a modest induction of genes involved in glycolysis, including Slc2a1 (Glut1) and Pfkp. To gain insight into the underlying epigenetic regulatory mechanisms, we performed H3K27ac profiling of healthy and border zone cardiomyocyte nuclei. We confirmed the switch from Mef2- to AP-1 chromatin association in border zone cardiomyocytes, and observed, in addition, an enrichment of PPAR/RXR binding motifs in the sites with reduced H3K27ac signal. We detected downregulation and accompanying epigenetic state changes at several key PPAR target genes including Ppargc1a (PGC-1a), Cpt2, Ech1, Fabpc3 and Vldrl in border zone cardiomyocytes. These data indicate that changes in epigenetic state and gene regulation underlie the maintained metabolic switch in border zone cardiomyocytes.

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Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial

Open Heart ◽

10.1136/openhrt-2021-001614 ◽

2021 ◽

Vol 8 (2) ◽

pp. e001614

Author(s):

Mohammad R Ostovaneh ◽

Raj R Makkar ◽

Bharath Ambale-Venkatesh ◽

Deborah Ascheim ◽

Tarun Chakravarty ◽

...

Keyword(s):

Myocardial Infarction ◽

Clinical Trial ◽

Myocardial Function ◽

Randomised Clinical Trial ◽

Scar Tissue ◽

Left Ventricular ◽

Lv Function ◽

Cardiac Events ◽

Lv Dysfunction ◽

Registration Number

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups.ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

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Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22020722 ◽

2021 ◽

Vol 22 (2) ◽

pp. 722

Author(s):

Yukino Ogura ◽

Kazuko Tajiri ◽

Nobuyuki Murakoshi ◽

DongZhu Xu ◽

Saori Yonebayashi ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Neutrophil Elastase ◽

Myocardial Injury ◽

Flow Cytometric Analysis ◽

Akt Signaling ◽

Border Zone ◽

Terminal Deoxynucleotidyl Transferase ◽

Deficient Mice

Neutrophils are recruited into the heart at an early stage following a myocardial infarction (MI). These secrete several proteases, one of them being neutrophil elastase (NE), which promotes inflammatory responses in several disease models. It has been shown that there is an increase in NE activity in patients with MI; however, the role of NE in MI remains unclear. Therefore, the present study aimed to investigate the role of NE in the pathogenesis of MI in mice. NE expression peaked on day 1 in the infarcted hearts. In addition, NE deficiency improved survival and cardiac function post-MI, limiting fibrosis in the noninfarcted myocardium. Sivelestat, an NE inhibitor, also improved survival and cardiac function post-MI. Flow cytometric analysis showed that the numbers of heart-infiltrating neutrophils and inflammatory macrophages (CD11b+F4/80+CD206low cells) were significantly lower in NE-deficient mice than in wild-type (WT) mice. At the border zone between intact and necrotic areas, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells was lower in NE-deficient mice than in WT mice. Western blot analyses revealed that the expression levels of insulin receptor substrate 1 and phosphorylation of Akt were significantly upregulated in NE-knockout mouse hearts, indicating that NE deficiency might improve cardiac survival by upregulating insulin/Akt signaling post-MI. Thus, NE may enhance myocardial injury by inducing an excessive inflammatory response and suppressing Akt signaling in cardiomyocytes. Inhibition of NE might serve as a novel therapeutic target in the treatment of MI.

