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
Campbell, Stephanie A and Hoffman, Brad G
2016

Myt3 suppression sensitizes islet cells to high glucose-induced cell death via Bim induction
Cell death & disease
Tennant, BR and Vanderkruk, B and Dhillon, J and Dai, D and Verchere, CB and Hoffman, BG
2016

The TrxG complex mediates cytokine induced de novo enhancer formation in islets
PloS one
Tennant, Bryan R and Hurley, Peter and Dhillon, Jasmine and Gill, Amol and Whiting, Cheryl and Hoffman, Brad G
2015

The core trithorax protein Wdr5 is essential for specification of pancreas progenitors into endocrine and exocrine cell lineages
DIABETOLOGIA
Campbell, SA and Tennant, BR and Whiting, CJ and Hoffman, BG
2015

Myt3 Mediates Laminin-V/Integrin-$ß$1-Induced Islet-Cell Migration via Tgfbi
Molecular Endocrinology
Tennant, Bryan R and Chen, Jenny and Shih, Alexis ZL and Luciani, Dan S and Hoffman, Brad G
2015

Myt3 Regulates Islet Spreading
Canadian Journal of Diabetes
Tennant, Bryan and Chen, Jenny and Hoffman, Brad
2014

Identification and analysis of murine pancreatic islet enhancers
Diabetologia
Tennant, BR and Robertson, AG and Kramer, M and Li, L and Zhang, X and Beach, M and Thiessen, N and Chiu, R and Mungall, K and Whiting, CJ and others
2013

Hyperinsulinemia drives diet-induced obesity independently of brain insulin production
Cell metabolism
Mehran, Arya E and Templeman, Nicole M and Brigidi, G Stefano and Lim, Gareth E and Chu, Kwan-Yi and Hu, Xiaoke and Botezelli, Jose Diego and Asadi, Ali and Hoffman, Bradford G and Kieffer, Timothy J and others
2012

The Brain Expresses the Insulin and Ins2+/-Mice Display Increased High-fat Food Intake
Canadian Journal of Diabetes
Mehran, Arya E and Hu, Xiaoke and Brigidi, G Stefano and Hoffman, Brad G and Bamji, Shernaz X and Clee, Susanne M and Johnson, James D
2012

The transcription factor Myt3 acts as a pro-survival factor in $ß$-cells
PloS one
Tennant, Bryan R and Islam, Ratib and Kramer, Marabeth M and Merkulova, Yulia and Kiang, Roger L and Whiting, Cheryl J and Hoffman, Brad G
2012

Maintenance of $ß$-Cell Maturity and Plasticity in the Adult Pancreas Developmental Biology Concepts in Adult Physiology
Diabetes
Szabat, Marta and Lynn, Francis C and Hoffman, Brad G and Kieffer, Timothy J and Allan, Douglas W and Johnson, James D
2012

Probabilistic inference for nucleosome positioning with MNase-based or sonicated short-read data
PloS one
Zhang, Xuekui and Robertson, Gordon and Woo, Sangsoon and Hoffman, Brad G and Gottardo, Raphael
2012

Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors
Diabetologia
Yang, YHC and Szabat, M and Bragagnini, C and Kott, K and Helgason, CD and Hoffman, BG and Johnson, JD
2011

Paracrine signaling loops in adult pancreatic islets: Netrins modulate beta cell apoptosis via Neogenin and Unc5a
DIABETOLOGIA
Yang, YHC and Hoffman, BG and Szabat, M and Bragagnini, C and Kott, K and Helgason, CD and Johnson, JD
2010

Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver
Genome research
Hoffman, Brad G and Robertson, Gordon and Zavaglia, Bogard and Beach, Mike and Cullum, Rebecca and Lee, Sam and Soukhatcheva, Galina and Li, Leping and Wederell, Elizabeth D and Thiessen, Nina and others
2010

Differentiation of mouse embryonic stem cells into endoderm without embryoid body formation
PLoS One
Kim, Peter TW and Hoffman, Brad G and Plesner, Annette and Helgason, Cheryl D and Verchere, C Bruce and Chung, Stephen W and Warnock, Garth L and Mui, Alice LF and Ong, Christopher J
2010

Genome-wide identification of DNA--protein interactions using chromatin immunoprecipitation coupled with flow cell sequencing
Journal of Endocrinology
Hoffman, Brad G and Jones, Steven JM
2009

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
Tucker, Catherine A and Kapanen, Anita I and Chikh, Ghania and Hoffman, Brad G and Kyle, Alastair H and Wilson, Ian M and Masin, Dana and Gascoyne, Randy D and Bally, Marcel and Klasa, Richard J
2008

A seriation approach for visualization-driven discovery of co-expression patterns in Serial Analysis of Gene Expression (SAGE) data
PloS one
Morozova, Olena and Morozov, Vyacheslav and Hoffman, Brad G and Helgason, Cheryl D and Marra, Marco A
2008

