J G Seidman

Harvard Medical School, Boston, Massachusetts, United States

Are you J G Seidman?

Claim your profile

Publications (455)6040.21 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Rationale: Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown etiology. Objective: To determine the contribution of de novo copy number variants (CNVs) in the etiology of sporadic CHD. Methods and Results: We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism (SNP) arrays and/or whole exome sequencing (WES). Results were experimentally validated using digital droplet PCR. We compared validated CNVs in CHD cases to CNVs in 1,301 healthy control trios. The two complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either SNP array (p=7x10-5, Odds Ratio (OR)=4.6) or WES data (p=6x10-4, OR=3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (p=0.02, OR=2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in WES and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q sub-telomeric deletions. Conclusions: We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.
    Circulation Research 09/2014; · 11.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: -The geographic isolation and homogeneous population of Iceland is ideally suited to ascertain clinical and genetic characteristics of hypertrophic cardiomyopathy (HCM) at the population level.
    Circulation 07/2014; · 15.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Spontaneous calcium release evoking delayed after-depolarization is believed to cause CPVT, a lethal human arrhythmia provoked by exercise or emotional stress. Beta-adrenergic blockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation and/or sympathetic denervation. To optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the CASQ2(Δ/Δ) mouse model of CPVT2. A heart telemetry device was implanted for continuous ECG recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by western blotting and confocal microscopy. Adult CASQ2(Δ/Δ) mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. Beta adrenergic blockers, propranolol and metoprolol attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with alpha blocking activity, phentolamine or labetalol, abolished both exercise and epinephrine-induced arrhythmia. To the contrary, injection of alpha adrenergic agonist phenylephrine reproducibly provoked VT. Isolated cardiomyocytes from CASQ2(Δ/Δ) mice had delayed calcium release waves upon exposure to sympathetic agonists which was abolished by phentolamine. Hearts of calsequestrin mutant mice expressed more alpha adreno-receptor1 compared to controls (p<0.05). We identified a contribution of alpha adrenergic pathway to pathogenesis of catecholamine-induced arrhythmia. Alpha blockade emerges an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to beta blockers.
    Heart rhythm: the official journal of the Heart Rhythm Society 04/2014; · 4.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report a five-generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and behavioral dementia in descendants of a 67-year-old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin-2 gene (UBQLN2) with X-linked inheritance in all studied affected individuals. As ubiquilin-2 positive inclusions were identified in brain we suggest that mutant peptide predisposes to protein misfolding and accumulation. Our findings expand the spectrum of neurodegenerative phenotypes caused by UBQLN2 mutations. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 04/2014; · 11.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.
    The Journal of clinical investigation 03/2014; · 15.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The transcriptome is subject to multiple changes during pathogenesis, including the use of alternate 5' start-sites that can affect transcription levels and output. Current RNA sequencing techniques can assess mRNA levels, but do not robustly detect changes in 5' start-site use. Here, we developed a transcriptome sequencing strategy that detects genome-wide changes in start-site usage (5'RNA-Seq) and applied this methodology to identify regulatory events that occur in hypertrophic cardiomyopathy (HCM). Compared with transcripts from WT mice, 92 genes had altered start-site usage in a mouse model of HCM, including four-and-a-half LIM domains protein 1 (Fhl1). HCM-induced altered transcriptional regulation of Fhl1 resulted in robust myocyte expression of a distinct protein isoform, a response that was conserved in humans with genetic or acquired cardiomyopathies. Genetic ablation of Fhl1 in HCM mice was deleterious, which suggests that Fhl1 transcriptional changes provide salutary effects on stressed myocytes in this disease. Because Fhl1 is a chromosome X-encoded gene, stress-induced changes in its transcription may contribute to gender differences in the clinical severity of HCM. Our findings indicate that 5'RNA-Seq has the potential to identify genome-wide changes in 5' start-site usage that are associated with pathogenic phenotypes.
