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Introduction
Additional affiliations
August 2013 - present
January 2013 - June 2013
October 2009 - December 2012
Publications
Publications (53)
Growth differentiation factor 11 (GDF11) and GDF8 (MSTN) are closely related TGF-β family proteins that interact with nearly identical signaling receptors and antagonists. However, GDF11 appears to activate SMAD2/3 more potently than GDF8 in vitro and in vivo. The ligands possess divergent structural properties, whereby substituting unique GDF11 am...
Background:
The human heart has limited capacity to generate new cardiomyocytes and this capacity declines with age. Because loss of cardiomyocytes may contribute to heart failure, it is crucial to explore stimuli of endogenous cardiac regeneration to favorably shift the balance between loss of cardiomyocytes and the birth of new cardiomyocytes in...
Growth differentiation factor 11 (GDF11) and GDF8 (MSTN) are closely related TGFβ family proteins that interact with nearly identical signaling receptors and antagonist proteins. However, GDF11 appears to activate SMAD2/3 in vitro and in vivo more potently than GDF8. The ligands possess divergent structural properties, whereby substituting unique G...
Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age‐related disease. The molecular mechanisms by which ExT induc...
The adult mammalian heart is incapable of clinically relevant regeneration. The regenerative deficit in adult mammalian heart contrasts with the fetal and neonatal heart, which demonstrate substantial regenerative capacity after injury. This deficiency in adult mammals is attributable to the lack of resident stem cells after birth, combined with an...
Calorie restriction (CR) improved healthspan in two longitudinal studies in nonhuman primates (NHPs), yet only the University of Wisconsin (UW) study demonstrated an increase in survival in CR monkeys relative to controls; the National Institute on Aging (NIA) study did not. Here, analysis of left ventricle samples showed that CR did not reduce car...
Administration of active growth differentiation factor 11 (GDF11) to aged mice can reduce cardiac hypertrophy, and low serum levels of GDF11 measured together with the related protein, myostatin (also known as GDF8), predict future morbidity and mortality in coronary heart patients. Using mice with a loxP-flanked ("floxed") allele of Gdf11 and Myh6...
Microvascular dysfunction in the heart and its association with periarteriolar fibrosis may contribute to the diastolic dysfunction seen in heart failure with preserved ejection fraction. Interleukin-33 (IL-33) prevents global myocardial fibrosis in a pressure overloaded left ventricle by acting via its receptor, ST2 (encoded by the gene, Il1rl1);...
The in vivo microenvironment of tissues provides myriad unique signals to cells. Thus, following isolation, many cell types change in culture, often preserving some but not all of their in vivo characteristics in culture. At least some of the in vivo microenvironment may be mimicked by providing specific cues to cultured cells. Here, we show that a...
ApoE enhances islet gene expression profile in vitro.
A) Whole rat pancreatic islets were cultured for a period of 14 days with or without ApoE under low glucose (5 mM) conditions. ApoE significantly increased the expression of key β-cell markers including Ins2, Ucn3, Glut2, Nkx2.2, Nkx6.1, Pcsk1, Sur1 and Pc. B) Whole rat pancreatic Islets were cu...
JAK/STAT inhibition does not affect islet viability.
Whole pancreatic rat islets were cultured for a period of 14 days with or without ApoE together with JAK/STAT inhibitors. Comparable levels of viable and dead cells were detected between the two groups. Scale bar, 50 uM. Data presented as mean ± SEM, where n.s. means not significant (n = 10).
(EP...
Whole islet gene expression profile is lost in adherent cultures in vitro.
Gene expression analysis of β-cell transcription factors from rat pancreatic whole islets cultured under low glucose (5 mM) conditions for 2 weeks shows reduced gene expression over time (n = 4).
(EPS)
Effect of ApoE on islets cultured in suspension and on human islets.
A) Whole human pancreatic islets were cultured for a period of 7 days under physiological glucose (11 mM) conditions with or without ApoE. Comparable levels of key β-cell markers was observed.
B) Human islets were cultured for 7 days in 804G coated plates with and without ApoE. Ea...
ApoE Treatment does not stimulate islet cell proliferation.
Whole rat pancreatic islets were cultured for a period of 14 days with or without ApoE together with BrdU. Very low levels of BrdU positive cells were detected in both groups. Scale bar, 50 uM. Data presented as mean ± SEM, where n.s. means not significant (n = 10).
(EPS)
Supporting information data.
This file contains the list of primers used in this study and supplementary materials and methods.
