Academic Appointments

Honors & Awards

  • Dean’s Postdoctoral Fellowship - Stanford School of Medicine, Stanford (2013)
  • Western States Affiliate Postdoctoral Fellowship, American Heart Association (2013 - 2014)
  • SUMS Seed Grant, Stanford University Mass Spectrometry (2014)
  • Seed Grant, Stanford Cardiovascular Institute (2014 - 2015)
  • Travel Award, Stanford Cardiovascular Institute (2014, 2015)
  • CIHR Fellow, Canadian Institutes of Health Research (CIHR) (2015 - 2017)
  • Translational Research and Applied Medicine (TRAM) Pilot Grant, Stanford School of Medicine (2015 - 2017)
  • Seed grant, Stanford Nano Shared Facilities (SNSF) (2016)
  • Career Development Award, American Heart Association (2018 - 2021)

Boards, Advisory Committees, Professional Organizations

  • Member, American Heart Association (2012 - Present)
  • Ad hoc reviewer, Disease Models & Mechanisms (2014 - Present)
  • Ad hoc reviewer, American Heart Association Sessions (2016 - Present)
  • Ad hoc reviewer, FASEB Journal (2016 - Present)
  • Ad hoc reviewer, European Heart Journal (2016 - Present)

Research & Scholarship

Current Research and Scholarly Interests

Duchenne muscular dystrophy (DMD) is an X-chromosome-linked genetic disease that is caused by a mutation in the dystrophin gene and affects 1 in every 3500 boys. DMD patients suffer progressive muscle wasting and eventual cardiorespiratory failure that results in an early death in the second or third decade of life. Although extensive research effort has been invested, lack of a good mouse model that mimics the cardiac failure hinders research. We have developed a novel mouse model that exhibit all the symptoms found in DMD patients and our research is aimed at understanding the cardiac failure in DMD for future therapeutic interventions. Our mouse model fully recapitulates the DMD symptoms because we also took into account of the size of human protection DNA on chromosomal ends (telomere) compared to mouse. We would like to study the cause of cardiac failure in our mouse model by 1) determine if telomere shortening is specific to cardiomyocytes, 2) evaluate the level of cellular damage caused by oxidative stress and 3) identify the source of oxidative stress. These experiments will help us to better understand cardiac failure in DMD patients and allow testing of therapeutic interventions.


  • Role of Telomere Erosion in Lethal Cardiomyopathy in Duchenne Muscular Dystrophy, Stanford University

    Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disease that is the most common myopathic disease in humans with a prevalence of one in every 3500 males. Although it has been known for 3 decades that DMD results from mutations in the dystrophin gene, no treatment is currently available to patients. Dystrophin is crucial to the formation of a dystrophin-glycoprotein complex (DGC), which connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix in both skeletal and cardiac muscles. In the heart, loss of dystrophin leads to an influx of extracellular calcium which triggers protease activation, myocyte death, necrosis, and inflammation often culminating in increased fibrosis and death in the third decade of life due to dilated cardiomyopathy.A conundrum and major limitation in study and development of therapies for DMD has been the lack of a mouse model that fully recapitulates the clinical phenotype, as mice that lack dystrophin (mdx model), unlike patients, exhibit only mild skeletal muscle defects, essentially no cardiac defects and have a relatively normal lifespan. The Blau lab reasoned that the difference in the manifestation of the disease in mice and humans could be telomere length, as mice have substantially longer telomeres than humans. This hypothesis proved true and they created a novel mouse model with somewhat shortened telomere lengths (similar to humans) that fully recapitulates the skeletal muscle (Cell. 2010;143:1059-1071; the mdx/mTRKO model) and cardiac muscle phenotype of DMD (unpublished). The histopathology and functional assays in this mouse model, including echocardiography (ECHO), electrocardiography (ECG), and magnetic resonance imaging (MRI) all mirror the human disease and culminate in premature death due to dilated cardiomyopathy. The goal of this proposal is to capitalize on this unique resource and elucidate how shortened telomeres in conjunction with dystrophin deficiency, in a non-proliferative tissue such as the heart, leads to dilated cardiomyopathy and death.

