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KAP1-mediated epigenetic repression in the forebrain modulates behavioral vulnerability to stress.
Johan Jakobsson1, Maria Isabel Cordero, Reto Bisaz
1School of Life Sciences, National Center of Competence in Research, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Neuron
|December 17, 2008
Summary
The study found that KAP1 (KRAB-associated protein 1) is crucial for regulating gene expression in mature mouse brain neurons. Its absence leads to anxiety and memory deficits, highlighting its role in epigenetic control of behavior.
Area of Science:
- Neuroscience
- Epigenetics
- Molecular Biology
Background:
- KRAB-zinc finger proteins (KRAB-ZFPs) are vertebrate-specific epigenetic repressors with largely unknown functions.
- KAP1 is an essential cofactor for KRAB-ZFPs.
Purpose of the Study:
- To investigate the role of KAP1 in mature neurons of the mouse brain.
- To understand the function of KRAB-ZFP-mediated repression in the context of behavior and gene expression.
Main Methods:
- Generation of mice with KAP1 deleted in the adult forebrain.
- Behavioral analyses including anxiety-like and exploratory activity tests, and spatial learning and memory assessments.
- Chromatin immunoprecipitation and gene expression analysis in the hippocampus.
Main Results:
- KAP1 is highly expressed and necessary for KRAB-mediated repression in mature neurons.
- Mice lacking KAP1 in the forebrain display increased anxiety, exploratory activity, and altered stress responses.
- Dysregulation of specific genes, including imprinted genes, was observed in the hippocampus of knockout mice.
- Chromatin analysis revealed decreased H3K9me3 and increased H3/H4 acetylation at the promoters of upregulated genes.
Conclusions:
- KAP1 plays a critical role in epigenetic gene regulation within the hippocampus.
- KRAB-ZFP-mediated epigenetic control involving KAP1 influences behavioral responses to stress.
- This mechanism is essential for normal cognitive function and emotional regulation in adult mice.
