Ching-Pin Chang Laboratory

Research in the CP Chang Laboratory, led by Ching-Pin Chang, MD, PhD, focuses on defining the molecular mechanisms underlying cardiomyopathy and heart failure and is establishing an epigenetic framework within which cardiac stress activates epigenomic changes in the heart to reprogram cardiac gene expression, causing cardiomyopathy. This group of medical scientists also committed to translating bench findings to clinical applications.

Achievements

Researchers in the CP Chang Laboratory have identified several new chromatin regulators that are stress-regulated to control cardiac hypertrophy and failure. These regulators include chromatin-remodeling factors, histone and DNA modifying enzymes, transcription co-factors, microRNA and long non-coding RNA (LncRNA). Understanding the epigenetic mechanisms that underlie heart failure will facilitate drug discovery process and the development of epigenetic therapy for heart failure.

The lab’s scientists have also generated mouse models of cardiomyopathy and models that allow researchers to study the repair mechanisms of vascular injury in adults.

Active Research

The Chang Lab focuses on the mechanisms of cardiovascular development, particularly the interaction between the three major types of cardiac cells (endocardial, myocardial and epicardial cells) and neural crest cells to generate heart tissues. Researchers in the lab are interested in transcriptional and signaling events that coordinate their interactions and assembly into heart tissues. The long-term goal is to understand the developmental mechanisms that control tissue formation and recapitulate the developmental processes for therapeutic or regenerative purposes. The laboratory aims to apply lessons learned from developmental studies to investigate the mechanisms of adult diseases.

Using pharmacological inhibitors, tissue-specific gene disruption and conventional gene knockout in mice, researchers in the lab have demonstrated that calcineurin/NFAT signaling plays two sequential and critical roles in the initiation and propagation of heart valve morphogenesis. The initiation of valve formation requires myocardial NFAT to repress the expression of VEGF (vascular endothelial growth factor). The interaction of VEGF with NFAT signaling during valve formation, and the molecular mechanism of NFAT-mediated VEGF repression are being studied.

Using tissue-specific gene knockout technology in mice, researchers in Chang Lab have generated mouse lines deficient in endocardial transcription factors or chromatin remodeling molecules. One of the mutant lines develops abnormal myocardial growth and trabeculation. These observations suggest that endocardial factors are required for myocardial development. Researchers are studying the molecular and cellular mechanisms of how endocardial cells control myocardial development. The lab has generated several mouse lines lacking myocardial or epicardial transcription factors or chromatin remodeling molecules. These mice fail to form mature myocardium, interventricular septum or coronary arteries. The molecular basis of these cardiac and vascular defects are being investigated.

Using compound gene mutations in mice, researchers in the lab have demonstrated that Pbx gene family members (homeodomain proto-oncogenes) are essential for the patterning of cardiac outflow tracts and great arteries. The molecular pathways controlled by Pbx genes during cardiac development are also being investigated.

The Chang Lab has generated a mouse model of cardiomyopathy and a mouse model that allows studying the signaling events during the repair process following vascular injury such as balloon angioplasty. These models are directly relevant to a specific type of human congestive heart failure and the restenosis following angioplasty and stenting seen in clinical cardiology. The pathogenesis of cardiomyopathy and the mechanisms of vascular restenosis following injury are being studied.

Chang Lab Publications

Selected peer-reviewed publications as well as reviews and book chapters from the CP Chang laboratory are listed below.

Stankunas K, Hang C, Tsun ZY, Chen H, , Lee NV, Wu J, Shing C, Baylor JH, Shou W, Iruela-Arispe L, Chang CP.  Endocardial Brg1 represses ADAMTS1 proteases to maintain the microenvronment for myocardial morphogenesis.  Dev. Cell 2008; 14(2):298-311.