    Goals: This proposal will determine the basis for cardiac failure and early death due to shortened telomeres in dystrophin deficient mice, a the novel mdx/mTRKO mouse model of DMD


    Stanford, CA

  • Development of Biomarkers for Duchenne Dilated Cardiomyopathy


    Stanford, CA


All Publications

  • Telomere shortening is a hallmark of genetic cardiomyopathies. Proceedings of the National Academy of Sciences of the United States of America Chang, A. C., Chang, A. C., Kirillova, A., Sasagawa, K., Su, W., Weber, G., Lin, J., Termglinchan, V., Karakikes, I., Seeger, T., Dainis, A. M., Hinson, J. T., Seidman, J., Seidman, C. E., Day, J. W., Ashley, E., Wu, J. C., Blau, H. M. 2018


    This study demonstrates that significantly shortened telomeres are a hallmark of cardiomyocytes (CMs) from individuals with end-stage hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) as a result of heritable defects in cardiac proteins critical to contractile function. Positioned at the ends of chromosomes, telomeres are DNA repeats that serve as protective caps that shorten with each cell division, a marker of aging. CMs are a known exception in which telomeres remain relatively stable throughout life in healthy individuals. We found that, relative to healthy controls, telomeres are significantly shorter in CMs of genetic HCM and DCM patient tissues harboring pathogenic mutations: TNNI3, MYBPC3, MYH7, DMD, TNNT2, and TTN Quantitative FISH (Q-FISH) of single cells revealed that telomeres were significantly reduced by 26% in HCM and 40% in DCM patient CMs in fixed tissue sections compared with CMs from age- and sex-matched healthy controls. In the cardiac tissues of the same patients, telomere shortening was not evident in vascular smooth muscle cells that do not express or require the contractile proteins, an important control. Telomere shortening was recapitulated in DCM and HCM CMs differentiated from patient-derived human-induced pluripotent stem cells (hiPSCs) measured by two independent assays. This study reveals telomere shortening as a hallmark of genetic HCM and DCM and demonstrates that this shortening can be modeled in vitro by using the hiPSC platform, enabling drug discovery.

    View details for PubMedID 30150400

  • Apelin and APJ orchestrate complex tissue-specific control of cardiomyocyte hypertrophy and contractility in the hypertrophy-heart failure transition. American journal of physiology. Heart and circulatory physiology Parikh, V. N., Liu, J., Shang, C., Woods, C., Chang, A. C., Zhao, M., Charo, D. N., Grunwald, Z., Huang, Y., Seo, K., Tsao, P. S., Bernstein, D., Ruiz-Lozano, P., Quertermous, T., Ashley, E. A. 2018


    The G protein coupled receptor APJ is a promising therapeutic target for heart failure. Constitutive deletion of APJ in the mouse is protective against the hypertrophy-heart failure transition via elimination of ligand-independent, beta-arrestin dependent stretch transduction. However, the cellular origin of this stretch transduction and the details of its interaction with apelin signaling remain unknown. We generated mice with conditional elimination of APJ in the endothelium (APJendo-/-) and myocardium (APJmyo-/-). No baseline difference was observed in LV function in APJendo-/-, APJmyo-/- or controls (APJendo+/+, APJmyo+/+). After exposure to transaortic constriction (TAC), APJendo-/- animals developed left ventricular failure while APJmyo-/- were protected. At the cellular level, carbon fiber stretch of freshly isolated single cardiomyocytes demonstrated decreased contractile response to stretch in APJ-/- cardiomyocytes compared to APJ+/+ cardiomyocytes. Calcium transient did not change with stretch in either APJ-/- or APJ+/+ cardiomyocytes. Application of apelin to APJ+/+ cardiomyocytes resulted in decreased calcium transient. Further, hearts of mice treated with apelin exhibited decreased phosphorylation at Troponin I (cTnI) N-terminal residues (Ser 22,23), consistent with increased calcium sensitivity. These data establish that APJ stretch transduction is mediated specifically by myocardial APJ, that APJ is necessary for stretch-induced increases in contractility, and that apelin opposes APJ's stretch-mediated hypertrophy signaling by lowering calcium transient while maintaining contractility through myofilament calcium sensitization. These findings underscore apelin's unique potential as a therapeutic agent that can simultaneously support cardiac function and protect against the hypertrophy-heart failure transition.

