Overview

Understanding how the genes critical to endocrine pancreas development, as well as ß-cell function and proliferation are regulated is essential for the development of novel strategies for the production of insulin- secreting cells, and for improving the efficacy of available transplantable material.

The recent development of several novel experimental techniques is beginning to make the elucidation of the mechanisms behind the control of ß-cell critical genes, on a global basis, a feasible and tractable task in mammalian biology. The utilization of these techniques to understand endocrine pancreas development and function is highly novel and potentially extremely significant in advancing our understanding of these processes and is the focus of our research.

Publications

Chromatin Regulators in Pancreas Development and Diabetes
Trends in Endocrinology & Metabolism
2016

Myt3 suppression sensitizes islet cells to high glucose-induced cell death via Bim induction
Cell death & disease
2016

Myt3 Mediates Laminin-V/Integrin-$ß$1-Induced Islet-Cell Migration via Tgfbi
Molecular Endocrinology
2015

The TrxG complex mediates cytokine induced de novo enhancer formation in islets
PloS one
2015

The core trithorax protein Wdr5 is essential for specification of pancreas progenitors into endocrine and exocrine cell lineages
DIABETOLOGIA
2015

Myt3 Regulates Islet Spreading
Canadian Journal of Diabetes
2014

Identification and analysis of murine pancreatic islet enhancers
Diabetologia
2013

Probabilistic inference for nucleosome positioning with MNase-based or sonicated short-read data
PloS one
2012

Hyperinsulinemia drives diet-induced obesity independently of brain insulin production
Cell metabolism
2012

The Brain Expresses the Insulin and Ins2+/-Mice Display Increased High-fat Food Intake
Canadian Journal of Diabetes
2012

The transcription factor Myt3 acts as a pro-survival factor in $ß$-cells
PloS one
2012

Maintenance of $ß$-Cell Maturity and Plasticity in the Adult Pancreas Developmental Biology Concepts in Adult Physiology
Diabetes
2012

Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors
Diabetologia
2011

Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver
Genome research
2010

Paracrine signaling loops in adult pancreatic islets: Netrins modulate beta cell apoptosis via Neogenin and Unc5a
DIABETOLOGIA
2010

Differentiation of mouse embryonic stem cells into endoderm without embryoid body formation
PLoS One
2010

Genome-wide identification of DNA--protein interactions using chromatin immunoprecipitation coupled with flow cell sequencing
Journal of Endocrinology
2009

Identification of transcripts with enriched expression in the developing and adult pancreas
Genome biology
2008

A seriation approach for visualization-driven discovery of co-expression patterns in Serial Analysis of Gene Expression (SAGE) data
PloS one
2008

Silencing Bcl-2 in models of mantle cell lymphoma is associated with decreases in cyclin D1, nuclear factor-$¿$B, p53, bax, and p27 levels
Molecular cancer therapeutics
2008

Expression of Groucho/TLE proteins during pancreas development
BMC developmental biology
2008

Analysis of the Gro/Tle Co-repressors in pancreatic development
Developmental Biology
2007

Genome-wide analysis of Nkx2. 2 binding sites using ChIP-tag sequencing (ChIP-TS)
Developmental Biology
2007

SAGE reveals expression of Wnt signalling pathway members during mouse prostate development
Gene expression patterns
2006

Identification of novel genes and transcription factors involved in spleen, thymus and immunological development and function
Genes and immunity
2006

Antagonistic effects of Grg6 and Groucho/TLE on the transcription repression activity of brain factor 1/FoxG1 and cortical neuron differentiation
Molecular and cellular biology
2005

Differentiation of islet like clusters from endoderm-derived mouse embryonic stem cells
AMERICAN JOURNAL OF TRANSPLANTATION
2005

Identification of transcription factors involved in spleen, thymus, and immunological development
FASEB JOURNAL
2005

A mouse atlas of gene expression: large-scale digital gene-expression profiles from precisely defined developing C57BL/6J mouse tissues and cells
Proceedings of the National Academy of Sciences of the United States of America
2005

Analysis of the distribution and regulation of three representative subtilase genes in sapstaining fungi
Fungal Genetics and Biology
2004

The expression of Rbp-L during pancreatic development and in various pancreatic cancer cell lines.
DEVELOPMENTAL BIOLOGY
2004

Identification of genes regulating mouse prostate development using serial analysis of gene expression.
DEVELOPMENTAL BIOLOGY
2004

Disruption of the Subtilase Gene, albin1, in Ophiostoma piliferum
Applied and environmental microbiology
2004

Cloning and genetic analysis of subtilases in sapstaining fungi
Current genetics
2002

Action of Ophiostoma piceae proteinase and lipase on wood nutrients
Canadian journal of microbiology
1998

Research

Unravelling the ß-cell Cistrome
The cis-regulatory factors that regulate gene expression in the ß-cell are largely unknown. In addition, currently, two of the major questions facing biologists are ‘how do transcription factors identify their binding sites amongst the huge number of potential binding sites within the genome?” and “how is transcription factor binding translated into gene expression?”.

To address these questions and begin to decipher the cis-regulatory factors regulating gene expression during ß-cell development and function we are using the recently developed ChIP-seq technique. This technique employs the power of “next generation” or flow cell sequencing for the identification of DNA obtained from chromatin immunoprecipitation experiments, allowing the global localization of transcription factor binding sites and of epigenetic modifications. As such, we are currently using ChIP-seq to, genome-wide, determine binding sites for transcription factors critical to ß-cell development and function, and for the localization of epigenetic histone modifications that are thought to be important determinants of transcription factor binding. In addition, we are using flow cell sequencing based strategies to interrogate the ß-cell transcriptome using a combination of Tag-seq and RNA-seq approaches that allow an unprecedented level of insight into gene expression levels and the abundance of different transcriptional variants.

By assessing the binding locations of transcription factors, and the localization of epigenetic marks, in combination with gene expression data we can not only gain insight into the basic biology of how transcription factors recognize appropriate binding sites and how different factors work to modulate target gene expression, but also gain insight into how ß-cell fate is established and how ß-cell function is regulated at a transcriptional level.

Grants

Canadian Diabetes Association 2013 Scholar Award - Project: "Transcriptional and epigenetic regulation of beta-cell genesis, function and survival." 2013-2018.

Honours & Awards

Canucks for Kids Fund Catalyst Grant - 2013

Research Group Members

Jocelyn Begin, Graduate Student
Stephanie Campbell, Graduate Research Assistant
Nina Maeshima, Research Associate
Cassandra McDonald, Research Assistant/Tech I
Yuka Obayashi, Graduate Student Research Trainee
Priya Suresh, Research Assistant
Benjamin Vanderkruk, Graduate Research Asst