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Differential activation mechanisms of two isoforms of Gcr1 transcription factor generated from spliced and un-spliced transcripts in Saccharomyces cerevisiae

Nucleic Acids Research ◽

10.1093/nar/gkaa1221 ◽

2020 ◽

Author(s):

Seungwoo Cha ◽

Chang Pyo Hong ◽

Hyun Ah Kang ◽

Ji-Sook Hahn

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcription Factor ◽

Target Genes ◽

Gene Encoding ◽

Metabolic Switch ◽

Differential Activation ◽

N Terminus ◽

Activation Mechanisms ◽

In Trans ◽

Separate Activation

Abstract Gcr1, an important transcription factor for glycolytic genes in Saccharomyces cerevisiae, was recently revealed to have two isoforms, Gcr1U and Gcr1S, produced from un-spliced and spliced transcripts, respectively. In this study, by generating strains expressing only Gcr1U or Gcr1S using the CRISPR/Cas9 system, we elucidate differential activation mechanisms of these two isoforms. The Gcr1U monomer forms an active complex with its coactivator Gcr2 homodimer, whereas Gcr1S acts as a homodimer without Gcr2. The USS domain, 55 residues at the N-terminus existing only in Gcr1U, inhibits dimerization of Gcr1U and even acts in trans to inhibit Gcr1S dimerization. The Gcr1S monomer inhibits the metabolic switch from fermentation to respiration by directly binding to the ALD4 promoter, which can be restored by overexpression of the ALD4 gene, encoding a mitochondrial aldehyde dehydrogenase required for ethanol utilization. Gcr1U and Gcr1S regulate almost the same target genes, but show unique activities depending on growth phase, suggesting that these isoforms play differential roles through separate activation mechanisms depending on environmental conditions.

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Cardiac-specific ablation of theSTAT3gene in the subacute phase of myocardial infarction exacerbated cardiac remodeling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00730.2014 ◽

2015 ◽

Vol 309 (3) ◽

pp. H471-H480 ◽

Cited By ~ 19

Author(s):

Daichi Enomoto ◽

Masanori Obana ◽

Akimitsu Miyawaki ◽

Makiko Maeda ◽

Hiroyuki Nakayama ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Remodeling ◽

Cardiac Fibrosis ◽

Biological Significance ◽

Weight Ratio ◽

Fluorescence Analysis ◽

Border Zone ◽

Intrinsic Activity ◽

Heart Weight ◽

Subacute Phase

STAT3 is a cardioprotective molecule against acute myocardial injury; however, recent studies have suggested that chronic STAT3 activation in genetically modified mice was detrimental after myocardial infarction (MI). In the present study, we assessed the biological significance of STAT3 activity in subacute MI using tamoxifen (TM)-inducible cardiac-specific STAT3 knockout (STAT3 iCKO) mice. After coronary ligation, STAT3 was rapidly activated in hearts, and its activation was sustained to the subacute phase. To make clear the pathophysiological roles of STAT3 activation specifically in subacute MI, MI was generated in STAT3 iCKO mice followed by TM treatment for 14 consecutive days beginning from day 11 after MI, which ablated the STAT3 gene in the subacute phase. Intriguingly, mortality was increased by TM treatment in STAT3 iCKO mice, accompanied by an increased heart weight-to-body weight ratio. Masson's trichrome staining demonstrated that cardiac fibrosis was dramatically exacerbated in STAT3 iCKO mice 24 days after MI (fibrotic circumference: 58.3 ± 6.7% in iCKO mice and 40.8 ± 9.3% in control mice), concomitant with increased expressions of fibrosis-related gene transcripts, including matrix metalloproteinase 9, procollagen 1, and procollagen 3. Echocardiography clarified that cardiac function was deteriorated in STAT3 iCKO mice (fractional shortening: 20.6 ± 4.1% in iCKO mice and 29.1 ± 6.0% in control mice). Dihydroethidium fluorescence analysis revealed that superoxide production was increased in STAT3 iCKO mice. Moreover, immunohistochemical analyses revealed that capillary density was decreased in STAT3 iCKO mice. Finally, STAT3 deletion in subacute MI evoked severe cardiac hypertrophy in the border zone. In conclusion, the intrinsic activity of STAT3 in the myocardium confers the resistance to cardiac remodeling in subacute MI.