Identification of transcripts with enriched expression in the developing and adult pancreas
Genome biology
Hoffman, Brad G and Zavaglia, Bogard and Witzsche, Joy and de Algara, Teresa Ruiz and Beach, Mike and Hoodless, Pamela A and Jones, Steven JM and Marra, Marco A and Helgason, Cheryl D
2008

Expression of Groucho/TLE proteins during pancreas development
BMC developmental biology
Hoffman, Brad G and Zavaglia, Bogard and Beach, Mike and Helgason, Cheryl D
2008

Analysis of the Gro/Tle Co-repressors in pancreatic development
Developmental Biology
Zavaglia, Bogard and Hoffman, Brad and Witzsche, Joy and Helgason, Cheryl D
2007

Genome-wide analysis of Nkx2. 2 binding sites using ChIP-tag sequencing (ChIP-TS)
Developmental Biology
Hoffman, Brad and Kok, Daniel and Witzsche, Joy and Hirst, Martin and Robertson, Gordon and Hoodless, Pamela A and Marra, Marco and others
2007

SAGE reveals expression of Wnt signalling pathway members during mouse prostate development
Gene expression patterns
Zhang, Tian-Jiao and Hoffman, Brad G and de Algara, Teresa Ruiz and Helgason, Cheryl D
2006

Identification of novel genes and transcription factors involved in spleen, thymus and immunological development and function
Genes and immunity
Hoffman, BG and Williams, KL and Tien, AH and Lu, V and de Algara, T Ruiz and Ting, Jp-y and Helgason, CD
2006

Differentiation of islet like clusters from endoderm-derived mouse embryonic stem cells
AMERICAN JOURNAL OF TRANSPLANTATION
Kim, PTW and Hoffman, BG and Morse, JL and Helgason, CD and Chung, SW and Warnock, GL and Verchere, CB and Mui, ALF and Ong, CJ
2005

Identification of transcription factors involved in spleen, thymus, and immunological development
FASEB JOURNAL
Helgason, CD and de Algara, TR and Charters, A and Hoffman, BG
2005

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

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
Siddiqui, Asim S and Khattra, Jaswinder and Delaney, Allen D and Zhao, Yongjun and Astell, Caroline and Asano, Jennifer and Babakaiff, Ryan and Barber, Sarah and Beland, Jaclyn and Bohacec, Slavita and others
2005

Disruption of the Subtilase Gene, albin1, in Ophiostoma piliferum
Applied and environmental microbiology
Hoffman, Brad and Breuil, Colette
2004

Analysis of the distribution and regulation of three representative subtilase genes in sapstaining fungi
Fungal Genetics and Biology
Hoffman, Brad and Breuil, Colette
2004

Identification of genes regulating mouse prostate development using serial analysis of gene expression.
DEVELOPMENTAL BIOLOGY
Zhang, TJ and de Algara, TR and Hoffman, B and Helgason, CD
2004

The expression of Rbp-L during pancreatic development and in various pancreatic cancer cell lines.
DEVELOPMENTAL BIOLOGY
Hoffman, BG and de Algara, TR and Helgason, CD
2004

Cloning and genetic analysis of subtilases in sapstaining fungi
Current genetics
Hoffman, Brad and Breuil, Colette
2002

Action of Ophiostoma piceae proteinase and lipase on wood nutrients
Canadian journal of microbiology
Abraham, Linda and Hoffman, Brad and Gao, Yong and Breuil, Colette
1998

Research

Functional Analysis of Myt3, a New Player in the Transcriptional Networks controlling ß-cell Development, Function and Apoptosis
It is clear that both genome wide approaches and more targeted gene specific approaches are necessary to fully understand the transcriptional networks driving endocrine development and ß-cell function. One of the transcription factors identified in our analysis of the ß-cell transcriptorne is Myt3 (also called Sf18). Myt3 is abundantly expressed in adult islets but to date its role in ß-cell development or function has not been characterized. Our work suggests that Myt3 plays an interesting role in ß-cell development and function, and specifically in ß-cell survival and insulin expression and secretion.

In specific the aims of this project are to fully characterize the expression of Myt3 in pancreas development, to identify the regulatory regions responsible for Myt3’s high level of specificity to pancreatic islets, and to elucidate the role of Myt3 in the transcription network driving insulin expression and secretion.

To achieve these results we intend to use classic techniques such as Immunohisotchemistry, luciferase reporter assays, RNAi based suppression studies, and the generation of Myt3 knock-out mice, as well as, a combination of computational, gene expression profiling and ChIP-qPCR studies to identify Myt3 target genes and regulators.

This work is expected to provide novel information on the regulation and functional significance of Myt3 in ß-cell development and function.

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

Benjamin Vanderkruk
Stephanie Campbell
Meilin An
Nina Maeshima, Research Associate
Cassandra McDonald, Research Assistant/Tech I
Yuka Obayashi, Graduate Student Research Trainee