Bajpai R, Chen DA, Rada-Iglesias A, Zhang J, Xiong Y, Helms J, Chang CP, Zhao Y, Swigut T, Wysocka J.  CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature 2010 ;463(7283):958-962

Hang C, Yang J, Han P, Cheng HL, Ashley E, Zhou B, Chang CP. Chromatin regulation by Brg1 underlies heart muscle development and disease. Nature 2010; 466(7302): 62-67

Han P, Hang CT, Yang J, Chang CP. Chromatin remodeling in cardiovascular development and physiology, Circulation Research 2011; 108: 378-96

Chang CP and Bruneau B. Epigenetics and cardiovascular development. Annual Review of Physiology 2012; 74:13.1–13.28

Li W, Xiong Y, Shang C, Twu K, Hang C, Yang J, Han P, Tsai FC, Stankunas K, Meyer T, Bernstein D, Pan M, Chang CP. Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development. Proc Natl Acad Sci 2013; 110 (5): 1738-43. [CHARGE Syndrome Foundation Highlight]

Xiong Y, Li W, Shang C, Chen RM, Han P, Yang J, Stankunas K, Wu B, Pan MG, Zhou B, Longaker MT, Chang CP. Brg1 governs a positive feedback circuit in the hair follicle for tissue regeneration and repair. Dev Cell 2013; 25(2):169-81. Commentary: Mesa KR and Greco V. Linking Morphogen and Chromatin in the hair follicle. Dev Cell 2013; 25(2):113-14

Frey JL, Brady CA, Jung H, Fuentes DR, Kozak MM, Johnson TM, Lin CY, Lin CJ, Swiderski DL, Vogel H, Bernstein JA, Attié-Bitach T, Chang CP, Wysocka J, Martin DM, Attardi LD. Inappropriate p53 activation during development induces features of CHARGE syndrome. Nature 2014 doi: 10.1038/nature13585

Han P, Li W, Lin CH, Yang J, Chang C, Jin KK, Xu W, Yang J, Lin CY, Lin CJ, Xiong Y, Zhou Bin, Ashley E, Chen V, Chen PS, Quertermous T. Chang CP. A long non-coding RNA protects the heart from pathological hypertrophy.  Nature 2014; 514(7520):102-6

Chang CP, Neilson JR, Bayle JH, Gestwicki JE, Kuo A, Graef  IA, Crabtree GR. A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis.  Cell 2004 ;118, 649-663. Cover story. Editorial commentary: Carmeliet P.  Sculpting heart valves with NFAT and VEGF. Cell 2004 118, 532-534.

Arron J, Winslow M, Polleri A, Chang CP, Wu H, Gao X, Neilson J, Chen L, Heit J, Kim S, Yamasaki N, Miyakawa T, Francke U, Graef I, Crabtree G.  NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 2006 ;441(7093):595-600

Wu H, Kao SC, Barriantos T, Baldwin S, Olson E, Crabtree GR, Zhou, B, Chang CP.  DSCR1 is a transcriptional target of NFATc1 within the endocardium during heart development.  J Biological Chemistry 2007;282(42):30673-9.

Jia Q, McDill BW, Li S, Deng C, Chang CP, Chen F. Smad signaling in the neural crest regulates the cardiac outflow tract remodeling through cell autonomous and non-cell autonomous effects. Developmental Biology  2007; 311(1): 172-84

El-Bizri N,  Guignabert C, Wang L,  Cheng A, Stankunas K, Desai K,  Chang CP, Helms J, Mishina Y,  Rabinovitch M.  SM22alpha-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development, and influences organogenesis.  Development 2008,135 (17):2981-91.

Stankunas K, Shang C, Twu KY, Kao SC, Jekins NA, Copeland N, Sanyal M, Selleri L, Cleary ML, Chang CP.  Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease.  Circulation Research 2008;103:702-709 Cover story.

Chang CP*, Stankunas K, Shang C, Kao SC, Twu KY, Cleary ML.  Pbx1 functions in distinct regulatory networks to pattern the great arteries and cardiac outflow tract. * Corresponding author.  Development 2008;135(21):3577-86.

Zeini M, Hang CT, Lehrer-Graiwer J, Zhou B, Chang CP.  Spatial and temporal regulation of coronary vessel formation by calcineurin/NFAT signaling. Development 2009;136 (19), 3335-3345.

