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Francis Lynn
PhD

Professor, Department of Surgery and School of Biomedical Engineering, Faculty of Medicine, University of British Columbia
Head of the Canucks for Kids Childhood Diabetes Laboratories
Lead of the BCCHR Diabetes Research Group
Investigator, BC Children's Hospital

transcriptional regulation in islet cells

The pancreas synthesizes and secretes endocrine hormones into the blood. The cells that produce these hormones are situated in tiny islands or groups of cells called islets of Langerhans, which are interspersed amongst the exocrine tissue. The most well known pancreatic hormone is insulin; it is produced in the pancreatic ß-cell and is secreted in response to the elevated blood glucose levels that accompany eating. Insulin travels in the bloodstream to the target tissues where it regulates removal of glucose from the blood: thereby normalizing glucose levels. There are no other hormones that have a similar role to insulin in humans and loss of insulin production or effectiveness results in a disease known as diabetes mellitus.

The classical model of gene regulation relies upon sequence-specific interactions of nuclear proteins, called transcription factors, with the promoter regions of genes. The gene regulatory outcome of transcription factor binding to DNA is dependent on both the intrinsic properties of the factor and the regulatory or promoter context. Transcription factors have an indispensable role in ß-cells. Our work has focused on a number of transcription factors important for ß-cells; the specific questions we are asking include:

1) What role do Sox factors play during pancreas development?

We have demonstrated that Sox9 and Sox4 are important during ß-cell development. Recent studies suggest that Sox4 also regulates the cell cycle of adult ß-cells. Current work seeks to understand how SOX4 increases the risk of developing Type 2 diabetes

2) What role does Npas4 play in adult ß-cells?

We have demonstrated that Npas4 is activated when ß-cells start to secrete insulin. Its role is to prevent excess ß-cell cell stress and we hypothesize that it is important for maintaining ß-cell function in those with diabetes. Current work is exploring the role of Npas4 in regulating feeding behaviour.

3) What role does the Mediator co-activator play in ß-cells?

We have demonstrated that Mediator complex proteins are indispensible for ß-cell development and remain important in the adult ß-cell. Ongoing studies with the Taubert Labare aimed at elucidating the mechanisms through which the Mediator complex prevents diabetes and how it regulates the function of glucagon-producing alpha cells

islet cell replacement

The Edmonton Protocol demonstrated the promise of islet transplantation as a treatment for those living with type 1 diabetes. Historically islet transplantation has relied on organ donors, which has a few drawbacks including: limited availability, heterogeneity in preparation and genetics, high cost, and need for lifelong immunosuppression. We wish to move beyond islet tranplantations and our research focusses on using pluripotent stem cells as a starting material. The specific areas we focus on are:

1) Can we make stem cell-derived beta cells that are fully mature and functional?

We have developed approaches to track the maturation of stem cell-derived beta cells and screening approaches to uncover what factors may be important for establishing glucose-induced insulin secretion after birth. Ongoing work aims to understand how these factors work.

2) Can we make stem cell-derived islets that are more resilient to transplantation stresses?

We have found a number of proteins that prevent stem cell-derived beta cell death. Currently, we are using our skills in genome engineering to generate stem cells that may be better able to resist the stresses that accompany transplantation so that fewer beta cells need to be transplanted

3) Can we make stem cell-derived islets that evade immune destruction?

We have discovered new ways for cloaking stem cell derived islets from the immune system. We are exploring how we might use this knowledge to remove the need for lifelong systemic immunosuppression following and islet cell transplantation.

Academic Affiliations

  • Associate Professor, , School of Biomedical Engineering, Faculty of Applied Science and Faculty of Medicine, University of British Columbia
  • Professor, Division of General Surgery, Department of Surgery, Faculty of Medicine, University of British Columbia
  • Research Theme: Childhood Diseases
  • Research Group(s): Diabetes

Contact Information

Location

950 West 28th Ave, Vancouver, BC, Canada, V5Z 4H4

(604) 875-2000 ext. 5426

flynn@bcchr.ca

theLynnLab

Generation and Validation of an Aryl Hydrocarbon Receptor Knockout Human Embryonic Stem Cell Line

Endocrinology

Noa Gang and Cuilan Nian and Ekaterina Filatov and Dahai Zhang and Myriam P Hoyeck and Bailey Laforest and Francis C Lynn and Jennifer E Bruin

DOI: 10.1210/endocr/bqaf189

02 / 2026

Truncated CD19 as a selection marker for the isolation of stem cell-derived -cells

Disease Models & Mechanisms

Luo Ting Huang and Raymond Jun-rui Gao and Dahai Zhang and Cuilan Nian and Willem Martzke and A. M. James Shapiro and Tatsuya Kin and Yaser Tahamtani and Francis C. Lynn

DOI: 10.1242/dmm.052376

01 / 2026

Transcriptional and temporal heterogeneity of developing a cells revealed by single-cell RNA sequencing

Biochemical and Biophysical Research Communications

Naoya Shimizu and Tomomi Taguchi and Miwa Himuro and Iichiro Shimomura and Francis C. Lynn and Hirotaka Watada and Shugo Sasaki and Takeshi Miyatsuka

DOI: 10.1016/j.bbrc.2025.152996

12 / 2025

Crosstalk between the aryl hydrocarbon receptor and hypoxia-inducible factor 1a pathways in human islet models

Islets

Gang, N. and van Allen, K.A. and Willmore, W.G. and Lynn, F.C. and Bruin, J.E.

DOI: 10.1080/19382014.2025.2526871

NPAS4 Depletion in POMC Neurons Protects From Obesity and Alters the Feeding-regulated Transcriptome in Male Mice

Endocrinology United States

Yoon, J.S. and Gamu, D. and Gibson, W.T. and Lynn, F.C.