    The Journal of clinical investigation 02/2014; · 15.39 Impact Factor
  • Diane Fatkin, Christine E Seidman, Jonathan G Seidman
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiomyopathies are a heterogeneous group of heart muscle diseases associated with heart failure, arrhythmias, and death. Genetic variation has a critical role in the pathogenesis of cardiomyopathies, and numerous single-gene mutations have been associated with distinctive cardiomyopathy phenotypes. Contemporaneously with these discoveries, there has been enormous growth of genome-wide sequencing studies in large populations, data that show extensive genomic variation within every individual. The considerable allelic diversity in cardiomyopathy genes and in genes predicted to impact clinical expression of disease mutations indicates the need for a more nuanced interpretation of single-gene mutation in cardiomyopathies. These findings highlight the need to find new ways to interpret the functional significance of suites of genetic variants, as well as the need for new disease models that take global genetic variant burdens, epigenetic factors, and cardiac environmental factors into account.
    Cold Spring Harbor perspectives in medicine. 01/2014; 4(1).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Two distinct alleles in the gene encoding apolipoprotein L1 (APOL1), a major component of HDL, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease (CKD). Approximately 14% of African-Americans carry two APOL1 risk alleles, accounting for the high CKD burden in this population. We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African-Americans. We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and CKD were confirmed (p=2.4 x 10-6). Among JHS participants with two APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without vs. 37/280 events among participants with two risk alleles; odds ratio (OR): 2.17, p=9.4 x 10-4). We replicated this novel association of APOL1 genotype with CVD in Women's Health Initiative (WHI) participants (66/292 events among participants without vs. 37/101 events among participants with two risk alleles; OR: 1.98, p=8.37 x 10-3; JHS and WHI combined, p=8.5 x 10-5; OR: 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and CKD. APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with two APOL1 risk alleles may benefit from intensive interventions to reduce CVD.
    Circulation Research 12/2013; · 11.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: -Integrin-linked kinase (ILK) is a serine-threonine kinase that has been linked to human and experimental heart failure, but its role in the heart is not fully understood. -To define the role of cardiomyocyte ILK, we generated cardiac-specific ILK knockout mice (CSILK-KO) using α-MHC-driven Cre expression. CSILK-KO spontaneously developed lethal dilated cardiomyopathy and heart failure with an early increase in apoptosis, fibrosis, and cardiac inflammation. To identify downstream effectors, we used deep sequence analysis of gene expression (DSAGE) to compare comprehensive transcriptional profiles of CSILK-KO and WT hearts from 10 day old mice before the development of cardiac dysfunction. ~2x10(6) cDNA clones from each genotype were sequenced, corresponding to 33,274 independent transcripts. 93 genes were altered, using nominal thresholds of >1.4-fold change and p<0.001. The most highly upregulated gene was osteopontin (47-fold increase, p=9.6x10(-45)), an inflammatory chemokine implicated in heart failure pathophysiology. ILK also regulated osteopontin expression in cardiomyocytes in vitro. Importantly, blocking antibodies to osteopontin mitigated but did not fully rescue the functional decline in CSILK-KO mice. -Cardiomyocyte-specific ILK deletion leads to a lethal cardiomyopathy characterized by cardiomyocyte death, fibrosis, and inflammation. Comprehensive profiling identifies ILK-dependent transcriptional effects and implicates osteopontin as a contributor to these phenotypes.
    Circulation Heart Failure 12/2013; · 6.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.
    Nature Genetics 10/2013; · 35.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dominant mutations in sarcomere proteins such as the myosin heavy chains (MHC) are the leading genetic causes of human hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy. We found that expression of the HCM-causing cardiac MHC gene (Myh6) R403Q mutation in mice can be selectively silenced by an RNA interference (RNAi) cassette delivered by an adeno-associated virus vector. RNAi-transduced MHC(403/+) mice developed neither hypertrophy nor myocardial fibrosis, the pathologic manifestations of HCM, for at least 6 months. Because inhibition of HCM was achieved by only a 25% reduction in the levels of the mutant transcripts, we suggest that the variable clinical phenotype in HCM patients reflects allele-specific expression and that partial silencing of mutant transcripts may have therapeutic benefit.