Wu B, Zhou B, Wang Y, Cheng HL, Hang C, Pu WT, Chang CP, Zhou B. Inducible cardiomyocyte-specific gene disruption directed by the rat Tnnt2 promoter in the mouse. Genesis 2009; 48, 63-72

Stankunas K, Ma G, Kuhnert F, Kuo CJ, Chang CP. VEGF signaling has distinct spatiotemporal roles during heart valve development. Developmental Biology 2010;347(2):325-36.

Lin CY, Lin CJ, Chen CH, Chen RM, Zhou B, Chang CP. The secondary heart field is a new site of calcineurin/Nfatc1 signaling for semilunar valve development. J Mol Cell Cardiology 2012; 52(5): 1096

Lin CJ, Lin CY, Chen CH, Zhou B, Chang CP. Partitioning of the heart: mechanism of cardiac septation and valve development. Development 2012; 139 (18): 3277-99

Wu B, Zhang Z, Lui W, Chen X, Wang Y, Chamberlain A, Moreno-Rodriquez RA, Markwald RR, O’Rourke RP, Sharp DJ, Zheng D, Lenz J, Baldwin HS, Chang CP, Zhou B. Endocardial Cells Form Coronary Arteries by Angiogenesis through Myocardial to Endocardial VEGF Signaling. Cell 2012; 1083-1096.

Zhang W, Chen H, *Chang CP, *Shou W. Molecular mechanism of ventricular trabeculation/compaction and the pathogenesis of the left ventricular noncompaction cardiomyopathy. Seminars in Medical Genetics, American Journal of Medical Genetics, 2013 Aug;163(3):144-56] *: corresponding author

Yang J, Zeini M, Lin CY, Lin CJ, Xiong Y, Shang C, Han P, Li W, Quertermous T, Zhou B, Chang CP. Epicardial calcineurin–NFAT signals through Smad2 to direct coronary smooth muscle cell and arterial wall development. Cardiovascular Research 2014;101(1):120-9

Karpinski SV, Kornyeyev D., El-Bizri N., Budas G, Fan P, Jiang Z, Yang J, Anderson ME, Shryock JC, Chang CP, Belardinelli L, Yao L. Intracellular Na overload causes oxidation of CaMKII and leads to Ca mishandling in isolated ventricular myocytes. J Mol Cell Cardiology 2014; 76: 247-256

Wu SP, Kao CY, Wang L, Creighton C, Yang J, Donti T, Harmancey R, Vasquez HG, Graham B, Bellen   H, Taegtmeyer H, Chang CP, Tsai MJ, and Tsai S. Increased COUP-TFII Expression in Adult Hearts Induces Mitochondrial Dysfunction Resulting in Heart Failure. Nature Comm. 2015 in press

Chang CP, Shen WF, Rozenfeld S, Lawrence HJ, Largman C, Cleary ML.  Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins.  Genes and Development 1995; 9(6):663-74

Shen WF, Chang CP, Rozenfeld S, Lawrence HJ, Cleary ML, Largman C.  Hox Homeodomain Proteins Exhibit Selective Complex Stability with Pbx and DNA.”  Nucleic Acids Research, 1996, Vol.24, No. 5, 898

Chang CP, Luciano Brocchieri, Shen WF, Largman C, Cleary ML.  Pbx modulation of Hox homeodomain N- terminal arms establishes a gradient of DNA-binding specificities across the Hox locus.  Molecular and Cellular Biology 1996; 16: 1734-1745

Smith KS, Jacobs Y, Chang CP, Cleary ML.  Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2.” Oncogene 1997; 14 (24): 2917-26

Chang CP, De Vivo I, Cleary ML.  The Hox cooperativity motif of chimeric oncoprotein E2a-Pbx1 is necessary and sufficient for oncogenesis.  Molecular and Cellular Biology 1997; 17(1): 81-88

Chang CP, Jacobs Y, Nakamura T, Jenkins NA, Copeland NG, Cleary ML.  Meis proteins are major In   vivo DNA binding partners for wild-type but not chimeric Pbx proteins.  Molecular and Cellular Biology 1997; 17 (10): 5679-5687.

