Relevant Degree Programs
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Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Mar 2019)
Cardiac malformations affect approximately 1% of human newborns and a large number of these are due to defects in the heart valves and septum. It has been suggested that cardiac valve diseases, which make up about one third of all cardiovascular defects, arise from underlying developmental malformations that occur during embryogenesis. Interestingly, the development of the heart valves (cardiac cushions) and tissues that form cartilage templates (such as the limb) share a number of key TFs, such as TWIST1, SOX9, and NFATC1 suggesting that they have similar transcriptional programs. It has been proposed that regulatory networks involved in cartilage formation, are also active during valve development and disease. The transcription factor SOX9 has an essential role in heart valve and cartilage formation and its loss leads to major congenital abnormalities in the embryo. Regardless of this critical role, little is known about how SOX9 regulates heart valve development or its transcriptional targets. Therefore, to identify transcriptional targets of SOX9 and elucidate the role of SOX9 in the developing valves, we have used ChIP-Seq on the E12.5 atrioventricular canal (heart valves) and limb buds. Comparisons of SOX9DNA-binding regions among tissues revealed both context-dependent and context–independent SOX9 interacting regions. Context-independent SOX9 binding suggests that SOX9 may play a role in regulating proliferation-associated genes across many tissues. Generation of two endothelial specific Sox9 mutants uncovers two potential roles for SOX9 in heart valve formation: first in the initial formation of valve mesenchyme and later in the survival and differentiation of valve mesenchyme. Analysis of tissue-specific SOX9-DNA binding regions with gene expression profiles from Sox9 mutant heart valves indicates that SOX9 directly regulates a collection of transcription factors known to be important for heart development. Taken together, this study identified that SOX9 controls transcriptional hierarchies involved in proliferation across tissues and heart valve differentiation. SOX9 transcriptional targets identified in this data could be used as predictive factors of heart valve disease, or as targets for new therapeutic strategies for disease and congenital defects.
No abstract available.
Malformations of the cardiovascular system are the most common type of birth defect in humans, affecting predominantly the formation of valves and septa. While many studies have addressed the role of specific genes during valve and septa formation, a global understanding is still largely incomplete. To address this deficit we have undertaken a genome-wide transcriptional profiling of the developing heart in the mouse. We generated and analyzed 19 Serial Analysis of Gene Expression (SAGE) libraries representing different regions of the mouse heart at multiple stages of embryonic development.We speculated that genes important for heart valve development would be differentially expressed in the valve forming regions, and have dynamic temporal expression patterns. We used our dataset to identify a novel list of valve enriched genes. Using k-means cluster analysis we also uncovered 14 distinct temporal gene expression patterns in the developing valves. Unique temporal expression patterns were found to be enriched for specific signalling pathway members and functional categories such as signal transduction, transcription factor activity, proliferation and apoptosis. The most highly expressed transcription factor within the developing valves was found to be Twist1. Analysis of gene expression changes in the Twist1 null developing valves revealed a novel phenotype consistent with a role of TWIST1 in controlling differentiation of mesenchymal cells following their transformation from endothelium in the mouse. Our data suggests that TWIST1 directly activates valve specific and cell motility gene expression in the atrio-ventricular canal, while suppressing expression of valve maturation markers. This work provides the first comprehensive temporal and spatial gene expression dataset for heart development during formation of the heart valves. It is a valuable resource for the elucidation of the molecular mechanisms underlying heart development.
No abstract available.