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Discovery and Characterization of Differentially Expressed Soybean MiRNAs and Their Targets During Soybean Mosaic Virus Infection Unveils Novel Insight Into Soybean-SMV Interaction

10.21203/rs.3.rs-775142/v1 ◽

2021 ◽

Author(s):

Bowen Li ◽

Adhimoolam Karthikeyan ◽

Liqun Wang ◽

Jinlong Yin ◽

Tongtong Jin ◽

...

Keyword(s):

Virus Infection ◽

Mosaic Virus ◽

Target Genes ◽

Soybean Mosaic Virus ◽

Expression Patterns ◽

Defense Responses ◽

Pcr Analysis ◽

Functional Annotations ◽

Additional Information ◽

Insight Into

Abstract Background: Soybean mosaic virus (SMV) is the most devastating pathogen of soybean. MicroRNAs (miRNAs) are a class of non-coding RNAs (21-24 nucleotides) and play important roles in regulating defense responses against pathogens. However, miRNA's response to SMV in soybean is not as well documented. Result: In this study, we analyzed 18 miRNA libraries, including three biological replicates from two soybean lines (Resistant and susceptible lines to SMV strain SC3 selected from the near-isogenic lines of Qihuang No. 1× Nannong1138-2) after virus infection at three different time intervals (0 dpi, 7 dpi, and 14 dpi). A total of 1,092 miRNAs, including 608 known miRNAs and 484 novel miRNAs were detected. Differential expression analyses identified the miRNAs responded during soybean-SMV interaction. Then, miRNAs potential target genes were predicted via data mining, and functional annotation was done by Gene Ontology (GO) analysis. Eventually, the expression patterns of several miRNAs validated by quantitative real-time PCR analysis are consistent with sequencing results. Conclusion: We have identified a large number of miRNAs and their target genes and also functional annotations. Our study provides additional information on soybean miRNAs and an insight into the role of miRNAs during SMV-infection in soybean.

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Abstract 5393: Increased C-Reactive Protein Expression Exacerbates Left Ventricular Dysfunction and Remodeling after Myocardial Infarction

Circulation ◽

10.1161/circ.118.suppl_18.s_541-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Toshiyuki Takahashi ◽

Toshihisa Anzai ◽

Hidehiro Kaneko ◽

Atsushi Anzai ◽

Yoshinori Mano ◽

...

Keyword(s):

Myocardial Infarction ◽

Angiotensin Ii ◽

Left Ventricular ◽

Receptor Expression ◽

Border Zone ◽

Histological Evaluation ◽

Control Group ◽

C Reactive Protein ◽

Reactive Protein ◽

Lv Remodeling

We have previously reported that elevated serum C-reactive protein (CRP) level after acute myocardial infarction (MI) is associated with adverse outcomes including cardiac rupture, left ventricular (LV) remodeling and cardiac death. Recent experimental studies have shown that CRP per se has some biological properties including proinflammatory and proapoptotic effects, suggesting a pathogenetic role of CRP in the remodeling process after MI. We tested the hypothesis that increased CRP expression would exacerbate adverse LV remodeling after MI through some deleterious effects of CRP. Transgenic mice with human CRP expression (CRP-Tg) and their nontransgenic littermates (Control) underwent proximal ligation of the left coronary artery. Despite increased serum CRP level and cardiac CRP expression in CRP-Tg mice, there was no difference in phenotype between CRP-Tg and control mice before MI. Mortality at five weeks after MI was not different between groups (CRP-Tg: 49%, n=35; Control: 38%, n=40, P =0.28). Five weeks after MI, echocardiography showed that CRP-Tg mice had more LV dilation (LVEDD, CRP-Tg: 5.8 ± 0.1 mm, n=14; Control: 5.2 ± 0.1 mm, n=17, P =0.002) and worse LV function (EF, CRP-Tg: 13 ± 2%, n=14; Control: 19 ± 1%, n=17, P =0.01). Hemodynamic studies indicated that LV +dP/dt (CRP-Tg: 2,947 ± 480 mmHg/s, n=9; Control: 3,788 ± 656 mmHg/s, n=10, P =0.02) and -dP/dt (CRP-Tg: −2,230 ± 48 mmHg/s, n=9; Control: −2,890 ± 161 mmHg/s, n=10, P =0.003) were lower in the CRP-Tg group than in the Control group, although infarct size was comparable. Histological evaluation at one week after MI showed a higher rate of apoptosis in the border zone of infarcted hearts from CRP-Tg mice (CRP-Tg: 1,434 ± 322 per 10 5 nuclei; Control: 596 ± 112 per 10 5 nuclei, n=6 for each, P =0.03). Quantitative RT-PCR showed that angiotensin II type 1a receptor and interleukin-6 were upregulated in viable LV samples from CRP-Tg mice compared with controls. Increased CRP expression exacerbates LV dysfunction and remodeling after MI, associated with increased apoptotic rates, increased angiotensin II receptor expression and exaggerated inflammatory response.