Derek P, Batchelor A, Chang CP, Cleary ML, and Wolberger, C.  Crystal structure of a HoxB1-Pbx1a heterodimer bound to DNA:  Role of the hexapeptide and a fourth homeodomain helix in complex formation.” Cell 1999; 96, 587-597

Chang CP, McDill BW, Neilson JR, Joist HE, Epstein JA, Crabtree GR, Chen F.  Calcineurin is required in the urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery.  J Clin Invest 2004;113(7):1051-8.  Editorial commentary: Mendelsohn C.  Functional obstruction: the renal pelvis rules.  J Clin Invest 2004;113(7): 957-959.

Kao SC, Wu H, Xie J, Chang CP, Ranish JA, Graef IA, Crabtree GR.  Calcineurin/NFAT signaling is required for neuregulin-regulated schwann cell differentiation.  Science 2009;323(5914):651-4.

Koss M, Bolze A, Brendolan A, Saggese M, Capellini TD, Bojilova E, Boisson B, Prall OW, Elliott DA, Solloway M, Lenti E, Hidaka C, Chang CP, Mahlaoui N, Harvey RP, Casanova JL, Selleri L. Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 Module. <;Dev Cell 2012; 22(5):913-26

Li W, Lin CY, Shang C, Han P, Xiong Y, Lin CJ, Yang J, Selleri L, Chang CP. Pbx1 activates Fgf10 in the mesenchyme of developing lungs. Genesis 2014; 52(5):399-407

Sheikh AY, Lin SA, Cao F, Cao YA, van der Bogt KE, Chu P, Chang CP, Contag CH, Robbins RC, Wu JC.  Molecular imaging of bone marrow mononuclear cell homing and engraftment in ischemic myocardium.  Stem Cells 2007;25(10):2677-2684.

Kofidis T, de Bruin JL, Hoyt G, Ho Y, Tanaka M, Yamane T, Lebl DR, Swijnenburg RJ, Chang CP, Quertermous T, Robbins RC.  Myocardial restoration with embryonic stem cell bioartificial tissue transplantation. J Heart Lung Transplant 2005;24(6):737-744.

Kofidis T, de Bruin JL, Hoyt G, Lebl DR, Tanaka M, Yamane T, Chang CP, Robbins RC.  Injectable bioartificial myocardial tissue for large-scale intramural cell transfer and functional recovery of injured heart muscle. J Thorac Cardiovasc Surg. 2004;128(4): 571-8

Pelletier MP, Chang CP, Vagelos R, Robbins RC. Alternative approach for use of a left ventricular assist device with a thrombosed prosthetic valve.  J Heart Lung Transplant 2002; 21(3):402-404.

Rugolotto M, Chang CP, Hu B, Schnittger I, Liang DH.  Clinical use of cardiac ultrasound performed with a hand-carried device in patients admitted for acute cardiac care.  Am J Cardiol 2002;90(9):1040-1042.

Lieber MR, Chang CP, Gallo M, Gauss G, Gerstein R, Islas A.  The mechanism of V(D)J recombination:  site-specificity, reaction fidelity, and immunologic diversity.  Semin Immunol 1994;6(3):143-153.

Chang CP, Chen L, Crabtree GR.  Sonographic staging of the developmental status of mouse embryos in utero.  Genesis 2003;36(1):7-11.

Xiong Y, Zhou B, Chang CP.  Analysis of the endocardial-to-mesenchymal transformation of heart valve development by a collagen gel culture assay.  Methods in Molecular Biology:  Cardiovascular Development 2012; 843:21-8

Hang C, Chang CP. Whole embryo culture for heart development studies. Methods in Molecular Biology:  Cardiovascular Development 2012; 843:3-9

Chang CP. Analysis of the patterning of great arteries with angiography and vascular casting.  Methods in Molecular Biology:  Cardiovascular Development 2012; 843:101-9

Wu SP, Kao CY, Wang L, Creighton C, Yang J, Donti T, Harmancey R, Vasquez HG, Graham B, Bellen   H, Taegtmeyer H, Chang CP, Tsai MJ, and Tsai S. Increased COUP-TFII Expression in Adult Hearts Induces Mitochondrial Dysfunction Resulting in Heart Failure. Nature Comm. 2015 in press