    View details for PubMedID 29775410

  • Short telomeres - A hallmark of heritable cardiomyopathies DIFFERENTIATION Chang, A. Y., Blau, H. M. 2018; 100: 31–36


    Cardiovascular diseases are the leading cause of death worldwide and the incidence increases with age. Genetic testing has taught us much about the pathogenic pathways that drive heritable cardiomyopathies. Here we discuss an unexpected link between shortened telomeres, a molecular marker of aging, and genetic cardiomyopathy. Positioned at the ends of chromosomes, telomeres are DNA repeats which serve as protective caps that shorten with each cell division in proliferative tissues. Cardiomyocytes are an anomaly, as they are largely non-proliferative post-birth and retain relatively stable telomere lengths throughout life in healthy individuals. However, there is mounting evidence that in disease states, cardiomyocyte telomeres significantly shorten. Moreover, this shortening may play an active role in the development of mitochondrial dysfunction central to the etiology of dilated and hypertrophic cardiomyopathies. Elucidation of the mechanisms that underlie the telomere-mitochondrial signaling axis in the heart will provide fresh insights into our understanding of genetic cardiomyopathies, and could lead to the identification of previously uncharacterized modes of therapeutic intervention.

    View details for PubMedID 29482077

    View details for PubMedCentralID PMC5889329

  • Humanizing the mdx mouse model of DMD: the long and the short of it NPJ REGENERATIVE MEDICINE Yucel, N., Chang, A. C., Day, J. W., Rosenthal, N., Blau, H. M. 2018; 3: 4


    Duchenne muscular dystrophy (DMD) is a common fatal heritable myopathy, with cardiorespiratory failure occurring by the third decade of life. There is no specific treatment for DMD cardiomyopathy, in large part due to a lack of understanding of the mechanisms underlying the cardiac failure. Mdx mice, which have the same dystrophin mutation as human patients, are of limited use, as they do not develop early dilated cardiomyopathy as seen in patients. Here we summarize the usefulness of the various commonly used DMD mouse models, highlight a model with shortened telomeres like humans, and identify directions that warrant further investigation.

    View details for PubMedID 29479480

  • Telomere shortening and metabolic compromise underlie dystrophic cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America Chang, A. C., Ong, S., Lagory, E. L., Kraft, P. E., Giaccia, A. J., Wu, J. C., Blau, H. M. 2016


    Duchenne muscular dystrophy (DMD) is an incurable X-linked genetic disease that is caused by a mutation in the dystrophin gene and affects one in every 3,600 boys. We previously showed that long telomeres protect mice from the lethal cardiac disease seen in humans with the same genetic defect, dystrophin deficiency. By generating the mdx(4cv)/mTR(G2) mouse model with "humanized" telomere lengths, the devastating dilated cardiomyopathy phenotype seen in patients with DMD was recapitulated. Here, we analyze the degenerative sequelae that culminate in heart failure and death in this mouse model. We report progressive telomere shortening in developing mouse cardiomyocytes after postnatal week 1, a time when the cells are no longer dividing. This proliferation-independent telomere shortening is accompanied by an induction of a DNA damage response, evident by p53 activation and increased expression of its target gene p21 in isolated cardiomyocytes. The consequent repression of Pgc1α/β leads to impaired mitochondrial biogenesis, which, in conjunction with the high demands of contraction, leads to increased oxidative stress and decreased mitochondrial membrane potential. As a result, cardiomyocyte respiration and ATP output are severely compromised. Importantly, treatment with a mitochondrial-specific antioxidant before the onset of cardiac dysfunction rescues the metabolic defects. These findings provide evidence for a link between short telomere length and metabolic compromise in the etiology of dilated cardiomyopathy in DMD and identify a window of opportunity for preventive interventions.

    View details for PubMedID 27799523

  • Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity NATURE MEDICINE Burridge, P. W., Li, Y. F., Matsa, E., Wu, H., Ong, S., Sharma, A., Holmstrom, A., Chang, A. C., Coronado, M. J., Ebert, A. D., Knowles, J. W., Telli, M. L., Witteles, R. M., Blau, H. M., Bernstein, D., Altman, R. B., Wu, J. C. 2016; 22 (5): 547-556


    Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.

