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Publications of the Week

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

By August 23, 2019August 26th, 2019No Comments

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This week we profile a recent publication in Cell Reports from the laboratory of
Dr. Brad Hoffman (pictured, right) at the BC Children’s Hospital Research Institute.

Can you provide a brief overview of your lab’s current research focus?

Our lab is currently focused on understanding the function of histone modifications, in specific histone H3 lysine 4 methylation, in regulating gene expression in pancreas development and in adult beta cell function. We are interested in determining why and how this histone modification is reduced in beta cells in type 2 diabetic patients, and what the repercussions of this might be to the function of these cells. Further, we have recently begun to try to determine the role of this histone modification in mediating learning and memory, and we hope to determine the relevance of this modification and its loss to Alzhiemer’s Disease.

What is the significance of the findings in this publication?

Although, histone H3 lysine 4  (H3K4) methylation has been widely thought to have a functional role in mediating gene expression, recent evidence suggests this may not in fact be the case. Several studies have now shown that previously reported function roles of H3K4 methylation are instead likely due to the co-activator activity of the complex that catalyzes H3K4 methylation. To address what role H3K4 methylation might play in pancreas development, we knocked out a component of this complex, called the TrxG complex, that allows the complex to maintain its co-activator activity, but preventing it from catalyzing H3K4 methylation. We find that while disrupting the co-activator activity of the complex dramatically impairs the induction of new genes during development, H3K4 methylation itself seems largely dispensable for gene activation and for bulk gene expression. However, particularly in the pancreatic acinar lineage, H3K4 methylation is essential for maintenance of the expression of terminal markers that are essential for acinar cell identity and function. This work suggests that H3K4 methylation does play a key role in mediating the expression of a subset of genes in mammalian systems, and raises the question of what its significance is in other cell types, including in developing and adult beta cells.

What are the next steps for this research?

We are now looking out the role of H3K4 methylation in the development of beta cells, and in adult beta cells. We have shown that H3K4 methylation is reduced in beta cells in type 2 diabetics, and are working on determining how and why this is occurring, and what the significance of this might be to T2D  pathophysiology.

This work was funded by:


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