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FgHtf1 Regulates Global Gene Expression towards Aerial Mycelium and Conidiophore Formation in the Cereal Fungal Pathogen Fusarium graminearum

Applied and Environmental Microbiology ◽

10.1128/aem.03024-19 ◽

2020 ◽

Vol 86 (9) ◽

Author(s):

Gaili Fan ◽

Huawei Zheng ◽

Kai Zhang ◽

Veena Devi Ganeshan ◽

Stephen Obol Opiyo ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Gene Family ◽

Fusarium Graminearum ◽

Target Genes ◽

Homeobox Gene ◽

Global Gene Expression ◽

Binding Motifs ◽

Content Type ◽

Aerial Growth

ABSTRACT The homeobox gene family of transcription factors (HTF) controls many developmental pathways and physiological processes in eukaryotes. We previously showed that a conserved HTF in the plant-pathogenic fungus Fusarium graminearum, Htf1 (FgHtf1), regulates conidium morphology in that organism. This study investigated the mechanism of FgHtf1-mediated regulation and identified putative FgHtf1 target genes by a chromatin immunoprecipitation assay combined with parallel DNA sequencing (ChIP-seq) and RNA sequencing. A total of 186 potential binding peaks, including 142 genes directly regulated by FgHtf1, were identified. Subsequent motif prediction analysis identified two DNA-binding motifs, TAAT and CTTGT. Among the FgHtf1 target genes were FgHTF1 itself and several important conidiation-related genes (e.g., FgCON7), the chitin synthase pathway genes, and the aurofusarin biosynthetic pathway genes. In addition, FgHtf1 may regulate the cAMP-protein kinase A (PKA)-Msn2/4 and Ca2+-calcineurin-Crz1 pathways. Taken together, these results suggest that, in addition to autoregulation, FgHtf1 also controls global gene expression and promotes a shift to aerial growth and conidiation in F. graminearum by activation of FgCON7 or other conidiation-related genes. IMPORTANCE The homeobox gene family of transcription factors is known to be involved in the development and conidiation of filamentous fungi. However, the regulatory mechanisms and downstream targets of homeobox genes remain unclear. FgHtf1 is a homeobox transcription factor that is required for phialide development and conidiogenesis in the plant pathogen F. graminearum. In this study, we identified FgHtf1-controlled target genes and binding motifs. We found that, besides autoregulation, FgHtf1 also controls global gene expression and promotes conidiation in F. graminearum by activation of genes necessary for aerial growth, FgCON7, and other conidiation-related genes.

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Donkey genome and insight into the imprinting of fast karyotype evolution

Scientific Reports ◽

10.1038/srep14106 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 12

Author(s):

Jinlong Huang ◽

Yiping Zhao ◽

Dongyi Bai ◽

Wunierfu Shiraigol ◽

Bei Li ◽

...