    View details for DOI 10.1038/nm.4087

    View details for PubMedID 27089514

  • A Notch-dependent transcriptional hierarchy promotes mesenchymal transdifferentiation in the cardiac cushion. Developmental dynamics : an official publication of the American Association of Anatomists Chang, A. C., Garside, V. C., Fournier, M., Smrz, J., Vrljicak, P., Umlandt, P., Fuller, M., Robertson, G., Zhao, Y., Tam, A., Jones, S. J., Marra, M. A., Hoodless, P. A., Karsan, A. 2014


    Background: Valvuloseptal defects are the most common congenital heart defects. Notch signaling induced endothelial-to-mesenchymal-transition (EMT) in the atrioventricular canal (AVC) cushions at murine embryonic day (E)9.5 is a required step during early valve development. Insights to the transcriptional network that is activated in endocardial cells (EC) during EMT and how these pathways direct valve maturation are lacking. Results: We show that in E11.5 AVC-EC retain the ability to undergo Notch-dependent EMT when explanted on collagen. EC-Notch inhibition at E10.5 blocks expression of known mesenchymal genes in E11.5 AVC-EC. To understand the genetic network and AVC development downstream of Notch signaling beyond E9.5, we constructed Tag-Seq libraries corresponding to different cell types of the E11.5 AVC and atrium in wild-type mice and in EC-Notch inhibited mice. We identified 1400 potential Notch targets in the AVC-EC, of which 124 are transcription factors (TF). From the 124 TFs, we constructed a transcriptional hierarchy and identify 10 upstream TFs within the network. Conclusion: We validated 4 of the upstream TFs as Notch targets that are enriched in AVC-EC. Functionally, we show these 4 TFs regulate EMT in AVC explant assays. These novel signaling pathways downstream of Notch are potentially relevant to valve development. Developmental Dynamics, 2014. © 2014 Wiley Periodicals, Inc.

    View details for DOI 10.1002/dvdy.24127

    View details for PubMedID 24633789

  • Notch activation augments nitric oxide/soluble guanylyl cyclase signaling in immortalized ovarian surface epithelial cells and ovarian cancer cells CELLULAR SIGNALLING El-Sehemy, A., Chang, A. C., Azad, A. K., Gupta, N., Xu, Z., Steed, H., Karsan, A., Fu, Y. 2013; 25 (12): 2780-2787


    Nitric oxide (NO) is generated by tumor, stromal and endothelial cells and plays a multifaceted role in tumor biology. Many physiological functions of NO are mediated by soluble guanylyl cyclase (sGC) and NO/sGC signaling has been shown to promote proliferation and survival of ovarian cancer cells. However, how NO/sGC signaling is modulated in ovarian cancer cells has not been studied. The evolutionarily conserved Notch signaling pathway plays an oncogenic role in ovarian cancer. Here, we report that all three ovarian cancer cell lines we examined express a higher level of GUCY1B3 (the β subunit of sGC) compared to non-cancerous immortalized ovarian surface epithelial (IOSE) cell lines. Interestingly, the highest expression of GUCY1B3 in ovarian cancer OVCAR3 cells is concurrent with the expression of Notch3. In IOSE cells, forced activation of Notch3 increases the expression of GUCY1B3, NO-induced cGMP production, and the expression of cGMP-dependent protein kinase (PKG), thereby enhancing NO- and cGMP-induced phosphorylation of vasodilator-stimulated phosphoprotein (VASP, a direct PKG substrate protein). In contrast, inhibition of Notch by DAPT reduces GUCY1B3 expression and NO-induced cGMP production and VASP phosphorylation in OVCAR3 cells. Finally, we confirmed that inhibition of sGC by ODQ decreases growth of ovarian cancer cells. Together, our work demonstrates that Notch is a positive regulator of NO/sGC signaling in IOSE and ovarian cancer cells, providing the first evidence that Notch and NO signaling pathways interact in IOSE and ovarian cancer cells.

    View details for DOI 10.1016/j.cellsig.2013.09.008

    View details for Web of Science ID 000328179800046

    View details for PubMedID 24041655

  • Notch-Dependent Regulation of the Ischemic Vasodilatory Response-Brief Report ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Chang, A. C., Patenaude, A., Lu, K., Fuller, M., Ly, M., Kyle, A., Golbidi, S., Wang, Y., Walley, K., Minchinton, A., Laher, I., Karsan, A. 2013; 33 (3): 510-?