Jin Yang, Konstantinos Savvatis, Jong Seok Kang, Peidong Fan, Hongyan Zhong, Karen Schwartz, Vivian Barry, Amanda Mikels-Vigdal, Serge Karpinski, Dmytro Kornyeyev, Joanne Adamkewicz, Xuhui Feng, Qiong Zhou, Ching Shang, Praveen Kumar, Dillon Phan, Mario Kasner, Begoña López, Javier Diez, Keith C. Wright, Roxanne L. Kovac, Peng-Sheng Chen, Thomas Quertermous, Victoria Smith, Lina Yao, Carsten Tschöpe, Ching-Pin Chang. Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nature Communications. 2016, Dec 14;7:13710. doi: 10.1038/ncomms13710.

Jin Yang, Xuhui Feng, Qiong Zhou, Wei Cheng, Ching Shang, Pei Han, Chiou-Hong Lin, Huei-Sheng Vincent Chen, Thomas Quertermous, Ching-Pin Chang. Endothelial Brg1-FoxM1 chromatin complex transmits cardiac stress to trigger pathological Ace/Ace2 switch and cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America. 2016.9; doi: 10.1073/pnas.1525078113.

Han P, Li W, Yang J, Shang C, Bernstein D, Chen HS, Quertermous T and Chang CP. Assembly of BRG1–G9a/GLP–DNMT3 repressive chromatin complex on Myh6 in pathologically stressed hearts. BBA Molecular Cell Research, 2016 Jul;1863(7 Pt B):1772-81.

Han P, Hang CT, Yang J, Chang CP. Chromatin remodeling in cardiovascular development and physiology, Circulation Research 2011; 108: 378-96

Chang CP and Bruneau B. Epigenetics and cardiovascular development. Annual Review of Physiology 2012; 74:13.1–13.28

Lin CJ, Lin CY, Chen CH, Zhou B, Chang CP. Partitioning of the heart: mechanism of cardiac septation and valve development. Development 2012; 139 (18): 3277-99

Zhang W, Chen H, *Chang CP, *Shou W. Molecular mechanism of ventricular trabeculation/compaction and the pathogenesis of the left ventricular noncompaction cardiomyopathy. Seminars in Medical Genetics, American Journal of Medical Genetics, 2013 Aug;163(3):144-56] *: corresponding author

Xiong Y, Zhou B, Chang CP.  Analysis of the endocardial-to-mesenchymal transformation of heart valve development by a collagen gel culture assay. Methods in Molecular Biology:  Cardiovascular Development 2012; 843:21-8

Hang C, Chang CP. Whole embryo culture for heart development studies. Methods in Molecular Biology:  Cardiovascular Development 2012; 843:3-9

Chang CP. Analysis of the patterning of great arteries with angiography and vascular casting. Methods in Molecular Biology:  Cardiovascular Development 2012; 843:101-9

Han P and Chang CP. Myheart hits the core of chromatin. Cell Cycle 2015;14(6):787-8 [Featured Article]

Devaux Y, Zangrando J, Schroen B, Creemers EE, Pedrazzini T, Chang CP, Dorn II GW, Thum T, Heymans S. Long noncoding RNAs in cardiac development and ageing. Nature Reviews Cardiology 2015 Apr 7. doi: 10.1038/nrcardio.2015.55. [Epub ahead of print]

Han P and Chang CP. Long non-coding RNA and Chromatin Remodeling. RNA Bio. 2015 Jul 15:0. [Epub ahead of print]

Han P, Yang J, Shang C, Chang CP. Chromatin Remodeling in Heart Failure. Cardiac and Vascular Biology: Epigenetics in Cardiac Disease, pp 103-124. Springer. 2016, November 22.

Chang Lab Faculty Researchers

Ching-Pin Chang, MD, PhD

Ching-Pin Chang, MD, PhD

Associate Professor of Medicine
Jin Yang, PhD

Jin Yang, PhD

Adjunct Assistant Research Professor of Medicine