DOI: 10.1210/endocr/bqaf083

HumanIslets.com: Improving accessibility, integration, and usability of human research islet data

Cell Metabolism

Ewald, J.D. and Lu, Y. and Ellis, C.E. and Worton, J. and Kolic, J. and Sasaki, S. and Zhang, D. and dos Santos, T. and Spigelman, A.F. and Bautista, A. and Dai, X.-Q. and Lyon, J.G. and Smith, N.P. and Wong, J.M. and Rajesh, V. and Sun, H. and Sharp, S.A. and Rogalski, J.C. and Moravcova, R. and Cen, H.H. and Manning Fox, J.E. and Atlas, E. and Bruin, J.E. and Mulvihill, E.E. and Verchere, C.B. and Foster, L.J. and Gloyn, A.L. and Johnson, J.D. and Pepper, A.R. and Lynn, F.C. and Xia, J. and MacDonald, P.E.

DOI: 10.1016/j.cmet.2024.09.001

A prioritized medium-throughput screen on human stem cell derived insulin secreting beta cells identifies FGF4, FGF5, FGF8F, FGF19 and FGF21 as protective factors

Biorxiv

Chu, C.M.J. and Kamal, S. and Huang, L.T. and Bayly, C.L. and Chen, S.-Y. and Omur, M.E. and Wasserman, W.W. and Lynn, F.C. and Johnson, J.D.

DOI: 10.1101/2025.02.12.637990

CCL22-expressing Stem Cell-derived Islet Grafts Recruit Regulatory T Cells in Mice

Transplantation

Filatov, E. and Sasaki, S. and Haque, M. and Kar, S. and Fung, V.C.W. and Mojibian, M. and Krentz, N.A.J. and MacDonald, K.N. and Salim, K. and Soukhatcheva, G. and Dai, D.L. and Orban, P.C. and Verchere, C.B. and Levings, M.K. and Lynn, F.C.

DOI: 10.1097/TP.0000000000005463

Tracking Insulin- and Glucagon-Expressing Cells In Vitro and In Vivo Using a Double-Reporter Human Embryonic Stem Cell Line

Diabetes

Mar, S. and Filatov, E. and Sasaki, S. and Mojibian, M. and Zhang, D. and Yang, A. and Nian, C. and Lynn, F.C.

DOI: 10.2337/db24-0756

Crosstalk between the aryl hydrocarbon receptor and hypoxia inducible factor 1a pathways impairs downstream dioxin response in human islet models

Biorxiv

Gang, N. and van Allen, K.A. and Willmore, W.G. and Lynn, F.C. and Bruin, J.E.

DOI: 10.1101/2024.09.25.615065

PDX1+ cell budding morphogenesis in a stem cell-derived islet spheroid system

Nature Communications

Zhao, J. and Liang, S. and Cen, H.H. and Li, Y. and Baker, R.K. and Ruprai, B. and Gao, G. and Zhang, C. and Ren, H. and Tang, C. and Chen, L. and Liu, Y. and Lynn, F.C. and Johnson, J.D. and Kieffer, T.J.

DOI: 10.1038/s41467-024-50109-2

An INSULIN and IAPP dual reporter enables tracking of functional maturation of stem cell-derived insulin producing cells

Molecular Metabolism

Bayly, C.L. and Dai, X.-Q. and Nian, C. and Orban, P.C. and Verchere, C.B. and MacDonald, P.E. and Lynn, F.C.

DOI: 10.1016/j.molmet.2024.102017

NPAS4 is an allostatic regulator of POMC neuronal activity during diet-induced obesity

bioRxiv

Yoon, J.S. and Gamu, D. and Gibson, W.T. and Lynn, F.C.

DOI: 10.1101/2024.01.12.574247

Transcriptional coactivator MED15 is required for beta cell maturation

Nature Communications

Kadhim, A.Z. and Vanderkruk, B. and Mar, S. and Dan, M. and Zosel, K. and Xu, E.E. and Spencer, R.J. and Sasaki, S. and Cheng, X. and Sproul, S.L.J. and Speckmann, T. and Nian, C. and Cullen, R. and Shi, R. and Luciani, D.S. and Hoffman, B.G. and Taubert, S. and Lynn, F.C.

DOI: 10.1038/s41467-024-52801-9

Characterizing the effects of Dechlorane Plus on -cells: a comparative study across models and species

Islets

van Allen, K.A. and Gang, N. and Hoyeck, M.P. and Perera, I. and Zhang, D. and Atlas, E. and Lynn, F.C. and Bruin, J.E.

DOI: 10.1080/19382014.2024.2361996

Single cell glucose-stimulated insulin secretion assay using nanowell-in-microwell plates

Lab on a Chip

Jang, D. and Matthews, K. and Deng, P. and Berryman, S.G. and Nian, C. and Duffy, S.P. and Lynn, F.C. and Ma, H.

DOI: 10.1039/d4lc00413b

Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease

Cell Metabolism

Kolic, J. and Sun, W.G. and Cen, H.H. and Ewald, J.D. and Rogalski, J.C. and Sasaki, S. and Sun, H. and Rajesh, V. and Xia, Y.H. and Moravcova, R. and Skovs?, S. and Spigelman, A.F. and Manning Fox, J.E. and Lyon, J. and Beet, L. and Xia, J. and Lynn, F.C. and Gloyn, A.L. and Foster, L.J. and MacDonald, P.E. and Johnson, J.D.

DOI: 10.1016/j.cmet.2024.06.001

Novel time-resolved reporter mouse reveals spatial and transcriptional heterogeneity during alpha cell differentiation

Diabetologia

Himuro, M. and Wakabayashi, Y. and Taguchi, T. and Katahira, T. and Suzuki, L. and Iida, H. and Ogihara, T. and Nishida, Y. and Sasaki, S. and Lynn, F.C. and Hiraoka, Y. and Oshima, S. and Okamoto, R. and Fujitani, Y. and Watada, H. and Miyatsuka, T.