    We have recently described that Notch activates nitric oxide (NO) signaling in the embryonic endocardium. Both Notch signaling and NO signaling have been shown to be important during adult arteriogenesis. Notch has been shown to be required for remodeling of the collateral vessels, whereas NO is required for the initial vasodilatory response to ischemia. Whether Notch also has an impact on the vasodilatory phase of arteriogenesis after ischemia is not known. We tested the hypothesis that endothelial cell-Notch function is required for NO induction and vasodilation, in response to ischemia in the adult vasculature.We observed a significant decrease in NO levels in the dorsal aorta using a mouse model where Notch was inhibited in endothelial cell in a Tet-inducible fashion. In a femoral artery ligation model, inhibition of endothelial cell-Notch reduced reperfusion and NO generation, as quantified by laser Doppler perfusion imaging and by phosphoendothelial NO synthase, nitrotyrosine, and phosphovasodilator-stimulated phosphoprotein staining, respectively.Endothelial Notch activation is required for NO production and reactive vasodilation in a femoral artery ligation model.

    View details for DOI 10.1161/ATVBAHA.112.300840

    View details for Web of Science ID 000314890200015

    View details for PubMedID 23288167

  • Twist1 Transcriptional Targets in the Developing Atrio-Ventricular Canal of the Mouse PLOS ONE Vrljicak, P., Cullum, R., Xu, E., Chang, A. C., Wederell, E. D., Bilenky, M., Jones, S. J., Marra, M. A., Karsan, A., Hoodless, P. A. 2012; 7 (7)


    Malformations of the cardiovascular system are the most common type of birth defect in humans, frequently affecting the formation of valves and septa. During heart valve and septa formation, cells from the atrio-ventricular canal (AVC) and outflow tract (OFT) regions of the heart undergo an epithelial-to-mesenchymal transformation (EMT) and invade the underlying extracellular matrix to give rise to endocardial cushions. Subsequent maturation of newly formed mesenchyme cells leads to thin stress-resistant leaflets. TWIST1 is a basic helix-loop-helix transcription factor expressed in newly formed mesenchyme cells of the AVC and OFT that has been shown to play roles in cell survival, cell proliferation and differentiation. However, the downstream targets of TWIST1 during heart valve formation remain unclear. To identify genes important for heart valve development downstream of TWIST1, we performed global gene expression profiling of AVC, OFT, atria and ventricles of the embryonic day 10.5 mouse heart by tag-sequencing (Tag-seq). Using this resource we identified a novel set of 939 genes, including 123 regulators of transcription, enriched in the valve forming regions of the heart. We compared these genes to a Tag-seq library from the Twist1 null developing valves revealing significant gene expression changes. These changes were consistent with a role of TWIST1 in controlling differentiation of mesenchymal cells following their transformation from endothelium in the mouse. To study the role of TWIST1 at the DNA level we performed chromatin immunoprecipitation and identified novel direct targets of TWIST1 in the developing heart valves. Our findings support a role for TWIST1 in the differentiation of AVC mesenchyme post-EMT in the mouse, and suggest that TWIST1 can exert its function by direct DNA binding to activate valve specific gene expression.

    View details for DOI 10.1371/journal.pone.0040815

    View details for Web of Science ID 000306466100074

    View details for PubMedID 22815831

  • Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development. Cellular and molecular life sciences : CMLS Garside, V. C., Chang, A. C., Karsan, A., Hoodless, P. A. 2012


    Congenital heart defects affect approximately 1-5 % of human newborns each year, and of these cardiac defects 20-30 % are due to heart valve abnormalities. Recent literature indicates that the key factors and pathways that regulate valve development are also implicated in congenital heart defects and valve disease. Currently, there are limited options for treatment of valve disease, and therefore having a better understanding of valve development can contribute critical insight into congenital valve defects and disease. There are three major signaling pathways required for early specification and initiation of endothelial-to-mesenchymal transformation (EMT) in the cardiac cushions: BMP, TGF-β, and Notch signaling. BMPs secreted from the myocardium set up the environment for the overlying endocardium to become activated; Notch signaling initiates EMT; and both BMP and TGF-β signaling synergize with Notch to promote the transition of endothelia to mesenchyme and the mesenchymal cell invasiveness. Together, these three essential signaling pathways help form the cardiac cushions and populate them with mesenchyme and, consequently, set off the cascade of events required to develop mature heart valves. Furthermore, integration and cross-talk between these pathways generate highly stratified and delicate valve leaflets and septa of the heart. Here, we discuss BMP, TGF-β, and Notch signaling pathways during mouse cardiac cushion formation and how they together produce a coordinated EMT response in the developing mouse valves.