    Science 10/2013; 342(6154):111-114. · 31.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.
    Nature Genetics 09/2013; 45(10):1113-20. · 35.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Humans and genetically engineered mice with recessively inherited CPVT develop arrhythmia which may arise due to malfunction or degradation of calsequestrin (CASQ2). We investigated the relation between protein level and arrhythmia severity in CASQ2D307H/D307H (D307H), compared to CASQ2Δ/Δ (KO) and wild type (WT) mice. CASQ2 expression and Ca(2+) transients were recorded in cardiomyocytes from neonatal or adult mice. Arrhythmia was studied in vivo using heart rhythm telemetry at rest, exercise and after epinephrine injection. CASQ2 protein was absent in KO heart. Neonatal D307H and WT hearts expressed significantly less CASQ2 protein than the level found in the adult WT. Adult D307H expressed only 20% of CASQ2 protein found in WT. Spontaneous Ca(2+) release was more prevalent in neonatal KO cardiomyocytes (89%) compared to 33-36% of either WT or D307H respectively, p<0.001. Adult cardiomyocytes from both mutant mice had more Ca(2+) abnormalities compared to control (KO: 82%, D307H 63%, WT 12%, p<0.01). Calcium oscillations were most common in KO cardiomyocytes. We then treated mice with bortezomib to inhibit CASQ2D307H degradation. Bortezomib increased CASQ2 expression in D307H hearts by ∼50% (p<0.05). Bortezomib-treated D307H mice had lower CPVT prevalence and less premature ventricular beats during peak exercise. No benefit against arrhythmia was observed in bortezomib treated KO mice. These results indicate that the mutant CASQ2D307H protein retains some of its physiological function. Its expression decreases with age and is inversely related to arrhythmia severity. Preventing the degradation of mutant protein should be explored as a possible therapeutic strategy in appropriate CPVT2 patients.
    Biochemical pharmacology 09/2013; · 4.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent human genetic studies have provided evidences that sporadic or inherited missense mutations in four-and-a-half LIM domain protein 1 (FHL1), resulting in alterations in FHL1 protein expression, are associated with rare congenital myopathies, including reducing body myopathy and Emery-Dreifuss muscular dystrophy. However, it remains to be clarified whether mutations in FHL1 cause skeletal muscle remodeling owing to gain- or loss- of FHL1 function. In this study, we used FHL1-null mice lacking global FHL1 expression to evaluate loss of function effects on skeletal muscle homeostasis. Histological and functional analyses of soleus, tibialis anterior, and sternohyoideus muscles demonstrated that FHL1-null mice develop an age-dependent myopathy associated with myofibrillar and intermyofibrillar (mitochondrial and sarcoplasmic reticulum) disorganization, impaired muscle oxidative capacity and increased autophagic activity. A longitudinal study established decreased survival rates in FHL1-null mice, associated with age-dependent impairment of muscle contractile function and a significantly lower exercise capacity. Analysis of primary myoblasts isolated from FHL1-null muscles demonstrated early muscle fiber differentiation and maturation defects, which could be rescued by re-expression of the FHL1A isoform, highlighting that FHL1A is necessary for proper muscle fiber differentiation and maturation in vitro. Overall, our data show that loss of FHL1 function leads to myopathy in vivo and suggest that loss of function of FHL1 may be one of the mechanisms underlying muscle dystrophy in patients with FHL1 mutations.
    Human Molecular Genetics 08/2013; · 7.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rapid advancement of next-generation sequencing technologies has made it possible to study expression profiles of microRNAs (miRNAs) comprehensively and efficiently. Multiplexing miRNA libraries by barcoding can significantly reduce sequencing cost per sample without compromising library quality. This unit provides a step-by-step protocol for isolating miRNAs and constructing multiplexed miRNA libraries. Also described is a custom computational pipeline for analyzing the multiplexed miRNA library sequencing reads generated by Illumina-based technology. Curr. Protoc. Mol. Biol. 103:4.17.1-4.17.14. © 2013 by John Wiley & Sons, Inc.