DOI: 10.1007/s00125-023-06028-w

HumanIslets: An integrated platform for human islet data access and analysis

bioRxiv

Ewald, J.D. and Lu, Y. and Ellis, C.E. and Worton, J. and Kolic, J. and Sasaki, S. and Zhang, D. and dos Santos, T. and Spigelman, A.F. and Bautista, A. and Dai, X.-Q. and Lyon, J.G. and Smith, N.P. and Wong, J.M. and Rajesh, V. and Sun, H. and Sharp, S.A. and Rogalski, J.C. and Moravcova, R. and Cen, H.H. and Manning Fox, J.E. and Atlas, E. and Bruin, J.E. and Mulvihill, E.E. and Bruce Verchere, C. and Foster, L.J. and Gloyn, A.L. and Johnson, J.D. and Pepper, A.R. and Lynn, F.C. and Xia, J. and MacDonald, P.E.

DOI: 10.1101/2024.06.19.599613

Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice

Diabetologia

Ben Vanderkruk and Nina Maeshima and Daniel J. Pasula and Meilin An and Cassandra L. McDonald and Priya Suresh and Dan S. Luciani and Francis C. Lynn and Brad G. Hoffman

DOI: 10.1007/s00125-023-05896-6

06 / 2023

Tracking insulin- and glucagon-expressing bihormonal cells during differentiation using an INSULIN and GLUCAGON double reporter human embryonic stem cell line

bioRxiv

Mar, S. and Filatov, E. and Nian, C. and Sasaki, S. and Zhang, D. and Lynn, F.C.

DOI: 10.1101/2023.04.19.537542

Retraction Note: Calcium-dependent transcriptional changes in human pancreatic islet cells reveal functional diversity in islet cell subtypes (Diabetologia, (2022), 65, 9, (1519-1533), 10.1007/s00125-022-05718-1)

Diabetologia

Yoon, J.S. and Sasaki, S. and Velghe, J. and Lee, M.Y.Y. and Winata, H. and Nian, C. and Lynn, F.C.

DOI: 10.1007/s00125-023-05983-8

In silico discovery of small molecules for efficient stem cell differentiation into definitive endoderm

Stem Cell Reports

Novakovsky, G. and Sasaki, S. and Fornes, O. and Omur, M.E. and Huang, H. and Bayly, C.L. and Zhang, D. and Lim, N. and Cherkasov, A. and Pavlidis, P. and Mostafavi, S. and Lynn, F.C. and Wasserman, W.W.

DOI: 10.1016/j.stemcr.2023.01.008

Calcium-dependent transcriptional profiles of human pancreatic islet cells reveal functional diversity in islet subpopulations

bioRxiv

Yoon, J.S. and Sasaki, S. and Velghe, J. and Zosel, K. and Lee, M.Y.Y. and Winata, H. and Nian, C. and Lynn, F.C.

DOI: 10.1101/2023.09.08.556709

Truncated CD19 as a selection marker for the isolation of stem cell derived -cells

bioRxiv

Huang, L.T. and Zhang, D. and Nian, C. and Lynn, F.C.

DOI: 10.1101/2023.04.05.535733

Islet amyloid polypeptide does not suppress pancreatic cancer

Molecular metabolism

Taylor, A.J. and Panzhinskiy, E. and Orban, P.C. and Lynn, F.C. and Schaeffer, D.F. and Johnson, J.D. and Kopp, J.L. and Verchere, C.B.

DOI: 10.1016/j.molmet.2023.101667

Human A2-CAR T Cells Reject HLA-A2+Human Islets Transplanted into Mice Without Inducing Graft-versus-host Disease

Transplantation

Ellis, C.E. and Mojibian, M. and Ida, S. and Fung, V.C.W. and Skovs?, S?. and McIver, E. and O'Dwyer, S. and Webber, T.D. and Braam, M.J.S. and Saber, N. and Sasaki, S. and Lynn, F.C. and Kieffer, T.J. and Levings, M.K.

DOI: 10.1097/TP.0000000000004709

Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic -cell proliferation via phosphorylation of HDAC5

iScience

Sasaki, S. and Nian, C. and Xu, E.E. and Pasula, D.J. and Winata, H. and Grover, S. and Luciani, D.S. and Lynn, F.C.

DOI: 10.1016/j.isci.2023.107311

Spatial and transcriptional heterogeneity of pancreatic beta cell neogenesis revealed by a time-resolved reporter system

Diabetologia

Shugo Sasaki and Michelle Y. Y. Lee and Yuka Wakabayashi and Luka Suzuki and Helena Winata and Miwa Himuro and Taka-aki Matsuoka and Iichiro Shimomura and Hirotaka Watada and Francis C. Lynn and Takeshi Miyatsuka

DOI: 10.1007/s00125-022-05662-0

05 / 2022

Dynamic Ins2 Gene Activity Defines -Cell Maturity States

Diabetes

Chu, C.M.J. and Modi, H. and Ellis, C. and Krentz, N.A.J. and Skovs?, S. and Zhao, Y.B. and Cen, H. and Noursadeghi, N. and Panzhinskiy, E. and Hu, X. and Dionne, D.A. and Xia, Y.H. and Xuan, S. and Huising, M.O. and Kieffer, T.J. and Lynn, F.C. and Johnson, J.D.

DOI: 10.2337/db21-1065

Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic -cell proliferation via phosphorylation of HDAC5 in mice

bioRxiv

Sasaki, S. and Nian, C. and Xu, E.E. and Pasula, D.J. and Winata, H. and Grover, S. and Luciani, D.S. and Lynn, F.C.

DOI: 10.1101/2022.12.23.521810

A versatile fluorescence-quenched substrate for quantitative measurement of glucocerebrosidase activity within live cells

Proceedings of the National Academy of Sciences of the United States of America

Deen, M.C. and Zhu, Y. and Gros, C. and Na, N. and Gilormini, P.-A. and Shen, D.L. and Bhosale, S. and Anastasi, N. and Wang, R. and Shan, X. and Harde, E. and Jagasia, R. and Lynn, F.C. and Vocadlo, D.J.