    View details for DOI 10.1007/s00018-012-1197-9

    View details for PubMedID 23161060

  • Notch Initiates the Endothelial-to-Mesenchymal Transition in the Atrioventricular Canal through Autocrine Activation of Soluble Guanylyl Cyclase DEVELOPMENTAL CELL Chang, A. C., Fu, Y., Garside, V. C., Niessen, K., Chang, L., Fuller, M., Setiadi, A., Smrz, J., Kyle, A., Minchinton, A., Marra, M., Hoodless, P. A., Karsan, A. 2011; 21 (2): 288-300


    The heart is the most common site of congenital defects, and valvuloseptal defects are the most common of the cardiac anomalies seen in the newborn. The process of endothelial-to-mesenchymal transition (EndMT) in the cardiac cushions is a required step during early valve development, and Notch signaling is required for this process. Here we show that Notch activation induces the transcription of both subunits of the soluble guanylyl cyclase (sGC) heterodimer, GUCY1A3 and GUCY1B3, which form the nitric oxide receptor. In parallel, Notch also promotes nitric oxide (NO) production by inducing Activin A, thereby activating a PI3-kinase/Akt pathway to phosphorylate eNOS. We thus show that the activation of sGC by NO through a Notch-dependent autocrine loop is necessary to drive early EndMT in the developing atrioventricular canal (AVC).

    View details for DOI 10.1016/j.devcel.2011.06.022

    View details for Web of Science ID 000294387300010

    View details for PubMedID 21839921

  • RUNX3 Maintains the Mesenchymal Phenotype after Termination of the Notch Signal JOURNAL OF BIOLOGICAL CHEMISTRY Fu, Y., Chang, A. C., Fournier, M., Chang, L., Niessen, K., Karsan, A. 2011; 286 (13): 11803-11813


    Notch is a critical mediator of endothelial-to-mesenchymal transition (EndMT) during cardiac cushion development. Slug, a transcriptional repressor that is a Notch target, is an important Notch effector of EndMT in the cardiac cushion. Here, we report that the runt-related transcription factor RUNX3 is a novel direct Notch target in the endothelium. Ectopic expression of RUNX3 in endothelium induces Slug expression and EndMT independent of Notch activation. Interestingly, RUNX3 physically interacts with CSL, the Notch-interacting partner in the nucleus, and induces Slug in a CSL-dependent, but Notch-independent manner. Although RUNX3 may not be required for the initial induction of Slug and EndMT by Notch, because RUNX3 has a much longer half-life than Slug, it sustains the expression of Slug thereby maintaining the mesenchymal phenotype. CSL binds to the Runx3 promoter in the atrioventricular canal in vivo, and inhibition of Notch reduces RUNX3 expression in the cardiac cushion of embryonic hearts. Taken together, our results suggest that induction of RUNX3 may be a mechanism to maintain Notch-transformed mesenchymal cells during heart development.

    View details for DOI 10.1074/jbc.M111.222331

    View details for Web of Science ID 000288797100087

    View details for PubMedID 21288908

  • Genomic analysis distinguishes phases of early development of the mouse atrio-ventricular canal PHYSIOLOGICAL GENOMICS Vrljicak, P., Chang, A. C., Morozova, O., Wederell, E. D., Niessen, K., Marra, M. A., Karsan, A., Hoodless, P. A. 2010; 40 (3): 150-157


