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Cooperative interactions enable singular olfactory receptor expression in mouse olfactory neurons.
Kevin Monahan1, Ira Schieren1, Jonah Cheung2
1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.
Elife
|September 22, 2017
Summary
Transcription factors Lhx2 and Ebf specify olfactory receptor (OR) enhancers, regulating gene choice. Their displacement caused widespread OR downregulation, while enhancer hubs promoted OR choice, supporting interchromosomal interactions in gene expression.
Area of Science:
- Genetics
- Molecular Biology
- Epigenetics
Background:
- Olfactory receptor (OR) genes exhibit monogenic and monoallelic expression.
- This process involves large heterochromatic domains sequestering OR gene clusters.
- Intergenic enhancers within these domains form interchromosomal hubs over active ORs.
Purpose of the Study:
- To investigate the role of nuclear organization and specific transcription factors in olfactory receptor gene choice.
- To elucidate the mechanism by which enhancers regulate OR expression within heterochromatic domains.
Main Methods:
- Functional analysis of transcription factors Lhx2 and Ebf in OR enhancer specification.
- Assessing the impact of Lhx2 and Ebf displacement on OR transcription.
- Investigating the effect of multi-enhancer hub assembly on OR choice frequency.
Main Results:
- Lhx2 and Ebf cooperatively bind to OR enhancers, defying heterochromatin.
- Displacement of Lhx2 and Ebf led to long-range, trans downregulation of OR transcription.
- Pre-assembly of enhancer hubs increased the frequency of cis-acting OR choice.
Conclusions:
- Lhx2 and Ebf are sufficient to specify OR enhancers and regulate OR choice.
- Interchromosomal interactions are crucial for singular OR choice.
- The study provides regulatory principles for stochastic, mutually exclusive gene expression.