DOI: 10.1073/pnas.2200553119

Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation

JCI Insight

Biggs, C.M. and Cordeiro-Santanach, A. and Prykhozhij, S.V. and Deveau, A.P. and Lin, Y. and Del Bel, K.L. and Orben, F. and Ragotte, R.J. and Saferali, A. and Mostafavi, S. and Dinh, L. and Dai, D. and Weinacht, K.G. and Dobbs, K. and de Bruin, L.O. and Sharma, M. and Tsai, K. and Priatel, J.J. and Schreiber, R.A. and Rozmus, J. and Hosking, M.C.K. and Shopsowitz, K.E. and McKinnon, M.L. and Vercauteren, S. and Seear, M. and Notarangelo, L.D. and Lynn, F.C. and Berman, J.N. and Turvey, S.E.

DOI: 10.1172/jci.insight.150849

Heterogeneity of Diabetes: -Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases

Canadian Journal of Diabetes

Cefalu, W.T. and Andersen, D.K. and Arreaza-Rubn, G. and Pin, C.L. and Sato, S. and Verchere, C.B. and Woo, M. and Rosenblum, N.D. and Rosenblum, N. and Cefalu, W. and Dhara, C. and James, S.P. and Makarchuk, M.-J. and Powers, A. and Estall, J. and Hoesli, C. and Millman, J. and Linnemann, A. and Johnson, J. and Hawkins, M. and Gloyn, A. and Huising, M.O. and Benninger, R.K.P. and Alma?a, J. and Hull-Meichle, R.L. and MacDonald, P. and Lynn, F. and Melero-Martin, J. and Yoshihara, E. and Stabler, C. and Sander, M. and Evans-Molina, C. and Engin, F. and Thompson, P. and Shalev, A. and Redondo, M.J. and Nadeau, K. and Bellin, M. and Udler, M.S. and Dennis, J. and Dash, S. and Zhou, W. and Snyder, M. and Booth, G. and Butte, A. and Florez, J.

DOI: 10.1016/j.jcjd.2021.09.126

Recapitulating pancreatic cell"cell interactions through bioengineering approaches: the momentous role of non-epithelial cells for diabetes cell therapy

Cellular and Molecular Life Sciences

Ghezelayagh, Z. and Zabihi, M. and Kazemi Ashtiani, M. and Ghezelayagh, Z. and Lynn, F.C. and Tahamtani, Y.

DOI: 10.1007/s00018-021-03951-2

Using hiPSC-CMs to Examine Mechanisms of Catecholaminergic Polymorphic Ventricular Tachycardia

Current Protocols

Arslanova, A. and Shafaattalab, S. and Ye, K. and Asghari, P. and Lin, L. and Kim, B. and Roston, T.M. and Hove-Madsen, L. and Van Petegem, F. and Sanatani, S. and Moore, E. and Lynn, F. and S?ndergaard, M. and Luo, Y. and Chen, S.R.W. and Tibbits, G.F.

DOI: 10.1002/cpz1.320

Author Correction: Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics.

Nature communications

Ast J and Arvaniti A and Fine NHF and Nasteska D and Ashford FB and Stamataki Z and Koszegi Z and Bacon A and Jones BJ and Lucey MA and Sasaki S and Brierley DI and Hastoy B and Tomas A and Hodson DJ

DOI: 10.1038/s41467-020-19101-4 PubMed: 33037231

10 / 2020

Spatial and transcriptional heterogeneity of -cell neogenesis revealed by a time-resolved reporter system

Sasaki S and Lee M and Wakabayashi Y and Suzuki L and Winata H and Himuro M and Matsuoka T and Shimomura I and Watada H and Lynn F and Miyatsuka T

DOI: 10.21203/rs.3.rs-46466/v1

08 / 2020

Premature termination codon readthrough upregulates progranulin expression and improves lysosomal function in preclinical models of GRN deficiency

Molecular Neurodegeneration

Frew, J. and Baradaran-Heravi, A. and Balgi, A.D. and Wu, X. and Yan, T.D. and Arns, S. and Shidmoossavee, F.S. and Tan, J. and Jaquith, J.B. and Jansen-West, K.R. and Lynn, F.C. and Gao, F.-B. and Petrucelli, L. and Feldman, H.H. and MacKenzie, I.R. and Roberge, M. and Nygaard, H.B.

DOI: 10.1186/s13024-020-00369-5

Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics

Nature Communications

Ast, J. and Arvaniti, A. and Fine, N.H.F. and Nasteska, D. and Ashford, F.B. and Stamataki, Z. and Koszegi, Z. and Bacon, A. and Jones, B.J. and Lucey, M.A. and Sasaki, S. and Brierley, D.I. and Hastoy, B. and Tomas, A. and D?Agostino, G. and Reimann, F. and Lynn, F.C. and Reissaus, C.A. and Linnemann, A.K. and D?Este, E. and Calebiro, D. and Trapp, S. and Johnsson, K. and Podewin, T. and Broichhagen, J. and Hodson, D.J.

DOI: 10.1038/s41467-020-14309-w

Lrrc55 is a novel prosurvival factor in pancreatic islets.

American journal of physiology. Endocrinology and metabolism

Makkar G and Shrivastava V and Hlavay B and Pretorius M and Kyle BD and Braun AP and Lynn FC and Huang C

DOI: 10.1152/ajpendo.00028.2019 PubMed: 31526288

09 / 2019

Ins2 gene bursting activity defines a mature -cell state

Modi H and Skovs S and Ellis C and Krentz NA and Zhao YB and Cen H and Noursadeghi N and Panzhinskiy E and Hu X and Dionne DA and Xuan S and Huising MO and Kieffer TJ and Lynn FC and Johnson JD

DOI: 10.1101/702589

07 / 2019

Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans

PLoS Genetics

Shomer, N. and Zacharie Kadhim, A. and Margaret Grants, J. and Cheng, X. and Alhusari, D. and Bhanshali, F. and Poon, A.F.-Y. and Ya Lee, M.Y. and Muhuri, A. and In Park, J. and Shih, J. and Lee, D. and Lee, S.-J.V. and Lynn, F.C. and Taubert, S.

DOI: 10.1371/journal.pgen.1008508

Friend and foe: -cell Ca 2+ signaling and the development of diabetes

Molecular Metabolism

Sabatini, P.V. and Speckmann, T. and Lynn, F.C.