(PDF)
Loss of cardiomyocytes is a major cause of heart failure, and while the adult heart has a limited capacity for cardiomyogenesis, little is known about what regulates this ability or whether it can be effectively harnessed. Here we show that 8 weeks of running exercise increase birth of new cardiomyocytes in adult mice (~4.6-fold). New cardiomyocyte...
Genetic and functional analyses of 120 mouse strains have identified a heart regeneration candidate gene that modulates the contractile sarcomeric apparatus. This gene, Tnni3k, controls the frequency of the mononuclear, diploid cardiomyocyte population, which affects cardiomyocyte proliferative potential after injury.
Background
Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysf...
Figure 1. The Interaction between GATA4 and TBX5 in Cardiac Gene Regulation
Rationale:
Growth differentiation factor 11 (GDF11) and 8 (GDF8) are members of the TGF-β superfamily sharing 89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al. reported that GDF11/8 levels increase with age in mouse serum.
Objective:
Here we...
Abstract
RATIONALE:
Growth differentiation factor 11 (GDF11) and 8 (GDF8) are members of the TGF-β superfamily sharing 89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al. reported that GDF11/8 levels increase with age in mouse serum.
OBJECTIVE:
He...
Differential DNA methylation exists in the epigenome of end-stage failing human hearts but
whether it contributes to disease progression is presently unknown. Here, we report that cardiac
specific deletion of Dnmt3b, the predominant DNA methyltransferase in adult mouse hearts,
leads to an accelerated progression to severe systolic insufficiency and...
Differential DNA methylation exists in the epigenome of end-stage failing human hearts but whether it contributes to disease progression is presently unknown. Here, we report that cardiac specific deletion of Dnmt3b, the predominant DNA methyltransferase in adult mouse hearts, leads to an accelerated progression to severe systolic insufficiency and...
Stimulation of the nitric oxide (NO) - soluble guanylate (sGC) - protein kinase G (PKG) pathway confers protection against acute ischaemia/reperfusion injury, but more chronic effects in reducing post-myocardial infarction (MI) heart failure are less defined. The aim of this study was to not only determine whether the sGC stimulator riociguat reduc...
Introduction Activation of the nitric oxide-protein kinase G pathway confers protection against acute ischemia/reperfusion injury, but more chronic effects in reducing post-myocardial infarction (MI) heart failure are less defined. The aim of this study was to determine whether riociguat, a selective soluble guanylate cyclase (sGC) stimulator, not...
Background
The epigenomes of healthy and diseased human hearts were recently examined by genome-wide DNA methylation profiling. Repetitive elements, heavily methylated in post-natal tissue, have variable methylation profiles in cancer but methylation of repetitive elements in the heart has never been examined.
Results
We analyzed repetitive elemen...
Table S1 - number of sequencing reads from LV samples.
Figure S7. (a-c) Average density plot for the methylation of ALR (a), ALR_ (b) and ALRb (c) comparing between EsCM (red) and CTRL (blue). Methylation density was consistently reduced in EsCM within the global coordinates of each repeat element (represented collectively here as 0.0 to 1.0 on the X-axis) as well as extending to the flanks (+3.0 and -...
CTRL versus EsCM comparison of each repeat element's methylation using unpaired Welch's t-test.
Figure S5 - count data of repeat sequences merged into respective families. All EsCM LV samples (EsCM 1 to 4) were compared against each of the CTRL samples (CTRL 1 to 4) using Fisher's exact test (P < 0.05 in at least 14 comparisons). Green color indicates hypomethylation in EsCM compared to the corresponding CTRL and red color indicates the conve...
Figure S8 - quantitative PCR using genomic DNA for the copy number abundance of SAT family repeat sequences (ALR, ALR_ and ALRb). (a-c) Quantification of copy number abundance for ALR (a), ALR_ (b) and ALRb (c) repeat elements was performed for EsCM and CTRL LV samples (EsCM A to H and CTRL 1 to 16), and normalized to the copy number for a control...
Distinct epigenomic patterns of DNA methylation exist in important elements of the cardiac genome in human end-stage cardiomyopathy but whether these contribute to disease progression is unknown. We examined and found that the main DNA methyltransferase expressed in the adult mammalian heart is DNMT3B. We therefore generated a conditional inducible...
Distinct epigenomic patterns of DNA methylation exist in important elements of the cardiac genome in human end-stage cardiomyopathy but whether these contribute to disease progression is unknown. We examined and found that the main DNA methyltransferase expressed in the adult mammalian heart is DNMT3B. We therefore generated a conditional inducible...
Abstract
BACKGROUND:
The epigenome refers to marks on the genome, including DNA methylation and histone modifications, that regulate the expression of underlying genes. A consistent profile of gene expression changes in end-stage cardiomyopathy led us to hypothesize that distinct global patterns of the epigenome may also exist.
