Francis Lynn

Associate Professor

Research Interests

Diabetes
ß-cell development
ß-cell biology
Human pluripotent stem cells
CRISPR/Cas
transcriptional regulation

Relevant Degree Programs

 

Biography

Francis Lynn completed his PhD in Ray Pederson's laboratory at UBC where he became interested in beta cells, diabetes and gene regulation. Postdoctoral studies with Michael German in San Francisco piqued his interest in beta cell development and small RNA biology.

His group is interested in understanding the mechanisms that regulate the formation of islet β-cells from pancreatic stem or progenitor cells during solid organ formation. They focus on the gene regulatory networks at play in the progenitor cells and how these networks change during differentiation to mature endocrine cells and in the long-term maintenance of the β-cell. They believe that a greater understanding of these genetic mechanisms and pathways will refine cell-based approaches for preventing and reversing the β-cell deterioration and loss that occur with diabetes.

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Doctoral students
Postdoctoral Fellows
Any time / year round

Research in the Lynn lab is targeted at understanding the insulin-producing pancreatic β-cell, how it fails during diabetes mellitus and how we can make surrogate cells to cure diabetes. We use a variety of models to study the regulatory pathways important for embryonic β-cell genesis and function. The current focus of research in the lab is understanding how DNA-binding transcription factors regulate β-cell formation and function, how they are reguated post-translationally and how they prevent β-cell dysfunction and diabetes. We currently have positions available for graduate students and postdoctoral scholars interested in studying the regulation of pancreatic β-cell development and function. Please contact me personally by e-mail with a cover letter outlining your interests, why you would like to join my lab, and please include your vita. Experience in cell and developmental biology, molecular biology or stem cell biology is preferred. More important are curiosity and passion about stem and developmental biology, and a talent for independent research, supported by a strong publication record.

Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
The cell cycle regulates mouse and human pancreas development (2018)

Diabetes is caused by a loss or dysfunction of insulin-producing pancreatic beta-cells. A potential treatment for diabetes is to replace these cells through transplantation. As there is a shortage of donor tissue, efforts to generate an unlimited source of functional insulin-producing beta-cells from human embryonic stem cells (hESCs) are ongoing. During pancreas development, proliferating pancreatic progenitors activate Neurog3, exit the cell cycle, and differentiate. The overarching goal of this thesis was to understand the role of the cell cycle in regulating Neurog3 expression and endocrine cell fate. First, the length of each cell cycle phase of pancreatic progenitors was measured using cumulative EdU labelling, determining an increase in G1 length in Pdx1+ progenitors from 4.5±0.4 to 7.2±0.8 hours between embryonic day (E)11.5 and E13.5. Next, two mouse models were used to show that cell cycle lengthening within pancreatic progenitors stimulates endocrine differentiation. Kras heterozygous loss-of-function mice have increased endocrine cell genesis that was correlated with an increase in progenitor cell cycle length. Ectopic expression of the cyclin-dependent kinase inhibitor Cdkn1b in Sox9+ progenitor cells resulted in a 2.7-fold increase in the number of Neurog3+ cells. As Cdkn1b is an inhibitor of G1-S cyclin-dependent kinases (Cdks), the effect of directly inhibiting Cdk2, Cdk4 and Cdk6 on endocrine differentiation was investigated. Treating embryonic pancreata, ex vivo, for 24 hours with Cdk inhibitors resulted in a 3-fold increase in the number of Neurog3+ cells. To investigate the consequences of CDK inhibition on human endocrine differentiation, a NEUROG3-2A-eGFP (N5-5) knock-in reporter CyT49 hESC line was generated using CRISPR-Cas9. CDK inhibition increased the number of GFP+ endocrine progenitor cells 1.7-fold. These findings suggest that G1 lengthening is required for normal mouse and human organogenesis and that cyclin-dependent kinases act directly to reduce Neurog3 protein. In the final chapter, single-cell transcriptomics was used to profile the gene expression and cell populations present during mouse and human endocrine development. In conclusion, these studies show that progenitor cell-cycle G1 lengthening, through its actions on stabilization of Neurog3, is an essential determinant of normal endocrine cell genesis.