DOI: 10.1016/j.molmet.2018.12.007

TrxG Complex Catalytic and Non-catalytic Activity Play Distinct Roles in Pancreas Progenitor Specification and Differentiation

Cell Reports

Campbell, S.A. and McDonald, C.L. and Krentz, N.A.J. and Lynn, F.C. and Hoffman, B.G.

DOI: 10.1016/j.celrep.2019.07.035

In vitro analyses of suspected arrhythmogenic thin filament variants as a cause of sudden cardiac death in infants

Proceedings of the National Academy of Sciences of the United States of America

Shafaattalab, S. and Li, A.Y. and Lin, E. and Stevens, C.M. and Dewar, L.J. and Lynn, F.C. and Sanatani, S. and Laksman, Z. and Morin, R.D. and van Petegem, F. and Hove-Madsen, L. and Peter Tieleman, D. and Davis, J.P. and Tibbits, G.F.

DOI: 10.1073/pnas.1819023116

Single cell transcriptome profiling of mouse and hESC-derived pancreatic progenitors

Krentz NAJ and Lee M and Xu EE and Sasaki S and Lynn FC

DOI: 10.1101/289470

03 / 2018

Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells.

Cell reports

Sabatini PV and Speckmann T and Nian C and Glavas MM and Wong CK and Yoon JS and Kin T and Shapiro AMJ and Gibson WT and Verchere CB and Lynn FC

PubMed: 29298418

01 / 2018

Single-Cell Transcriptome Profiling of Mouse and hESC-Derived Pancreatic Progenitors

Stem Cell Reports

Krentz, N.A.J. and Lee, M.Y.Y. and Xu, E.E. and Sproul, S.L.J. and Maslova, A. and Sasaki, S. and Lynn, F.C.

DOI: 10.1016/j.stemcr.2018.11.008

The p300 and CBP transcriptional coactivators are required for -cell and a-cell proliferation

Diabetes

Wong, C.K. and Wade-Vallance, A.K. and Luciani, D.S. and Brindle, P.K. and Lynn, F.C. and Gibson, W.T.

DOI: 10.2337/db17-0237

Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy

Orphanet Journal of Rare Diseases

McMillan, H.J. and Telegrafi, A. and Singleton, A. and Cho, M.T. and Lelli, D. and Lynn, F.C. and Griffin, J. and Asamoah, A. and Rinne, T. and Erasmus, C.E. and Koolen, D.A. and Haaxma, C.A. and Keren, B. and Doummar, D. and Mignot, C. and Thompson, I. and Velsher, L. and Dehghani, M. and Vahidi Mehrjardi, M.Y. and Maroofian, R. and Tchan, M. and Simons, C. and Christodoulou, J. and Martn-Hernndez, E. and Guillen Sacoto, M.J. and Henderson, L.B. and McLaughlin, H. and Molday, L.L. and Molday, R.S. and Yoon, G.

DOI: 10.1186/s13023-018-0825-3

Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells

Cell Reports

Sabatini, P.V. and Speckmann, T. and Nian, C. and Glavas, M.M. and Wong, C.K. and Yoon, J.S. and Kin, T. and Shapiro, A.M.J. and Gibson, W.T. and Verchere, C.B. and Lynn, F.C.

DOI: 10.1016/j.celrep.2017.12.033

The Polycomb-Dependent Epigenome Controls Cell Dysfunction, Dedifferentiation, and Diabetes

Cell Metabolism

Lu, T.T.-H. and Heyne, S. and Dror, E. and Casas, E. and Leonhardt, L. and Boenke, T. and Yang, C.-H. and Sagar and Arrigoni, L. and Dalgaard, K. and Teperino, R. and Enders, L. and Selvaraj, M. and Ruf, M. and Raja, S.J. and Xie, H. and Boenisch, U. and Orkin, S.H. and Lynn, F.C. and Hoffman, B.G. and Grn, D. and Vavouri, T. and Lempradl, A.M. and Pospisilik, J.A.

DOI: 10.1016/j.cmet.2018.04.013

The Polycomb-dependent epigenome controls -cell dysfunction, dedifferentiation and diabetes

bioRxiv

Lu, T.T.-H. and Heyne, S. and Dror, E. and Casas, E. and Leonhardt, L. and Boenke, T. and Yang, C.-H. and Sagar and Arrigoni, L. and Dalgaard, K. and Teperino, R. and Enders, L. and Selvaraj, M. and Ruf, M. and Raja, S.J. and Xie, H. and Boenisch, U. and Orkin, S.H. and Lynn, F.C. and Hoffman, B.G. and Grn, D. and Vavouri, T. and Lempradl, A. and Andrew Pospisilik, J.

DOI: 10.1101/205641

Phosphorylation of NEUROG3 Links Endocrine Differentiation to the Cell Cycle in Pancreatic Progenitors

Developmental Cell

Krentz, N.A.J. and van Hoof, D. and Li, Z. and Watanabe, A. and Tang, M. and Nian, C. and German, M.S. and Lynn, F.C.

DOI: 10.1016/j.devcel.2017.02.006

SOX4 allows facultative-cellproliferation through repression of cdkn1a

Diabetes

Xu, E.E. and Sasaki, S. and Speckmann, T. and Nian, C. and Lynn, F.C.

DOI: 10.2337/db16-1074

Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces Cell Proliferation

Cell Metabolism

Szabat, M. and Page, M.M. and Panzhinskiy, E. and Skovs?, S?. and Mojibian, M. and Fernandez-Tajes, J. and Bruin, J.E. and Bround, M.J. and Lee, J.T.C. and Xu, E.E. and Taghizadeh, F. and O'Dwyer, S. and Van De Bunt, M. and Moon, K.-M. and Sinha, S. and Han, J. and Fan, Y. and Lynn, F.C. and Trucco, M. and Borchers, C.H. and Foster, L.J. and Nislow, C. and Kieffer, T.J. and Johnson, J.D.

