Cooperative interactions enable singular olfactory receptor expression

Abstract

16The monogenic and monoallelic expression of only one out of >1000 olfactory receptor (ORs) and trans downregulation of OR transcription, whereas pre-assembly of a multi-enhancer hub increased the 24 frequency of OR choice in cis. Our data provide genetic support for the requirement and sufficiency of 25 interchromosomal interactions in singular OR choice and generate general regulatory principles for stochastic, 26 mutually exclusive gene expression programs.

Homeotic Regulation of Olfactory Receptor Choice via NFI-dependent Heterochromatic Silencing and Genomic Compartmentalization

“…We obtained ~2,000 peaks genome wide, with NFI motifs significantly enriched in these peaks, but we did not detect Nfi binding on zone 4/5 OR promoters (data not shown). This, however, is not surprising, since due to cellular heterogeneity none of the transcription factors known to regulate OR expression can be detected on OR promoters (Monahan et al, 2017). However, we detect Nfia signal on Greek Islands despite the lack of full NFI motifs on these enhancers (Supplemental Figure S5E).…”

“…Native chip was performed as described in detail (Monahan et al, 2017). Unless otherwise indicated all steps were carried out at 4°C.…”

“…OR compartments, which assemble due to downregulation of Lamin b receptor (Lbr) in OSN progenitors, also contribute to singular OR choice, by promoting assembly of an adjacent multi-chromosomal enhancer hub that associates with one of the previously silenced ORs, activating its transcription (Clowney et al, 2012;Markenscoff-Papadimitriou et al, 2014). This multi-enhancer hub consists of intergenic OR enhancers, the Greek Islands, which are bound by Lhx2, Ebf and Ldb1(Markenscoff-Papadimitriou et al, 2014;Monahan et al, 2019;Monahan et al, 2017). This tripartite protein complex promotes the highly specific interchromosomal contacts between Greek Islands, creating a strong transactivating complex responsible for the de-silencing and robust transcriptional activation of one of the compartmentalized OR alleles.…”

Activity and stress during a critical period regulate olfactory sensory neuron differentiation

“…This suggests transcription factor cooperativity and dLsd1 are both important for OR expression in flies. In mice, one of the few transcription factors known to regulate vertebrate OR expression, Lhx2 (Kolterud et al, 2004), requires cooperativity to maintain OR expression and counteract heterochromatin formation in OSNs (Monahan et al, 2017).…”

“…Transcription factor cooperativity defies heterochromatin formation and stabilizes Or59b expression. In mice, Lhx2, one of the few transcription factors known to regulate vertebrate OR expression (Kolterud et al, 2004), also requires cooperativity to block heterochromatin formation and establish OR expression (Monahan et al, 2017).…”