Pamela Hoodless

Professor

Research Classification

Embryonic Development
Genomics
Heart Valve / Valvular Diseases
Liver
Stem Cells and Organogenesis
Developmental Genetics

Research Interests

Embryology
transcriptional regulation
Epigenetics
Heart valve formation
Liver development

Relevant Degree Programs

 

Research Methodology

Genomics
Genetic models
Single cell analysis

Recruitment

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Master's students
Doctoral students
2020
2021

Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
Analysis of transcriptional targets of SOX9 during embryonic heart valve development reveals a critical network of transcription factors (2016)

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.

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The dynamic gene expression patterns during in vivo maturation of mouse hepatoblasts (2013)

No abstract available.

Genomic analysis of embryonic heart development in the mouse (2010)

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.

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Gene Expression Profiling Reveals Novel Attributes of the Mouse Definitive Endoderm (2009)

No abstract available.

Master's Student Supervision (2010 - 2018)
Transcriptional regulation by the Hippo signaling pathway in the liver (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.

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Expression and function of APELA : a potential regulator of cell growth in human cancers (2016)

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.

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Publications

 
 

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