    Current protocols in molecular biology / edited by Frederick M. Ausubel ... [et al.] 07/2013; Chapter 4:Unit4.17.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant segregated with microtia and hearing loss in the family and was not seen in 6,500 individuals sequenced by the NHLBI Exome Sequencing Project or in 218 control individuals sequenced in this study. HOXA2 has been shown to be critical for outer and middle ear development through mouse models and has previously been associated with autosomal recessive bilateral microtia. Our data extends these conclusions and defines HOXA2 haploinsufficiency as the first genetic cause for autosomal dominant nonsyndromic microtia. This article is protected by copyright. All rights reserved.
    Human Mutation 06/2013; · 5.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.
    Nature 05/2013; · 38.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: -The transcription factor NKX2-5 is crucial for heart development and mutations in this gene have been implicated in diverse congenital heart diseases (CHD) and conduction defects (CD) in mouse models and humans. Whether NKX2-5 mutations have a role in adult-onset heart disease is unknown. METHODS AND RESULTS: -Mutation screening was performed in 220 probands with adult-onset dilated cardiomypathy (DCM). Six NKX2-5 coding sequence variants were identified, including 3 non-synonymous variants. A novel heterozygous mutation, I184M, located within the NKX2-5 homeodomain (HD), was identified in one family. A subset of family members had CHD, but there was an unexpectedly high prevalence of DCM. Functional analysis of I184M in vitro demonstrated a striking increase in protein expression when transfected into COS-7 cells or HL-1 cardiomyocytes, due to reduced degradation by the ubiquitin-proteasome system (UPS). In functional assays, DNA binding activity of I184M was reduced, resulting in impaired activation of target genes, despite increased expression levels of mutant protein. CONCLUSIONS: -Certain NKX2-5 HD mutations show abnormal protein degradation via the UPS and partially impaired transcriptional activity. We propose that this class of mutation can impair heart development and mature heart function, and contribute to NKX2-5-related cardiomyopathies with graded severity.
    Circulation Cardiovascular Genetics 05/2013; · 6.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Loss-of-function and certain missense mutations in the Wnt co-receptor LRP5 significantly decrease or increase bone mass, respectively. These human skeletal phenotypes have been recapitulated in mice harboring Lrp5 knockout and knockin mutations. We hypothesized that measuring mRNA expression in diaphyseal bone from mice with Lrp5 wild-type (Lrp5(+/+) ), knockout (Lrp5(-/-) ), and high bone mass (HBM)-causing (Lrp5(p.A214V/+) ) alleles could identify genes and pathways that regulate or are regulated by LRP5 activity. We performed RNA-seq on pairs of tibial diaphyseal bones from four 16-week-old mice with each of the aforementioned genotypes. We then evaluated different methods for controlling for contaminating non-skeletal tissue (i.e., blood, bone marrow, and skeletal muscle) in our data. These methods included pre-digestion of diaphyseal bone with collagenase and separate transcriptional profiling of blood, skeletal muscle and bone marrow. We found that collagenase digestion reduced contamination, but also altered gene expression in the remaining cells. In contrast, in silico filtering of the diaphyseal bone RNA-seq data for highly expressed blood, skeletal muscle, and bone marrow transcripts significantly increased the correlation between RNA-seq data from an animal's right and left tibiae and from animals with the same Lrp5 genotype. We conclude that reliable and reproducible RNA-seq data can be obtained from mouse diaphyseal bone and that lack of LRP5 has a more pronounced effect on gene expression than the HBM-causing LRP5 missense mutation. We identified 84 differentially expressed protein-coding transcripts between LRP5 "sufficient" (i.e., Lrp5(+/+) and Lrp5(p.A214V/+) ) and "insufficient" (Lrp5(-/-) ) diaphyseal bone, and far fewer differentially expressed genes between Lrp5(p.A214V/+) and Lrp5(+/+) diaphyseal bone. © 2013 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2013; · 6.