Each mammalian olfactory sensory neuron stochastically expresses only one out of  thousands of olfactory receptor alleles and the molecular mechanism for this selection remains as one of the biggest puzzles in neurobiology. Through constructing and analyzing a mathematical model based on extensive experimental observations , we identified an evolutionarily optimized three-layer regulation mechanism that robustly generates single-allele expression. Zonal separation reduces the number of competing alleles. Bifunctional LSD1 and cooperative histone modification dynamics minimize multiple allele epigenetic activation and alleles trapped in incomplete epigenetic activation states. Subsequent allele competition for a limited number of enhancers through cooperative binding serves as final safeguard for single allele expression. The identified design principles demonstrate the importance of molecular cooperativity in selecting and maintaining monoallelic olfactory receptor expression.
Multiple-objective optimization is common in biological systems. In the mammalian olfactory system, each sensory neuron stochastically expresses only one out of up to thousands of olfactory receptor (OR) gene alleles; URLanism level the types of expressed ORs need to be maximized. Existing models focus only on monoallele activation, and cannot explain recent observations in mutants, especially the reduced global diversity of expressed ORs in G9a/GLP knockouts. In this work we integrated existing information on OR expression, and proposed an evolutionarily optimized three-layer regulation mechanism , which includes zonal segregation, epigenetic barrier crossing coupled to a negative feedback loop that mechanistically differs from previous theoretical proposals, and a novel enhancer competition step. This model not only recapitulates monoallelic OR expression, but also elucidates how the olfactory system maximizes and maintains the diversity of OR expression. The model has multiple predictions validated by existing experimental results, and particularly underscores cooperativity and synergy as a general design principle for multi-objective optimization in biology
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Each mammalian olfactory
Multiple-objective optimization is common in biological systems. In the mammalian olfactory system, each
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up to
R
alleles and the molecular mechanism for this selection remains as one of the biggest puzzles in neurobiology. Through constructing and analyzing a mathematical model based on extensive experimental observations , we identified
(OR) gene alleles; URLanism level the types of expressed ORs need to be maximized. Existing models focus only on monoallele activation, and cannot explain recent observations in mutants, especially the reduced global diversity of expressed ORs in G9a/GLP knockouts. In this work we integrated existing information on OR expression, and proposed
R
that robustly generates single-allele expression. Zonal separation reduces the number of competing alleles. Bifunctional LSD1 and cooperative histone modification dynamics minimize multiple allele epigenetic activation and alleles trapped in incomplete epigenetic activation states. Subsequent allele competition for a limited number of enhancers through cooperative binding serves as final safeguard for single allele
, which includes zonal segregation, epigenetic barrier crossing coupled to a negative feedback loop that mechanistically differs from previous theoretical proposals, and a novel enhancer competition step. This model not only recapitulates monoallelic OR expression, but also elucidates how the olfactory system maximizes and maintains the diversity of OR
R
identified design principles demonstrate the importance of molecular cooperativity in selecting and maintaining monoallelic olfactory receptor expression.
model has multiple predictions validated by existing experimental results, and particularly underscores cooperativity and synergy as a general design principle for multi-objective optimization in biology