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The roles of SOX4 and MED15 in the development and maintenance of pancreatic β-cells (2017)

Pancreatic beta-cells (β-cells) are essential for the maintenance of blood glucose homeostasis, as the primary insulin-secreting cells of the body. During embryogenesis, β-cells differentiate from pancreatic progenitor cells, and following birth, these cells re-enter the cell-cycle and proliferate to maintain a sufficient adult population of β-cells. Transcription factors (TFs) such as neurogenin3 (Neurog3) are essential for endocrine cell specification within the pancreas, while other TFs are required in adult β-cells to maintain their function. Despite the identification of many TFs throughout β-cell development, how TFs regulate the transition between cell states, and how these TFs engage the RNA Polymerase II holoenzyme to regulate transcription is unknown. To address these questions, this thesis examines the role of Sry-related HMG-box 4 (SOX4) and Mediator 15 (MED15) in β-cell development and the adult β-cell state.Work in this thesis has established that in mice, SOX4 is expressed in pancreatic progenitor cells and cooperates with NEUROG3 to activate Neurog3 expression. This demonstrated a requirement for SOX4 in endocrine progenitor cell specification. SOX4 continued to be expressed in endocrine specified cells, and was essential for Neurod1 and Pax4 induction, TFs required for β-cell specification. High-fat diet (HFD)-fed mice with inducible SOX4 deletion in β-cells also exhibited glucose intolerance, due to decreased β-cell mass and replication rate. Loss of Sox4 led to the upregulation of the cell-cycle inhibitor Cdkn1a, a gene that prevents G1-S cell-cycle transition. Additionally, Med15 deletion in pancreatic progenitors demonstrated reduced NEUROG3 expression, and reduced endocrine cell numbers. MED15 deletion following endocrine specification also led to reduced β-cell numbers. Finally, Ins1-Cre facilitated deletion of MED15 in β-cells revealed that its function varied depending on cell-state, with compromised β-cell function if expression is lost during β-cell maturation. These data are the first to determine when SOX4 is required for pancreatic endocrine specification in mice and which targets are directly regulated by SOX4. In addition, the first known in-vivo role for MED15 in mammals is identified, demonstrating that it is an indispensable factor for β-cell differentiation and function. Collectively, these findings contribute to the understanding of how TFs regulate β-cell states.

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The role of NPAS4 in glucose homeostasis (2016)

Type 2 diabetes is characterized by hyperglycemia associated with reduced insulin secretion from pancreatic beta cells and impaired insulin sensitivity at peripheral target tissues. There is a growing body of evidence that supports the importance of bHLH-PAS domain transcription factors in promoting beta cell function. With the recent identification of neuronal PAS domain protein 4 (NPAS4) within the central nervous system, studies were undertaken to determine whether NPAS4 is expressed in beta cells, how its expression is regulated in response to changing environmental signals and uncover the functional significance of NPAS4 in the maintenance of glucose homeostasis. Together, experiments within this thesis demonstrate that NPAS4 is expressed within the pancreatic beta cell and is rapidly upregulated in response to membrane depolarization and calcium influx. Further, this induction was impaired in a mouse model of beta cell dysfunction and within islets from individuals with T2D. Overexpression studies performed in vitro identified NPAS4 as a novel negative regulator of insulin expression and GLP-1 potentiated insulin secretion. Furthermore, NPAS4 protected beta cells from maladaptive cellular pathways that promote cell dysfunction and death; including endoplasmic reticulum stress and activation of HIF1α. Finally, the characterization of three different Npas4 mouse knockout models suggests that continued NPAS4 expression in the beta cell is required to maintain differentiation status and cellular function. An independent role for NPAS4 in the maintenance of glucose homeostasis was also discovered in other Pdx1-Cre expressing cells, likely within the hypothalamus. Together, the data suggest beta cells induce NPAS4 expression during periods of cellular activity and acts as a protective factor to protect cells in order to promote the maintenance of euglycemia.

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Publications

 
 

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