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Valvular Interstitial Cells (VICs) are a common substrate for congenital and adult heart disease yet the signaling mechanisms governing their formation during early valvulogenesis are incompletely understood. We developed an unbiased strategy to identify genes important in endocardial epithelial-to-mesenchymal transformation (EMT) using a spatial transcriptional profile. Endocardial cells overlaying the cushions of the atrioventricular canal (AVC) and outflow tract (OFT) undergo an EMT to yield VICs. RNA sequencing (RNA-seq) analysis of gene expression between AVC, OFT, and ventricles (VEN) isolated from chick and mouse embryos at comparable stages of development (chick HH18; mouse E11.0) was performed. EMT occurs in the AVC and OFT cushions, but not VEN at this time. 198 genes in the chick (n=1) and 105 genes in the mouse (n=2) were enriched 2-fold in the cushions. Gene regulatory networks (GRN) generated from cushion-enriched gene lists confirmed TGFβ as a nodal point and identified NF-κB as a potential node. To reveal previously unrecognized regulators of EMT four candidate genes, Hapln1, Id1, Foxp2, and Meis2, and a candidate pathway, NF-κB, were selected. In vivo spatial expression of each gene was confirmed by in situ hybridization and a functional role for each in endocardial EMT was determined by siRNA knockdown in a collagen gel assay. Our spatial-transcriptional profiling strategy yielded gene lists which reflected the known biology of the system. Further analysis accurately identified and validated previously unrecognized novel candidate genes and the NF-κB pathway as regulators of endocardial cell EMT in vitro.
    Journal of Molecular and Cellular Cardiology 04/2013; · 5.15 Impact Factor

Publication Stats

27k Citations
6,040.21 Total Impact Points

Institutions

  • 1983–2014
    • Harvard Medical School
      • • Department of Genetics
      • • Department of Medicine
      Boston, Massachusetts, United States
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, MA, United States
  • 2007–2013
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 2004–2013
    • University of Vermont
      • Department of Molecular Physiology and Biophysics
      Burlington, VT, United States
  • 1991–2013
    • Howard Hughes Medical Institute
      Maryland, United States
  • 1989–2012
    • Boston Children's Hospital
      • • Division of Genetics
      • • Division of Infectious Diseases
      Boston, MA, United States
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1987–2012
    • Brigham and Women's Hospital
      • • Center for Brain Mind Medicine
      • • Department of Medicine
      Boston, MA, United States
  • 2011
    • University of Chicago
      • Department of Pediatrics
      Chicago, IL, United States
  • 2010
    • The University of Tokyo
      • Faculty & Graduate School of Medicine
      Tokyo, Tokyo-to, Japan
  • 2001–2009
    • Minneapolis Heart Institute
      Minneapolis, Minnesota, United States
  • 2005–2008
    • University of Pittsburgh
      • Department of Medicine
      Pittsburgh, Pennsylvania, United States
  • 2003
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 1999
    • Weill Cornell Medical College
      • Division of Cardiology
      New York City, New York, United States
  • 1996–1999
    • Massachusetts Eye and Ear Infirmary
      • Department of Otolaryngology
      Boston, MA, United States
  • 1995
    • Chang Gung Memorial Hospital
      T’ai-pei, Taipei, Taiwan
  • 1994
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
  • 1986–1992
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 1990–1991
    • LSU Medical Center
      • Department of Medicine
      Shreveport, Louisiana, United States
  • 1988
    • Sinai Hospital
      Baltimore, Maryland, United States
  • 1984
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
  • 1981
    • National Cancer Institute (USA)
      • Laboratory of Cell Biology
      Maryland, United States
  • 1977–1980
    • National Institute of Child Health and Human Development
      Maryland, United States
  • 1978
    • National Institutes of Health
      • Molecular Targets Laboratory
      Bethesda, MD, United States