Master's Student Supervision (2010-2017)
Development and maintenance of the hepatic phenotype is a tightly controlled process regulated by both master regulatory transcription factors and signaling pathways. Perturbations in these transcriptional networks are frequently seen in diseases such as liver cancer. The Hippo signaling pathway has been implicated in regulation of liver size and dysregulation of this pathway contributes to tumorigenesis. The primary mechanism of action of the Hippo pathway is to inhibit nuclear localization of the transcriptional co-regulator YAP, and thereby preventing YAP from binding to the TEAD family of transcription factors. Although it has been established that YAP plays a role in promoting cell proliferation, how it regulates its transcriptional targets in the liver have yet to be well-characterized. In this study, I show that YAP-overexpression in the adult mouse liver results in a shift from a mature hepatocyte to a hepatic progenitor-like gene expression pattern. Comparison of differentially expressed genes by RNA-seq revealed downregulation of hepatocyte metabolism genes and re-expression of hepatoblast genes, including Glypican-3 (Gpc3). Analysis of ChIP-seq data from both mouse liver and the human hepatoma cell line, HepG2, identified putative Gpc3 enhancers regulated by TEAD and HNF4a. I interrogated these regions using luciferase assays and identified important TEAD and HNF4a binding motifs necessary for transcriptional regulation. In addition, pathway analysis identified enrichment of the ERBB signaling pathway in the YAP-overexpressing liver. Examination of individual ERBB receptors identified upregulation of Her2 (Erbb2), which is normally enriched in hepatoblasts compared to hepatocytes. Analysis of HepG2 ChIP-seq data revealed a TEAD peak at the HER2 promoter. Using luciferase assays, I identified an important TEAD binding site contributing to transcriptional activity. Functionally, I found YAP to regulate EGF-induced HepG2 cell proliferation and PI3K-AKT signaling. This work explored novel mechanisms of gene regulation by YAP in the liver., I found that YAP activation results in re-expression of hepatic progenitor genes such as Gpc3 and Her2. Furthermore, I found the ERBB signaling pathway to be an important growth mediator downstream of YAP.
Apela, a novel gene identified by our laboratory, is expressed in mouse definitive endoderm, neural tube, and mouse embryonic stem cells (mESCs). In humans, APELA is expressed in embryonic stem cells, induced adult pluripotent stem cells (iPSCs) as well as adult kidney and prostate. APELA peptide signals through the G-protein coupled receptor, the APJ receptor, to regulate zebrafish definitive endoderm migration and cardiac development. Interestingly, the mRNA of Apela can mediate p53-dependent mESCs cell apoptosis. These findings suggest that Apela can functions as a peptide or as a lncRNA. Signaling pathways that are critical during embryogenesis are also important in cancer development and progression. However, thus far, whether APELA exerts any biological functions that regulate cancer progression is completely unknown. In this study, analysis of the cancer genome atlas (TCGA) RNA sequencing datasets reveals that APELA mRNA is expressed in different human cancer including in ovarian cancer. Real-time quantitative PCR analyses of clinical human ovarian cancer samples show that APELA mRNA levels are higher in ovarian clear cell carcinoma (OCCC), than other subtypes. Using a CRISPR/Cas9-mediated knockout approach, I have demonstrated that APELA knockout suppresses cell growth in the ovarian clear cell carcinoma cell line, OVISE. Decreased cell growth induced by APELA knockout can be partially attenuated by treating cells with recombinant human APELA protein. In addition, flow cytometry analyses show that APELA knockout induces G2/M phase arrest in OVISE cells. Western blot results show that the phosphorylation levels of ERK1/2, AKT, and cyclin B1 expression levels are significantly down-regulated in the APELA deficient OVISE cells. Moreover, our results indicate that in the APELA knockout cells, decreased cell growth is dependent on the expression of wildtype p53. Unexpectedly, knockout APELA does not affect cell growth in Ewing sarcoma cell line A673, which has high expression of APELA at mRNA level. Interestingly, the APJ receptor is expressed in A673 cells but not in OVISE cells, which strongly suggests that APELA can exert its function through APJ-independent pathway in OVISE cells. In summary, our study demonstrates that APLEA may be an important factor that mediates the progression of OCCC.