    Valve formation during embryonic heart development involves a complex interplay of regional specification, cell transformations, and remodeling events. While many studies have addressed the role of specific genes during this process, a global understanding of the genetic basis for the regional specification and development of the heart valves is incomplete. We have undertaken genome-wide transcriptional profiling of the developing heart valves in the mouse. Four Serial Analysis of Gene Expression libraries were generated and analyzed from the mouse atrio-ventricular canal (AVC) at embryonic days 9.5-12.5, covering the stages from initiation of endothelial to mesenchymal transition (EMT) through to the beginning of endocardial cushion remodeling. We identified 14 distinct temporal patterns of gene expression during AVC development. These were associated with specific functions and signaling pathway members. We defined the temporal distribution of mesenchyme genes during the EMT process and of specific Notch and transforming growth factor-beta targets. This work provides the first comprehensive temporal dataset during the formation of heart valves. These results identify molecular signatures that distinguish different phases of early heart valve formation allowing gene expression and function to be further investigated.

    View details for DOI 10.1152/physiolgenomics.00142.2009

    View details for Web of Science ID 000274287000004

    View details for PubMedID 19952280

  • Differential Regulation of Transforming Growth Factor beta Signaling Pathways by Notch in Human Endothelial Cells JOURNAL OF BIOLOGICAL CHEMISTRY Fu, Y., Chang, A., Chang, L., Niessen, K., Eapen, S., Setiadi, A., Karsan, A. 2009; 284 (29): 19452-19462


    Notch and transforming growth factor beta (TGFbeta) play critical roles in endothelial-to-mesenchymal transition (EndMT), a process that is essential for heart development. Previously, we have shown that Notch and TGFbeta signaling synergistically induce Snail expression in endothelial cells, which is required for EndMT in cardiac cushion morphogenesis. Here, we report that Notch activation modulates TGFbeta signaling pathways in a receptor-activated Smad (R-Smad)-specific manner. Notch activation inhibits TGFbeta/Smad1 and TGFbeta/Smad2 signaling pathways by decreasing the expression of Smad1 and Smad2 and their target genes. In contrast, Notch increases SMAD3 mRNA expression and protein half-life and regulates the expression of TGFbeta/Smad3 target genes in a gene-specific manner. Inhibition of Notch in the cardiac cushion of mouse embryonic hearts reduces Smad3 expression. Notch and TGFbeta synergistically up-regulate a subset of genes by recruiting Smad3 to both Smad and CSL binding sites and cooperatively inducing histone H4 acetylation. This is the first evidence that Notch activation affects R-Smad expression and that cooperative induction of histone acetylation at specific promoters underlies the selective synergy between Notch and TGFbeta signaling pathways.

    View details for DOI 10.1074/jbc.M109.011833

    View details for Web of Science ID 000267908300037

    View details for PubMedID 19473993

  • Probing the structure and function of an archaeal C/D-box methylation guide sRNA RNA-A PUBLICATION OF THE RNA SOCIETY Omer, A. D., Zago, M., Chang, A., Dennis, P. P. 2006; 12 (9): 1708-1720


    The genome of the hyperthermophilic archaeon Sulfolobus solfataricus contains dozens of small C/D-box sRNAs that use a complementary guide sequence to target 2'-O-ribose methylation to specific locations within ribosomal and transfer RNAs. The sRNAs are approximately 50-60 nucleotides in length and contain two RNA structural kink-turn (K-turn) motifs that are required for assembly with ribosomal protein L7Ae, Nop5, and fibrillarin to form an active ribonucleoprotein (RNP) particle. The complex catalyzes guide-directed methylation to target RNAs. Earlier work in our laboratory has characterized the assembly pathway and methylation reaction using the model sR1 sRNA from Sulfolobus acidocaldarius. This sRNA contains only one antisense region situated adjacent to the D-box, and methylation is directed to position U52 in 16S rRNA. Here we have investigated through RNA mutagenesis, the relationship between the sR1 structure and methylation-guide function. We show that although full activity of the guide requires intact C/D and C'/D' K-turn motifs, each structure plays a distinct role in the methylation reaction. The C/D motif is directly implicated in the methylation function, whereas the C'/D' element appears to play an indirect structural role by facilitating the correct folding of the RNA. Our results suggest that L7Ae facilitates the folding of the K-turn motifs (chaperone function) and, in addition, is required for methylation activity in the presence of Nop5 and Fib.

    View details for DOI 10.1261/rna.31506

    View details for Web of Science ID 000240145400012

    View details for PubMedID 16861619

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