METHODS AND RESULTS:...
The epigenome refers to marks on the genome, including DNA methylation and histone modifications, that regulate the expression of underlying genes. A consistent profile of gene expression changes in end-stage cardiomyopathy led us to hypothesize that distinct global patterns of the epigenome may also exist.
We constructed genome-wide maps of DNA me...
Rapidly advancing high-throughput sequencing technology is now bringing attention to many basic biological aspects of the human genome. DNA methylation refers to the epigenetic modification of cytosine nucleotides by a methyl group that occurs throughout the genome. Owing to its significant influence on protein-DNA interactions and subsequent gene-...
Genome-wide maps of DNA regulatory elements and their interaction with transcription factors may form a framework for understanding regulatory circuits and gene expression control in human disease, but how these networks, comprising transcription factors and DNA-binding proteins, form complexes, interact with DNA and modulate gene expression remain...
Average conservation plot from the analysis of the p53-RELA binding sites using CEAS demonstrating that the 12,311 tag locations of binding sites unique to disease were strongly conserved across species.
Details of human cardiomyopathic and normal control left ventricular explants.
Location of p53-RELA binding sites relative to genomic structures, as annotated using CEAS in Ji et al. [17]. Proximal promoters, 1 kb upstream from RefSeq 5' start; immediate downstream, 1 kb from RefSeq 3' end.
Conservation between the human, rat and mouse GIS regulatory sequences is shown. Box represents the putative NF-κB motif.
The previously described mir-21 promoter [30]was cloned upstream of firefly luciferase (miPPR21-Luc) and transfected together with TK-renilla control, with or without plasmids encoding p53 and RELA, and incubated with or without NFI as indicated. Assays are presented as mean ± standard error for four independent replicates.
H3K4me3 and control IgG ChIP were performed on cardiac fibroblasts in the presence of DFX. Results represent fold enrichment of real-time qPCR for the previously described mir-21 promoter (miPPR-21) and GIS. ChIP results are presented as mean ± standard error for two independent experiments performed in triplicate.
Figure S3. (a) All EsCM LV samples (EsCM 1 to 4) were compared against each of the CTRL samples (CTRL 1 to 4) using Fisher's exact test (P < 0.05 in at least 14 comparisons). Green color indicates hypomethylation in EsCM compared to the corresponding CTRL and red color indicates the converse, hypermethylation in EsCM. The color bar on the vertical...
List of transcription factor motifs enriched in the subset of p53-RELA binding sites (total of 1,344 sites) containing the bona fide κB motif.
List of transcription factor motifs enriched in the previously published [22]genome-wide RELA binding sites dataset (PET2 and PET3 clusters).
Figure S6 - the count data of repeat sequences merged into respective classes. All EsCM LV samples (EsCM 1 to 4) were compared against each of the CTRL samples (CTRL 1 to 4) using Fisher's exact test (P < 0.05 in at least 14 comparisons). Green color indicates hypomethylation in EsCM compared to the corresponding CTRL and red color indicates the co...
Figure S1 - schematic view of the analysis workflow. (a) Methylated DNA immunoprecipitation (MeDIP) was conducted to isolate methylated DNA fragments across four end-stage cardiomyopathic (EsCM 1 to 4) and four normal healthy control (CTRL A to D) hearts as listed in Additional file 2 and as published [10]. (b) MeDIP samples were sequenced using an...
(a) H9c2 cardiac cells were treated with or without doxorubicin (an activator of p53). Small RNAs were isolated and quantified using TaqMan miRNA assays. (b) Primary neonatal rat cardiac fibroblasts were incubated in normoxia or <1% hypoxia for 48 h and mir-21 quantification was performed. miRNA quantification is shown as mean ± standard error from...
Mycobacterium tuberculosis (Mtb) manipulates cells of the innate immune system to provide the bacteria with a sustainable intracellular niche. Mtb spread through aerosol carrying them deep into the lungs, where they are internalized by phagocytic cells, such as neutrophils (PMNs), dendritic cells (DCs), and macrophages. PMNs undergo accelerated apo...
Questions
Question (1)
The probe works well on frozen sections but resin is very tricky. It works sometimes and sometimes not (despite following the same protocol). Now I am down to have sections that are PAS stained, still in resin, and wonder if anyone has any experience with this type of material and double staining. Are they compatible? My current protocol for resin has 10 min Sodium thiocyanate (1M) 80C, 0.4 % pepsin in 0.1M HCl 37C pretreatment, quenching and PFA fix before hybridization. Thanks for your help!
