2025 Theses Doctoral

The HUSH Complex as an Epigenetic Regulator of Olfactory Receptor Choice

Osterhoudt, Alexa

The Human Silencing Hub (HUSH) complex is responsible for transcription-mediated silencing of retroelements that invade vertebrate genomes. Here, we show that the same surveillance mechanism is deployed for the transcription-mediated silencing of olfactory receptor genes in differentiating olfactory sensory neurons. Co-option of this anti-retrotransposon surveillance mechanism for the heterochromatic silencing of the largest mammalian gene family enables distributed transcriptional choice of the whole olfactory receptor repertoire, instead of biased expression of a few zonally dorsal ORs with the strongest ability to activate transcription at early stages.

This buffering mechanism assures that the rapid evolutionary expansion of the OR superfamily during the transition to terrestrial environments results in a meaningful expansion of the chemical spectrum that can be detected by olfactory sensory neurons. Thus, the emergence of HUSH facilitated vertebrate evolution in two parallel ways: it made retroelement proliferation tolerated by somatic cells and the expansion of gene families with retroelement-like genomic features, like the olfactory receptors, evolutionarily advantageous.