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TrxG Complex Catalytic and Non-catalytic Activity Play Distinct Roles in Pancreas Progenitor Specification and
Stephanie A Campbell1, Cassandra L McDonald2, Nicole A J Krentz1
1Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4E3, Canada; Diabetes Research Group, British Columbia Children's Hospital Research Institute, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
Cell Reports
|August 15, 2019
Summary
Trithorax group (TrxG) complexes regulate gene expression for pancreas development. Their catalytic activity and H3K4 methylation maintain transcriptional stability, crucial for endocrine and acinar cell differentiation.
Area of Science:
- Developmental Biology
- Epigenetics
- Molecular Biology
Background:
- Pancreas development relies on precise gene regulation for progenitor cell proliferation and differentiation.
- H3K4 methylation and Trithorax group (TrxG) complexes are epigenetic regulators implicated in developmental processes.
Purpose of the Study:
- To investigate the role of H3K4 methylation and TrxG complexes in mediating gene expression during pancreas development.
- To elucidate how TrxG complex assembly and catalytic activity impact endocrine and acinar cell differentiation.
Main Methods:
- Utilized pancreas progenitor spheroids to study TrxG complex assembly and differentiation.
- Employed in vivo loss-of-function models in PDX1+ cells to assess TrxG catalytic activity.
- Analyzed cell cycle progression, apoptosis, lineage allocation, and gene expression variance.
Main Results:
- Disruption of TrxG complex assembly, not catalytic activity, impaired endocrine differentiation in vitro.
- In vivo loss of TrxG catalytic activity led to increased apoptosis and G1 phase progenitors.
- Pancreas progenitors shifted to the acinar lineage, reducing endocrine progenitors (NEUROG3+).
- Later developmental stages showed decreased acinar and endocrine cell numbers, with incomplete acinar cell differentiation due to altered gene expression.
Conclusions:
- TrxG co-activator activity is essential for gene induction during pancreas development.
- TrxG catalytic activity and H3K4 methylation are critical for maintaining transcriptional stability and proper cell differentiation.
- Dysregulation of TrxG complexes disrupts pancreas development, affecting both progenitor cell fate and terminal differentiation.
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