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Histone deacetylase activity is required for embryonic stem cell differentiation
Jeong-Heon Lee1, Suzanne R L Hart, David G Skalnik
1Herman B Wells Center for Pediatric Research, Section of Pediatric Hematology/Oncology, Department of Pediatrics and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Genesis (New York, N.Y. : 2000)
|February 3, 2004
Summary
Mammalian embryonic stem cells undergo significant epigenetic changes during differentiation, involving dynamic shifts in histone and cytosine methylation. Inhibiting histone deacetylation blocks this crucial developmental process.
Area of Science:
- Developmental Biology
- Epigenetics
- Stem Cell Biology
Background:
- Mammalian development relies on cell lineage commitment, which is regulated by epigenetic mechanisms controlling chromatin structure.
- Embryonic stem cells (ES cells) provide a model system to study these dynamic epigenetic changes during differentiation.
Purpose of the Study:
- To investigate global and gene-specific epigenetic modifications during in vitro differentiation of murine ES cells.
- To determine the role of specific epigenetic marks, such as histone acetylation and methylation, in ES cell differentiation.
Main Methods:
- Analysis of global histone acetylation and methylation (H3-Lys9, H3-Lys4) during ES cell differentiation.
- Assessment of global cytosine methylation patterns.
- Chromatin immunoprecipitation to examine promoter regions of key developmental genes (Oct4, Brachyury).
- Pharmacological inhibition of histone deacetylases using trichostatin A.
Main Results:
- Global histone acetylation decreased rapidly upon differentiation induction, while H3-Lys9 methylation increased.
- H3-Lys4 methylation showed transient decreases followed by recovery, and cytosine methylation slightly increased.
- Chromatin structure at Oct4 and Brachyury promoters changed in correlation with gene expression.
- Trichostatin A treatment prevented ES cell differentiation, highlighting the necessity of histone deacetylation.
Conclusions:
- Murine ES cell differentiation involves significant global and gene-specific chromatin remodeling.
- Dynamic epigenetic modifications, particularly histone acetylation and methylation, are critical for regulating cell fate decisions during development.
- Targeting epigenetic modifications offers potential therapeutic avenues for developmental disorders.