- Endothelial Sash1 Is Required for Lung Maturation through Nitric Oxide Signaling (2019)
Cell Reports, 27 (6), 1769-1780.e4
- Hepatocyte Nuclear Factor 4-Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019)
- Repressive Epigenetic Signatures Safeguard the Liver (2019)
Developmental Cell, 50 (1), 3-4
- The emergent landscape of the mouse gut endoderm at single-cell resolution (2019)
Nature, 569 (7756), 361-367
- Expression patterns of Yes-associated protein 1 in the developing mouse liver (2018)
Gene Expression Patterns, 29, 10-17
- S1P stimulates proliferation by upregulating CTGF expression through S1PR2-mediated YAP activation (2018)
Molecular Cancer Research, 16 (10), 1543-1555
- YAP transcriptionally regulates ErbB2 to promote liver cell proliferation (2018)
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1861 (9), 854-863
- APELA promotes tumour growth and cell migration in ovarian cancer in a p53-dependent manner (2017)
Gynecologic Oncology, 147 (3), 663-671
- Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives (2017)
Cell Reports, 20 (9), 2116-2130
- The role of the innate immune response regulatory gene ABCF1 in mammalian embryogenesis and development (2017)
PLoS ONE, 12 (5)
- Huntingtin interacting proteins 14 and 14-like are required for chorioallantoic fusion during early placental development (2015)
Developmental Biology, 397 (2), 257-266
- MEF2B mutations in non-Hodgkin lymphoma dysregulate cell migration by decreasing MEF2B target gene activation (2015)
Nature Communications, 6
- SOX9 modulates the expression of key transcription factors required for heart valve development (2015)
Development (Cambridge), 142 (24), 4340-4350
- A Notch-dependent transcriptional hierarchy promotes mesenchymal transdifferentiation in the cardiac cushion (2014)
Developmental Dynamics, 243 (7), 894-905
- A regulatory network controls nephrocan expression and midgut patterning (2014)
Development (Cambridge), 141 (19), 3772-3781
- Coxsackievirus-Induced miR-21 Disrupts Cardiomyocyte Interactions via the Downregulation of Intercalated Disk Components (2014)
PLoS Pathogens, 10 (4)
- Delineating MEIS1 cis-regulatory elements active in hematopoietic cells (2014)
Leukemia, 28 (2), 433-436
- Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation (2014)
Cell Reports, 9 (1), 261-271
- IFPA Meeting 2013 Workshop Report II: Use of 'omics' in understanding placental development, bioinformatics tools for gene expression analysis, planning and coordination of a placenta research network, placental imaging, evolutionary approaches to underst (2014)
Placenta, 35 (SUPPL)
- Barnacle: Detecting and characterizing tandem duplications and fusions in transcriptome assemblies (2013)
BMC Genomics, 14 (1)
- Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development (2013)
Cellular and Molecular Life Sciences, 70 (16), 2899-2917
- Genome-wide microRNA and messenger RNA profiling in rodent liver development implicates mir302b and mir20a in repressing transforming growth factor-beta signaling (2013)
Hepatology, 57 (6), 2491-2501
- Identification and analysis of murine pancreatic islet enhancers (2013)
Diabetologia, 56 (3), 542-552
- Rare Copy Number Variants Contribute to Congenital Left-Sided Heart Disease (2012)
PLoS Genetics, 8 (9)
- The TG-interacting factor TGIF1 regulates stress-induced proinflammatory phenotype of endothelial cells (2012)
Journal of Biological Chemistry, 287 (46), 38913-38921
- The TGF-β/smad repressor TG-interacting factor 1 (TGIF1) plays a role in radiation-induced intestinal injury independently of a smad signaling pathway (2012)
PLoS ONE, 7 (5)
- The transcription factor encyclopedia. (2012)
Genome biology, 13 (3)
- Twist1 transcriptional targets in the developing atrio-ventricular canal of the mouse (2012)
PLoS ONE, 7 (7)
- Notch Initiates the Endothelial-to-Mesenchymal Transition in the Atrioventricular Canal through Autocrine Activation of Soluble Guanylyl Cyclase (2011)
Developmental Cell, 21 (2), 288-300
- The next generation: Using new sequencing technologies to analyse gene regulation (2011)
Respirology, 16 (2), 210-222
- De novo assembly and analysis of RNA-seq data (2010)
Nature Methods, 7 (11), 909-912
- Expression of two novel transcripts in the mouse definitive endoderm (2010)
Gene Expression Patterns, 10 (2-3), 127-134
- Foxh1 and Foxa2 are not required for formation of the midgut and hindgut definitive endoderm (2010)
Developmental Biology, 337 (2), 471-481
- Genomic analysis distinguishes phases of early development of the mouse atrio-ventricular canal (2010)
Physiological Genomics, 40 (3), 150-157
- Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver (2010)
Genome Research, 20 (8), 1037-1051
- Genome-wide relationship between histone H3 lysine 4 mono- and tri-methylation and transcription factor binding (2008)
