Pamela Hoodless

Professor

Research Interests

Developmental Genetics
Embryology
Embryonic Development
Epigenetics
Heart Valve / Valvular Diseases
Heart valve formation
Liver
Liver development
Stem Cells and Organogenesis
transcriptional regulation

Relevant Thesis-Based Degree Programs

Affiliations to Research Centres, Institutes & Clusters

Research Options

I am available and interested in collaborations (e.g. clusters, grants).
 
 

Research Methodology

Genomics
Genetic models
Single cell analysis

Recruitment

Master's students
Doctoral students
2023

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Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Delineating migratory events in liver and heart development using single-cell transcriptomics (2022)

The cellular complexity and small scale of the mouse embryonic liver and heart valves have constrained analyses probing cell type diversity and differentiation during their development. To address this, we have analyzed 29 single-cell RNA-seq libraries from embryonic day (E)7.5 to E12.5 and have validated the spatiotemporal distribution of identified cell lineages by histology. To assess liver development, we have analyzed 45,334 cells and have detailed the developmental trajectories taken during the early emergence of liver parenchymal and non-parenchymal cell lineages. These analyses describe the development of hepatoblasts, liver endothelium, and mesenchyme from endoderm progenitor specification at E7.5 to liver bud formation at E10.5. Our data detail the divergence of vascular and sinusoidal endothelia, the specification of hepatoblasts, and the emergence of distinct mesothelial cell types. We further identify a novel, hybrid hepatomesenchymal cell type that we hypothesize plays a role in liver bud formation. To delineate atrioventricular (AV) valve development, we have analyzed 48,822 cells from publicly available and newly generated single-cell datasets. These data provide insight into the epithelial-to-mesenchymal transformations from endocardium (EndMT) and epicardium (EpiMT) that contribute to AV mesenchyme during development. During EndMT, we detail the bifurcation of valve mesenchymal and endocardial lineages, which our data suggest involves the sporadic activation of epithelial-mesenchymal plasticity. During EpiMT, scRNA-seq data and histology identify a unique activated epicardial population that emerges at the onset of this process. We further use our transcriptomic data to deconvolve signals that may influence the initiation and progression of EndMT and EpiMT.Lastly, we have assessed the role of AV mesenchymal master regulator SOX9 during EndMT by comparing Sox9 endothelial-specific mutant and wildtype AV canals. Our data show developmental arrest during EndMT without Sox9, including the failure of endocardial transdifferentiation to mesenchyme and the accumulation of endocardium exhibiting epithelial-mesenchymal plasticity.These data reveal surprising diversity during the emergence of liver and AV cell lineages. As a resource, they will serve as comprehensive single-cell atlases of liver and AV lineage establishment for researchers studying the development of these tissues or the reactivation of developmental processes in disease and regenerative contexts.

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Analysis of transcriptional targets of SOX9 during embryonic heart valve development reveals a critical network of transcriptional 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

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Inferring regulators of liver development using single cell sequencing and organoids (2022)

The liver regulates most chemical levels in the blood, breaking down and processing nutrients, metabolizing drugs, and excreting waste products through a product called bile. These critical tasks are mainly fulfilled by cells called hepatocytes, which are supported by endothelial, mesenchymal, and immune cells. Herein, we analyze the earliest stages of mouse embryonic liver development using single cell transcriptomics of cells from embryonic day (E) 7.5 to E10.5 embryos. Single cell transcriptomics shows that by E10.5 the endothelial and mesenchymal cells already express many liver-specific markers, such as Lyve1 and Gdf2, respectively. In the first part of this thesis, I expanded the CellPhoneDB database to provide a list of possible ligand-receptor interactions in the early liver bud at E9.5 and E10.5. This analysis yields many known interactions, in addition to many interactions which do not yet have known roles in liver development. The novel interactions include signaling from the hepatoblast (hepatocyte precursor) ligand LECT2 to the liver sinusoidal endothelial cell receptor TIE1, and from the stellate cell ligands RSPO3 and DKK1 to hepatoblast receptors. Next, I developed a multilineage organoid model of liver development. Our goal is to use the organoids for high throughput screening of these ligand-receptor interactions using shRNA-based knockdown of genes or small molecules to activate or inhibit the interactions or their downstream pathways. This model starts from human pluripotent stem cells and uses a differentiation protocol that allows for concomitant differentiation of the mesenchymal, endothelial, and hepatocyte lineages. Preliminary experiments show evidence of these lineages, but further characterization is required to determine how closely they resemble their in vivo counterparts. The second part of this thesis focuses on transcription factor and gene regulatory analysis of the differentiating hepatoblasts, which will eventually give rise to hepatocytes. This analysis identified NR5A2 as a putative regulator of hepatoblast development and/or differentiation in E9.5 livers. The critical role of NR5A2 in Zebrafish development, but currently unvalidated role in human or mouse liver development suggests that further research into NR5A2 is warranted.

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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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