Keyword(s):

Target Genes ◽

Karyotype Evolution ◽

De Novo ◽

Cycle Phase ◽

Satellite Sequences ◽

Chromatid Segregation ◽

Karyotypic Instability ◽

Wild Ass ◽

Genome Assemblies ◽

Insight Into

Abstract The donkey, like the horse, is a promising model for exploring karyotypic instability. We report the de novo whole-genome assemblies of the donkey and the Asiatic wild ass. Our results reflect the distinct characteristics of donkeys, including more effective energy metabolism and better immunity than horses. The donkey shows a steady demographic trajectory. We detected abundant satellite sequences in some inactive centromere regions but not in neocentromere regions, while ribosomal RNAs frequently emerged in neocentromere regions but not in the obsolete centromere regions. Expanded miRNA families and five newly discovered miRNA target genes involved in meiosis may be associated with fast karyotype evolution. APC/C, controlling sister chromatid segregation, cytokinesis and the establishment of the G1 cell cycle phase were identified by analysis of miRNA targets and rapidly evolving genes.

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Mesenchymal stem cells with overexpression of Angiotensin-converting enzyme-2 improved the microenvironment and cardiac function in a rat model of myocardial infarction

10.1101/2020.05.03.075283 ◽

2020 ◽

Author(s):

Chao Liu ◽

Yue Fan ◽

Hong-Yi Zhu ◽

Lu zhou ◽

Yu Wang ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Angiotensin Converting Enzyme ◽

Cardiac Function ◽

Heart Function ◽

Tube Formation ◽

Border Zone ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2

AbstractBackgroundAngiotensin-converting enzyme-2 (ACE2) overexpression improves left ventricular remodeling and function in diabetic cardiomyopathy; however, the effect of ACE2-overexpressed mesenchymal stem cells (MSCs) on myocardial infarction (MI) remains unexplored. This study aimed to investigate the effect of ACE2-overexpression on the function of MSCs and the therapeutic efficacy of MSCs for MI.MethodsMSCs were transfected with Ace2 gene using lentivirus, and then transplanted into the border zone of ischemic heart. The renin-angiotensin system (RAS) expression, nitric oxide synthase (NOS) expression, paracrine factors, anti-hypoxia ability, tube formation of MSCs, and heart function were determined.ResultsMSCs expressed little ACE2. ACE2-overexpression decreased the expression of AT1 and VEGF apparently, up-regulated the paracrine of HGF, and increased the synthesis of Angiotensin 1-7 in vitro. ACE2-overexpressed MSCs showed a cytoprotective effect on cardiomyocyte, and an interesting tube formation ability, decreased the heart fibrosis and infarct size, and improved the heart function.ConclusionTherapies employing MSCs with ACE2 overexpression may represent an effective treatment for improving the myocardium microenvironment and the cardiac function after MI.

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Non-Coding Genome, Transcription Factors, and Sex Determination

Sexual Development ◽

10.1159/000519725 ◽

2021 ◽

pp. 1-13

Author(s):

Francis Poulat

Keyword(s):

Transcription Factors ◽

Sex Determination ◽

Target Genes ◽

Regulatory Elements ◽

Eukaryotic Cells ◽

Genomic Profiling ◽

Binding Motifs ◽

Male And Female ◽

Genome Transcription ◽

Control Complex

In vertebrates, gonadal sex determination is the process by which transcription factors drive the choice between the testicular and ovarian identity of undifferentiated somatic progenitors through activation of 2 different transcriptional programs. Studies in animal models suggest that sex determination always involves sex-specific transcription factors that activate or repress sex-specific genes. These transcription factors control their target genes by recognizing their regulatory elements in the non-coding genome and their binding motifs within their DNA sequence. In the last 20 years, the development of genomic approaches that allow identifying all the genomic targets of a transcription factor in eukaryotic cells gave the opportunity to globally understand the function of the nuclear proteins that control complex genetic programs. Here, the major transcription factors involved in male and female vertebrate sex determination and the genomic profiling data of mouse gonads that contributed to deciphering their transcriptional regulation role will be reviewed.

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