HP1B and H3K9me3 Regulate Olfactory Receptor Choice and 2 Transcriptional Identity [RNA-Seq]

Diverse epigenetic regulatory mechanisms ensure and regulate cellular diversity. Among others, the histone 3 lysine 9 me3 (H3K9me3) post translational modification participates in silencing lineage-inappropriate genes. H3K9me3 restricts access of transcription factors and other regulatory proteins to genes that control cell fate. Mouse olfactory sensory neurons (OSN) select to express one olfactory receptor (OR) gene out of 2,600 possibilities. This monoallelic and stochastic OR choice happens as OSNs differentiate and undergo dramatic changes in nuclear architecture. OR genes from different chromosomes converge into specialized nuclear bodies and chromatin compartments, as H3K9me3 and chromatin binding proteins including heterochromatin protein 1 (HP1) are incorporated. In this work, we have uncovered an unexpected role for HP1b in OR choice and neuronal identity that cannot be rescued by HP1a in vivo. With the use of a conditional knock-in mouse model that replaces HP1b for HP1a, we observe changes in H3K9me3 levels and DNA accessibility over OR gene clusters. These changes alter the expression paTerns that partition the mouse olfactory epithelium into five OR expression zones, which results in a reduced OR repertoire leading to a loss of olfactory sensory neuron diversity. We propose that HP1b modulates the competition of OR-promoters for enhancers to promote receptor diversity, by establishing repression gradients in a zonal fashion.