HP1β and H3K9me3 Regulate Olfactory Receptor Choice and Transcriptional Identity

  1. Martín Escamilla-del-Arenal
  2. Rachel Duffié
  3. Hani Shayya
  4. Valentina Loconte
  5. Axel Ekman
  6. Lena Annika Street
  7. Adan Horta
  8. Daniele Canzio
  9. Kevin Monahan
  10. Carolyn Larabell
  11. Marko Jovanovic
  12. Stavros Lomvardas

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Abstract

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 cell-fate controlled genes. In mice, olfactory sensory neurons (OSN) 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 HP1β in OR choice and neuronal identity that cannot be rescued by HP1α in vivo . With the use of a conditional knock-in mouse model that replaces HP1β for HP1α, we observe changes in H3K9me3 levels, DNA accessibility, and Hi-C contacts over OR gene clusters. These changes alter the expression patterns 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 HP1β modulates the competition of OR-promoters for enhancers to promote receptor diversity, by establishing repression gradients in a zonal fashion.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/17992629.

    Summary

    This paper highlights a role for HP1β and H3K9me3 in modulating the spatial patterning of olfactory receptor genes in the main olfactory epithelium. While it was known that HP1 and H3K9me3 are crucial in silencing olfactory receptor genes that are not expressed in a given olfactory sensory neuron, the authors provide evidence that HP1β has a special role that can not be compensated for by HP1α. Furthermore, the authors provide data for a model where olfactory receptor genes harboring strong promoters have a high probability of being expressed and, consequentially, need to be heterochromatinized by HP1β and H3K9me3 in order to express olfactory receptor genes from weaker promoters. In particular, they show that olfactory receptors expressed in more dorsal zone 5 are under weaker promoters than those in zone 1, leading to a zone-specific enrichment of heterochromatin at strong promoters. While it was known that olfactory receptor genes compete for monoallelic expression and that olfactory receptor gene expression is spatially restricted, this level of detail about which olfactory receptor genes may have an advantage over others was not shown prior to this work. The data presented in this manuscript are supportive of the authors' proposed model and the manuscript is well written.

    Major points

    • In reading the results section of Figure 1 and Figure 2, I was left wondering where HP1α can be found in the OSN genome, if not at olfactory receptor genes, and whether this localization is observed in other tissues. In other words, is there a "default" localization pattern for HP1α that is preserved in OSNs, so HP1β is needed at olfactory receptor genes? It would be helpful to clarify this point with a supplemental figure. Furthermore, are HP1α and HP1β expressed at different times during OSN development? This question can be answered with additional commentary in the text.

    • In Figure 4D, it would be useful to see the number of genes that are significantly different in swap and control groups to gain a fuller appreciation of the extent to which swap impacts OR gene expression and in what zone. One way to do this includes denoting genes that pass a significance threshold in the existing Figure 4D. An alternative approach could be creating volcano plots (depicting log2foldchange on x-axis, adjusted p-value on y-axis) for each zone. In reading Figure 4D, I was left wondering the degree to which OR gene expression changes and which zone(s) those OR genes belong to.

    • In Figure 5, the authors present single cell RNA-seq data from mature OSNs and mention "non-OR genes were nearly unaffected (not shown)." Given the relationship between OR gene expression and dorsal-ventral gene expression, I was curious to know whether dorsal-ventral gene expression is unaffected in swap mice. This point can be addressed with additional commentary in the text.

    • The authors report that in the absence of HP1β, strong promoters lose heterochromatin in zone 5. I was left wondering how similar swap zone-5 heterochromatin and OR expression are to zone-1 in wildtype animals. In other words, to what extent does removing HP1β "convert" zone-5 heterochromatin and OR gene expression into patterns seen in wildtype zone-1? This question can be addressed either with additional commentary in the text or an additional figure panel that explicitly compares WT zone-1 and swap zone-5 OR expression.

    Minor point

    • Figure 1 depicts differences in HP1α and HP1β expression. In the discussion of this figure, it would be helpful to know more information about other forms of HP1, such as HP1-gamma, to gain a fuller appreciation for the specificity of HP1β's role in olfactory receptor gene regulation.

    Competing interests

    I am at the same institute and have collaborated with one of the authors of this work. While I did not contribute to this manuscript in any form, I declare this relationship for transparency.

    Use of Artificial Intelligence (AI)

    The author declares that they did not use generative AI to come up with new ideas for their review.

  2. Version published to 10.1101/2025.08.21.671605 on bioRxiv