DOI: 10.1016/j.cmet.2015.10.016

Generation of a conditional allele of the transcription factor Atonal Homolog 8 (Atoh8)

PLoS ONE

Ejarque, M. and Mir-Coll, J. and Gomis, R. and German, M.S. and Lynn, F.C. and Gasa, R.

DOI: 10.1371/journal.pone.0146273

Reawakening the duct cell progenitor?

Endocrinology

Verchere, C.B. and Lynn, F.C.

DOI: 10.1210/en.2015-2008

Npas4 transcription factor expression is regulated by calcium signaling pathways and prevents tacrolimus-induced cytotoxicity in pancreatic beta cells

Journal of Biological Chemistry

Speckmann, T. and Sabatini, P.V. and Nian, C. and Smith, R.G. and Lynn, F.C.

DOI: 10.1074/jbc.M115.704098

Using CRISPR-Cas9 genome editing to enhance cell based therapies for the treatment of diabetes mellitus

Genome Editing

Krentz, N.A.J. and Lynn, F.C.

DOI: 10.1007/978-3-319-34148-4_8

Use-dependent activation of neuronal Kv1.2 channel complexes.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Baronas VA and McGuinness BR and Brigidi GS and Gomm Kolisko RN and Vilin YY and Kim RY and Lynn FC and Bamji SX and Yang R and Kurata HT

DOI: 10.1523/jneurosci.4518-13.2015 PubMed: 25716850

02 / 2015

SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models

Diabetologia

Xu, E.E. and Krentz, N.A.J. and Tan, S. and Chow, S.Z. and Tang, M. and Nian, C. and Lynn, F.C.

DOI: 10.1007/s00125-015-3507-x

All-encomPASsing regulation of -cells: PAS domain proteins in -cell dysfunction and diabetes

Trends in Endocrinology and Metabolism

Sabatini, P.V. and Lynn, F.C.

DOI: 10.1016/j.tem.2014.11.002

Quetiapine treatment in youth is associated with decreased insulin secretion

Journal of Clinical Psychopharmacology

Ngai, Y.F. and Sabatini, P. and Nguyen, D. and Davidson, J. and Chanoine, J.-P. and Devlin, A.M. and Lynn, F.C. and Panagiotopoulos, C.

DOI: 10.1097/JCP.0000000000000118

Glycoprotein 130 receptor signaling mediates a-cell dysfunction in a rodent model of type 2 diabetes

Diabetes

Chow, S.Z. and Speck, M. and Yoganathan, P. and Nackiewicz, D. and Hansen, A.M. and Ladefoged, M. and Rabe, B. and Rose-John, S. and Voshol, P.J. and Lynn, F.C. and Herrera, P.L. and Mller, W. and Ellingsgaard, H. and Ehses, J.A.

DOI: 10.2337/db13-1121

Characterization of polyhormonal insulin-producing cells derived in vitro from human embryonic stem cells

Stem Cell Research

Bruin, J.E. and Erener, S. and Vela, J. and Hu, X. and Johnson, J.D. and Kurata, H.T. and Lynn, F.C. and Piret, J.M. and Asadi, A. and Rezania, A. and Kieffer, T.J.

DOI: 10.1016/j.scr.2013.10.003

TALEN/CRISPR-mediated eGFP knock-in add-on at the OCT4 locus does not impact differentiation of human embryonic stem cells towards endoderm

PLoS ONE

Krentz, N.A.J. and Nian, C. and Lynn, F.C.

DOI: 10.1371/journal.pone.0114275

Identification and analysis of murine pancreatic islet enhancers

Diabetologia

Tennant, B.R. and Robertson, A.G. and Kramer, M. and Li, L. and Zhang, X. and Beach, M. and Thiessen, N. and Chiu, R. and Mungall, K. and Whiting, C.J. and Sabatini, P.V. and Kim, A. and Gottardo, R. and Marra, M.A. and Lynn, F.C. and Jones, S.J.M. and Hoodless, P.A. and Hoffman, B.G.

DOI: 10.1007/s00125-012-2797-5

The transcription factor atonal homolog 8 regulates Gata4 and friend of Gata-2 during vertebrate development

Journal of Biological Chemistry

Rawnsley, D.R. and Xiao, J. and Lee, J.S. and Liu, X. and Mericko-Ishizuka, P. and Kumar, V. and He, J. and Basu, A. and Lu, M. and Lynn, F.C. and Pack, M. and Gasa, R. and Kahn, M.L.

DOI: 10.1074/jbc.M113.463083

Npas4 Is a novel activity-Regulated cytoprotective factor in pancreatic -Cells

Diabetes

Sabatini, P.V. and Krentz, N.A.J. and Zarrouki, B. and Westwell-Roper, C.Y. and Nian, C. and Uy, R.A. and Shapiro, A.M.J. and Poitout, V. and Lynn, F.C.

DOI: 10.2337/db12-1527

Noncoding RNAs

Experimental Diabetes Research

Hardikar, A.A. and Walker, M.D. and Lynn, F.

DOI: 10.1155/2012/629249

Maintenance of -cell maturity and plasticity in the adult pancreas: Developmental biology concepts in adult physiology

Diabetes

Szabat, M. and Lynn, F.C. and Hoffman, B.G. and Kieffer, T.J. and Allan, D.W. and Johnson, J.D.

DOI: 10.2337/db11-1361

Regulation of GIP and GLP1 receptor cell surface expression by N-glycosylation and receptor heteromerization

PLoS ONE

Whitaker, G.M. and Lynn, F.C. and McIntosh, C.H.S. and Accili, E.A.

DOI: 10.1371/journal.pone.0032675

A mouse model for monitoring islet cell genesis and developing therapies for diabetes

DMM Disease Models and Mechanisms

Shimajiri, Y. and Kosaka, Y. and Scheel, D.W. and Lynn, F.C. and Kishimoto, N. and Wang, J. and Zhao, S. and German, M.S.

DOI: 10.1242/dmm.002998

Sequence and epigenetic determinants in the regulation of the Math6 gene by Neurogenin3

Differentiation

Pujadas, G. and Felipe, F. and Ejarque, M. and Sanchez, L. and Cervantes, S. and Lynn, F.C. and Gomis, R. and Gasa, R.