Genome Research, 18 (12), 1906-1917
- Global analysis of in vivo Foxa2-binding sites in mouse adult liver using massively parallel sequencing (2008)
Nucleic Acids Research, 36 (14), 4549-4564
- Identification of transcripts with enriched expression in the developing and adult pancreas (2008)
Genome Biology, 9 (6)
- Slug is a direct Notch target required for initiation of cardiac cushion cellularization (2008)
Journal of Cell Biology, 182 (2), 315-325
- A systematic screen for genes expressed in definitive endoderm by Serial Analysis of Gene Expression (SAGE) (2007)
BMC Developmental Biology, 7
- Dynamic expression of Thyrotropin-releasing hormone in the mouse definitive endoderm (2007)
Developmental Dynamics, 236 (10), 2909-2917
- Dynamics of expression of growth differentiation factor 15 in normal and PIN development in the mouse (2007)
Differentiation, 75 (4), 325-336
- Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties (2007)
Proceedings of the National Academy of Sciences of the United States of America, 104 (14), 5878-5882
- Large-scale production of SAGE libraries from microdissected tissues, flow-sorted cells, and cell lines (2007)
Genome Research, 17 (1), 108-116
- Embryonic fibroblasts from mice lacking Tgif were defective in cell cycling (2006)
Molecular and Cellular Biology, 26 (11), 4302-4310
- Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect (2006)
Journal of Clinical Investigation, 116 (10), 2808-2816
- Hippi is essential for node cilia assembly and Sonic hedgehog signaling (2006)
Developmental Biology, 300 (2), 523-533
- A mouse atlas of gene expression: Large-scale digital gene-expression profiles from precisely defined developing C57BL/6J mouse tissues and cells (2005)
Proceedings of the National Academy of Sciences of the United States of America, 102 (51), 18485-18490
- Notch Activation Results in Phenotypic and Functional Changes Consistent with Endothelial-to-Mesenchymal Transformation (2004)
Circulation Research, 94 (7), 910-917
- FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse (2001)
Genes and Development, 15 (10), 1257-1271
- Formation of the definitive endoderm in mouse is a Smad2-dependent process (2000)
Development, 127 (14), 3079-3090
- Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor β-related signaling (2000)
Journal of Biological Chemistry, 275 (3), 2063-2070
- Dominant-negative Smad2 mutants inhibit activin/Vg1 signaling and disrupt axis formation in Xenopus (1999)
Developmental Biology, 207 (2), 364-379
- Smad2 and Smad3 positively and negatively regulate TGFβ-dependent transcription through the forkhead DNA-binding protein FAST2 (1998)
Molecular Cell, 2 (1), 109-120
- Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo (1998)
Cell, 92 (6), 797-808
- Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2 (1998)
Journal of Biological Chemistry, 273 (40), 25628-25636
- The Tlx-2 homeobox gene is a downstream target of BMP signalling and is required for mouse mesoderm development (1998)
Development, 125 (10), 1877-1887
- Inhibitory control of neural differentiation in mammalian cells (1997)
Development Genes and Evolution, 207 (1), 19-28
- Mechanism and function of signaling by the TGFβ superfamily (1997)
Current Topics in Microbiology and Immunology, 228, 235-272
- Mothers against decapentaplegic-related protein 2 expression in avian granulosa cells is up-regulated by transforming growth factor β during ovarian follicular development (1997)
Endocrinology, 138 (9), 3659-3665
- Phosphorylation of MADR2 by the TGF-B receptor on both serines 465 and 467 is required for association with DPC4 and TGF-B signaling (1997)
FASEB Journal, 11 (9)
- MADR1, a MAD-related protein that functions in BMP2 signaling pathways (1996)
Cell, 85 (4), 489-500
- MADR2 is a substrate of the TGFβ receptor and its phosphorylation is required for nuclear accumulation and signaling (1996)
Cell, 87 (7), 1215-1224
- MADR2 maps to 18q21 and encodes a TGFβ-regulated MAD-related protein that is functionally mutated in colorectal carcinoma (1996)
Cell, 86 (4), 543-552
- Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst (1994)
Proceedings of the National Academy of Sciences of the United States of America, 91 (16), 7598-7602
- The winged-helix transcription factor HNF-3β is required for notochord development in the mouse embryo (1994)
Cell, 78 (4), 575-588
- Characterization of Liver-Enriched Proteins Binding to a Developmentally Demethylated Site Flanking the Avian apoVLDLII Gene (1992)
DNA and Cell Biology, 11 (10), 755-765
- Developmental regulation of specific protein interactions with an enhancerlike binding site far upstream from the avian very-low-density apolipoprotein II gene (1990)
Molecular and Cellular Biology, 10 (1), 154-164