Heterochromatin-Mediated Gene Silencing Facilitates the Diversification of Olfactory Neurons

• G9a and GLP help to generate stochastic olfactory receptor (OR) choice
• OSN diversity exhibits a G9a/GLP dose dependency
• The “one receptor per neuron” rule is violated in the absence of G9a and GLP
• Loss of H3K9me3 at OR clusters impairs OR nuclear topology

SummaryAn astounding property of the nervous system is its cellular diversity. This diversity, which was initially realized by morphological and electrophysiological differences, is ultimately produced by variations in gene-expression programs. In most cases, these variations are determined by external cues. However, a growing number of neuronal types have been identified in which inductive signals cannot explain the few but decisive transcriptional differences that cause cell diversification. Here, we show that heterochromatic silencing, which we find is governed by histone methyltransferases G9a (KMT1C) and GLP (KMT1D), is essential for stochastic and singular olfactory receptor (OR) expression. Deletion of G9a and GLP dramatically reduces the complexity of the OR transcriptome, resulting in transcriptional domination by a few ORs and loss of singularity in OR expression. Thus, our data suggest that, in addition to its previously known functions, heterochromatin creates an epigenetic platform that affords stochastic, mutually exclusive gene choices and promotes cellular diversity.

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