DOI: 10.1016/j.diff.2011.05.006

Serotonin regulates pancreatic beta cell mass during pregnancy

Nature Medicine

Kim, H. and Toyofuku, Y. and Lynn, F.C. and Chak, E. and Uchida, T. and Mizukami, H. and Fujitani, Y. and Kawamori, R. and Miyatsuka, T. and Kosaka, Y. and Yang, K. and Honig, G. and Van Der Hart, M. and Kishimoto, N. and Wang, J. and Yagihashi, S. and Tecott, L.H. and Watada, H. and German, M.S.

DOI: 10.1038/nm.2173

Rfx6 directs islet formation and insulin production in mice and humans

Nature

Smith, S.B. and Qu, H.-Q. and Taleb, N. and Kishimoto, N.Y. and Scheel, D.W. and Lu, Y. and Patch, A.-M. and Grabs, R. and Wang, J. and Lynn, F.C. and Miyatsuka, T. and Mitchell, J. and Seerke, R. and Dsir, J. and Eijnden, S.V. and Abramowicz, M. and Kacet, N. and Weill, J. and Renard, M.-E. and Gentile, M. and Hansen, I. and Dewar, K. and Hattersley, A.T. and Wang, R. and Wilson, M.E. and Johnson, J.D. and Polychronakos, C. and German, M.S.

DOI: 10.1038/nature08748

Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors

Endocrine-Related Cancer

Wang, Y.-C. and Gallego-Arteche, E. and Iezza, G. and Yuan, X. and Matli, M.R. and Choo, S.-P. and Zuraek, M.B. and Gogia, R. and Lynn, F.C. and German, M.S. and Bergsland, E.K. and Donner, D.B. and Warren, R.S. and Nakakura, E.K.

DOI: 10.1677/ERC-08-0127

Meta-regulation: microRNA regulation of glucose and lipid metabolism

Trends in Endocrinology and Metabolism

Lynn, F.C.

DOI: 10.1016/j.tem.2009.05.007

Identification of the bHLH factor Math6 as a novel component of the Embryonic Pancreas Transcriptional Network

PLoS ONE

Lynn, F.C. and Sanchez, L. and Gomis, R. and German, M.S. and Gasa, R.

DOI: 10.1371/journal.pone.0002430

Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insulinotropic polypeptide receptor

Journal of Medicinal Chemistry

Kodra, J.T. and J?rgensen, A.S. and Andersen, B. and Behrens, C. and Brand, C.L. and Christensen, I.T. and Guldbrandt, M. and Jeppesen, C.B. and Knudsen, L.B. and Madsen, P. and Nishimura, E. and Sams, C. and Sidelmann, U.G. and Pedersen, R.A. and Lynn, F.C. and Lau, J.

DOI: 10.1021/jm7015599

Mouse let-7 miRNA populations exhibit RNA editing that is constrained in the 5'-seed/cleavage/anchor regions and stabilize predicted mmu-let-7a:mRNA duplexes

Genome Research

Reid, J.G. and Nagaraja, A.K. and Lynn, F.C. and Drabek, R.B. and Muzny, D.M. and Shaw, C.A. and Weiss, M.K. and Naghavi, A.O. and Khan, M. and Zhu, H. and Tennakoon, J. and Gunaratne, G.H. and Corry, D.B. and Miller, J. and McManus, M.T. and German, M.S. and Gibbs, R.A. and Matzuk, M.M. and Gunaratne, P.H.

DOI: 10.1101/gr.078246.108

Induction of pancreatic islet cell differentiation by the neurogenin-neuroD cascade

Differentiation

Gasa, R. and Mrejen, C. and Lynn, F.C. and Skewes-Cox, P. and Sanchez, L. and Yang, K.Y. and Lin, C.-H. and Gomis, R. and German, M.S.

DOI: 10.1111/j.1432-0436.2007.00228.x

Post-translational regulation of the beta-cell specific factor Nkx6.1

Developmental Biology

Anastasia Mavropoulos and Francis C. Lynn and Skewes-Cox Peter and Michael T. MacManus and Michael S. German

DOI: 10.1016/j.ydbio.2007.03.262

06 / 2007

Sox9 coordinates a transcriptional network in pancreatic progenitor cells

Proceedings of the National Academy of Sciences of the United States of America

Lynn, F.C. and Smith, S.B. and Wilson, M.E. and Yang, K.Y. and Nekrep, N. and German, M.S.

DOI: 10.1073/pnas.0704054104

MicroRNA expression is required for pancreatic islet cell genesis in the mouse

Diabetes

Lynn, F.C. and Skewes-Cox, P. and Kosaka, Y. and McManus, M.T. and Harfe, B.D. and German, M.S.

DOI: 10.2337/db07-0175

Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat

Biochemical and Biophysical Research Communications

Piteau, S. and Olver, A. and Kim, S.-J. and Winter, K. and Pospisilik, J.A. and Lynn, F. and Manhart, S. and Demuth, H.-U. and Speck, M. and Pederson, R.A. and McIntosh, C.H.S.

DOI: 10.1016/j.bbrc.2007.08.115

The HMG box transcription factor Sox4 contributes to the development of the endocrine pancreas

Diabetes

Wilson, M.E. and Yang, K.Y. and Kalousova, A. and Lau, J. and Kosaka, Y. and Lynn, F.C. and Wang, J. and Mrejen, C. and Episkopou, V. and Clevers, H.C. and German, M.S.

DOI: 10.2337/diabetes.54.12.3402

A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Lynn FC and Thompson SA and Pospisilik JA and Ehses JA and Hinke SA and Pamir N and McIntosh CH and Pederson RA

PubMed: 12475913

01 / 2003

Glucose-dependent Insulinotropic Polypeptide (GIP): Development of DP IV-resistant analogues with therapeutic potential

Advances in Experimental Medicine and Biology

Hinke, S.A. and Lynn, F. and Ehses, J. and Pamir, N. and Manhart, S. and Khn-Wache, K. and Rosche, F. and Demuth, H.-U. and Pederson, R.A. and McIntosh, C.H.S.

Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis

American Journal of Physiology - Endocrinology and Metabolism

Pamir, N. and Lynn, F.C. and Buchan, A.M.J. and Ehses, J. and Hinke, S.A. and Pospisilik, J.A. and Miyawaki, K. and Yamada, Y. and Seino, Y. and McIntosh, C.H.S. and Pederson, R.A.

DOI: 10.1152/ajpendo.00270.2002

Dipeptidyl peptidase IV inhibitor treatment stimulates -cell survival and islet neogenesis in streptozotocin-induced diabetic rats

Diabetes

Pospisilik, J.A. and Martin, J. and Doty, T. and Ehses, J.A. and Pamir, N. and Lynn, F.C. and Piteau, S. and Demuth, H.-U. and McIntosh, C.H.S. and Pederson, R.A.

DOI: 10.2337/diabetes.52.3.741

Structure-activity relationships of glucose-dependent insulinotropic polypeptide (GIP)

Biological Chemistry

Hinke, S.A. and Gelling, R. and Manhart, S. and Lynn, F. and Pederson, R.A. and Khn-Wache, K. and Rosche, F. and Demuth, H.-U. and Coy, D. and McIntosh, C.H.S.

DOI: 10.1515/BC.2003.046

Glucose-dependent insulinotropic polypeptide (GIP): development of DP IV-resistant analogues with therapeutic potential.

Advances in experimental medicine and biology

Hinke SA and Lynn F and Ehses J and Pamir N and Manhart S and Khn-Wache K and Rosche F and Demuth HU and Pederson RA and McIntosh CH

PubMed: 12675251

Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats

Diabetes

Lynn, F.C. and Pamir, N. and Ng, E.H.C. and McIntosh, C.H.S. and Kieffer, T.J. and Pederson, R.A.

DOI: 10.2337/diabetes.50.5.1004

Glucose-dependent insulinotropic polypeptide stimulation of lipolysis in differentiated 3T3-L1 cells: Wortmannin-sensitive inhibition by insulin

Endocrinology

McIntosh, C.H.S. and Bremsak, I. and Lynn, F.C. and Gill, R. and Hinke, S.A. and Gelling, R. and Nian, C. and McKnight, G. and Jaspers, S. and Pederson, R.A.

DOI: 10.1210/endo.140.1.6464

Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor ile-thiazolidide

Metabolism: Clinical and Experimental

Pauly, R.P. and Demuth, H.-U. and Rosche, F. and Schmidt, J. and White, H.A. and Lynn, F. and McIntosh, C.H.S. and Pederson, R.A.

DOI: 10.1016/S0026-0495(99)90090-2

Characterization of the carboxyl-terminal domain of the rat glucose- dependent insulinotropic polypeptide (GIP) receptor. A role for serines 426 and 427 in regulating the rate of internalization

Journal of Biological Chemistry

Wheeler, M.B. and Gelling, R.W. and Hinke, S.A. and Tu, B. and Pederson, R.A. and Lynn, F. and Ehses, J. and McIntosh, C.H.S.

DOI: 10.1074/jbc.274.35.24593

HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane- associated huntingtin in the brain

Nature Genetics

Kalchman, M.A. and Koide, H.B. and McCutcheon, K. and Graham, R.K. and Nichol, K. and Nishiyama, K. and Kazemi-Esfarjani, P. and Lynn, F.C. and Wellington, C. and Metzler, M. and Goldberg, Y.P. and Kanazawa, I. and Gietz, R.D. and Hayden, M.R.

DOI: 10.1038/ng0597-44

Post-transcriptional Control of ß-cell genesis

Once transcribed there are further opportunities for gene regulation, including regulation of mRNA stability and regulation of the translation of mRNA into protein. These forms of regulation are known as post-transcriptional regulation and play crucial roles in both normal physiology and organismal development. Recently a novel class of genes, known as microRNAs (miRNAs), has been described that can post-transcriptionally regulate gene expression.

We have demonstrated that microRNAs are necessary for ß-cell formation and play a vital role in the Sox9-expressing progenitor cells prior to activation of Neurogenin3. Future work is focussed on understanding:

Which microRNAs are important for normal ß-cell genesis
How specific microRNAs impinge on the ß-cell developmental program
How micrcRNAs regulate normal ß-cell function
If specific microRNAs can drive or enhance ß-cell differentiation from human embryonic stem cells.

Transcriptional Control of ß-cell genesis

The central dogma of molecular biology posits that nuclear genomic DNA is transcribed into RNA, which is then translated into protein. These processes are highly regulated and dynamic changes in gene expression are necessary for normal development to occur. The classical model of gene regulation relies upon sequence-specific interactions of nuclear proteins called transcription factors with the promoter regions of genes. The gene regulatory outcome of transcription factor binding to DNA is dependent on both the intrinsic properties of the factor and the regulatory or promoter context. Transcription factors have an indispensable role during all the stages of ß-cell differentiation.

Our past work has focussed on two transcription factors that are important for ß-cell develcpment: Sox9 and Math6. Sox9, an SRY/HMGbox transcription factor, is expressed in the progenitor cells within the developing pancreas and is downregulated during ß-cell differentiation. We have demonstrated that Sox9 plays a bifunctional role in these cells: maintaining undifferentiated characteristics and positively regulating the pro-endocrine factor Neurogenin3. We do not currently understand what factors are necessary for switching between these two roles and this is an area of future research. Math6 is a basic-helix-loop-helix factor that is expressed downstream of Neurogenin3 and modulates the endocrine differentiation program possibly through regulating Neurogenin3 expression. We have generated both germline and conditional null Math6 mice and are currently trying to further understand its role in the formation of ß-cells.

Grants

Canucks for Kids Fund Catalyst Grant - 2013

Honours & Awards

Michael Smith Foundation for Health Research Scholar - 2012

Juvenile Diabetes Association Career Development Award - 2011

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