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Published on: January 26, 2018
Wdr5-mediated H3K4me3 coordinately regulates cell differentiation, proliferation termination, and survival in
Zhe Zhang1, Chun Yang1, Zixu Wang1
1MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
Abstract:
Food digestion requires the cooperation of different digestive organs. The differentiation of digestive organs is crucial for larvae to start feeding. Therefore, during digestive organogenesis, cell identity and the tissue morphogenesis must be tightly coordinated but how this is accomplished is poorly understood. Here, we demonstrate that WD repeat domain 5 (Wdr5)-mediated H3K4 tri-methylation (H3K4me3) coordinately regulates cell differentiation, proliferation and apoptosis in zebrafish organogenesis of three major digestive organs including intestine, liver, and exocrine pancreas. During zebrafish digestive organogenesis, some of cells in these organ primordia usually undergo differentiation without apoptotic activity and gradually reduce their proliferation capacity. In contrast, cells in the three digestive organs of wdr5-/- mutant embryos retain progenitor-like status with high proliferation rates, and undergo apoptosis. Wdr5 is a core member of COMPASS complex to implement H3K4me3 and its expression is enriched in digestive organs from 2 days post-fertilization (dpf). Further analysis reveals that lack of differentiation gene expression is due to significant decreases of H3K4me3 around the transcriptional start sites of these genes; this histone modification also reduces the proliferation capacity in differentiated cells by increasing the expression of apc to promote the degradation of β-Catenin; in addition, H3K4me3 promotes the expression of anti-apoptotic genes such as xiap-like, which modulates p53 activity to guarantee differentiated cell survival. Thus, our findings have discovered a common molecular mechanism for cell fate determination in different digestive organs during organogenesis, and also provided insights to understand mechanistic basis of human diseases in these digestive organs.
Insights
WD repeat domain 5 (Wdr5) protein regulates digestive organ development in zebrafish by controlling cell differentiation, proliferation, and apoptosis through H3K4 tri-methylation. This epigenetic mechanism ensures proper organogenesis and cell survival.
Area of Science:
- Developmental Biology
- Epigenetics
- Zebrafish Model Organisms
Background:
- Digestive organ development requires precise coordination of cell differentiation, proliferation, and apoptosis.
- The molecular mechanisms governing coordinated cell fate determination during organogenesis are not fully understood.
Purpose of the Study:
- To investigate the role of WD repeat domain 5 (Wdr5) in coordinating cell fate during the organogenesis of the intestine, liver, and exocrine pancreas in zebrafish.
- To elucidate the epigenetic mechanisms, specifically H3K4 tri-methylation (H3K4me3), underlying Wdr5-mediated regulation of digestive organ development.
Main Methods:
- Utilized zebrafish (Danio rerio) as a model organism.
- Generated and analyzed wdr5 knockout (wdr5-/-) mutant embryos.
- Assessed cell differentiation, proliferation, and apoptosis in digestive organ primordia.
- Investigated H3K4me3 levels at gene promoters using techniques such as ChIP-seq (Chromatin immunoprecipitation sequencing) or similar epigenetic analyses.
- Examined the expression of key genes involved in cell cycle regulation (e.g., APC, β-Catenin) and apoptosis (e.g., xiap-like, p53).
Main Results:
- Wdr5 is essential for proper organogenesis of the intestine, liver, and exocrine pancreas in zebrafish.
- Loss of Wdr5 leads to retention of progenitor-like cell status, increased proliferation, and elevated apoptosis in digestive organs.
- Wdr5-mediated H3K4me3 is crucial for the expression of differentiation genes.
- H3K4me3 regulates differentiated cell proliferation by modulating APC/β-Catenin signaling and promotes survival by upregulating anti-apoptotic genes like xiap-like.
Conclusions:
- Wdr5-mediated H3K4me3 acts as a common molecular mechanism coordinating cell differentiation, proliferation, and apoptosis during the organogenesis of multiple digestive organs.
- This epigenetic regulation ensures proper tissue morphogenesis and cell fate determination.
- Findings provide insights into the mechanistic basis of human diseases affecting digestive organs.
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