Olfactory receptor genes make the case for inter-chromosomal interactions

Abstract

The partitioning of the interphase nucleus into chromosome territories generally precludes DNA from making specific and reproducible inter-chromosomal contacts. However, with the development of powerful genomic and imaging tools for the analysis of the 3D genome, and with their application on an increasing number of cell types, it becomes apparent that regulated, specific, and functionally important inter-chromosomal contacts exist. Widespread and stereotypic inter-chromosomal interactions are at the center of chemosensation, where they regulate the singular and stochastic expression of olfactory receptor genes. In olfactory sensory neurons (OSNs) coalescence of multiple intergenic enhancers to a multi-chromosomal hub orchestrates the expression of a single OR allele, whereas convergence of the remaining OR genes from 18 chromosomes into a few heterochromatic compartments mediates their effective transcriptional silencing. In this review we describe the role of interchromosomal interactions in OR gene choice, and we describe other biological systems where such genomic interactions may contribute to regulatory robustness and transcriptional diversification.

Figure 1:

Olfactory receptor enhancers drive expression of the active OR gene in cis and in trans Intergenic olfactory receptor (OR) enhancers, residing in OR clusters aggregate in cis and in trans to drive the expression of the active OR allele (A) in olfactory sensory neurons (OSNs). Long-range enhancer interactions are mediated by Ldb1, and Ldb1 knockout OSNs don’t form an enhancer hub, precluding the expression of any OR gene (B). Deletion of a single enhancer abolishes its interaction with the enhancer hub and reduces the expression of local OR genes (C), illustrating the principle that OR enhancers are necessary in cis and redundant in trans.

Figure 2:

Actively transcribed genes interact around sites of concentrated transcriptional machinery Highly specific transcriptional hubs form in (A) olfactory sensory neurons (OSNs) when olfactory receptor (OR) enhancers co-bound by Lhx2, EBF and Ldb1 from multiple chromosomes coalesce in cis and in trans to drive expression of the active OR allele. Large and stable transcriptional hubs form at (B) embryonic stem cell (ESC) super-enhancers bound by ESC transcription factors and co-activators Mediator and Brd4, which can converge with other super-enhancers tens of megabases away. These hubs are distinct from the transient, non-specific interactions (C) between actively transcribed genes around highly dynamic pol II clusters.

Figure 3:

Diverse nuclear architecture facilitate chemosensory receptor choice in olfactory sensory neurons (OSNs) and are involved in cellular responses to stimuli. Singular expression of one olfactory receptor (OR) depends on the aggregation of silenced OR genes into a unique OR compartment and the interaction of the active OR allele with a multi-chromosomal, multi-enhancer hub (A), whereas singular expression of a trace amine-associated receptor (TAAR) is regulated locally by the repositioning of the active allele away from the nuclear lamina (B). Inter-chromosomal interactions facilitate the stochastic activation of IFN-β during cellular response to virus infection in mammalian cells (C) and play a crucial role in the yeast heat shock response (D), where HSF1 target genes aggregate for coordinated transcription.