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Cell type-specific interchromosomal interactions as a mechanism for transcriptional diversity

Adan Horta, Kevin Monahan, Lisa Bashkirova, Stavros Lomvardas

Preprint posted on March 23, 2018 https://www.biorxiv.org/content/early/2018/03/23/287532

Kissing in the nucleus after all? A new preprint reports highly specific regulatory interactions between olfactory receptor genes and their putative enhancers in trans.

Selected by Boyan Bonev

Why is it important?

Changes in 3D nuclear architecture can affect transcriptional output and disruptions in topology can result in pathogenic phenotypes. However, most regulatory interactions are thought to be constrained to the same chromosome due to the polymer nature of chromatin. Therefore, interchromosomal contacts are usually infrequent and there is a considerable debate whether they encode any meaningful regulatory information. In addition, whether these interactions are dynamically rewired during development and what are the consequences for gene expression is unclear.

 

What are the key findings?

In this preprint Lomvardas and colleagues explore the dynamics of 3D nuclear architecture using the fascinating developmental system of olfactory sensory neurons (OSN), where each neuron expresses stochastically only one out of more than 1000 olfactory receptors. Using stage and cell-type sorted primary progenitors and differentiated neurons, the authors perform genome-wide analysis of chromatin interactions with Hi-C. They show that olfactory receptor genes interact dynamically in trans only in differentiating and mature OSN, but not in progenitor cells or cortical neurons (Figure 1). Furthermore, the enhancers controlling olfactory gene expression (called “greek islands”) also interact strongly in trans in a cell-type specific manner. Finally, using an elegant system to purify neurons expressing only one olfactory receptor, they convincingly show that enhancer-promoter interactions between “greek islands” and the promoters of olfactory receptor genes occur dynamically and are correlated with the transcriptional state of the gene. In conclusion, the authors provide strong evidence that interchromosomal interactions can occur with high specificity and that they may be instructive to regulate gene expression.

Olfactory receptor genes interacting in trans (Horta et. al., bioRxiv 2018)

Questions arising

What are the molecular mechanisms behind the selectivity of olfactory receptor gene expression and the specificity of the enhancer-promoter interactions?

How and when are such interactions established during the transition between progenitor cells and mature neurons?

Are interchromosomal regulatory interactions specific to olfactory neurons or are they present in other postmitotic cell types?

 

Related Research

Monahan, K., et. al. & Lomvardas, S. Ldb1 mediates trans enhancement in mammals . bioRxiv (2018).
Clowney, E. J. & Lomvardas, S. Nuclear Aggregation of Olfactory Receptor Genes Governs Their Monogenic Expression. Cell 151, 724–737 (2012).
Johanson, T. et. al., & Rhys A. No kissing in the nucleus: Unbiased analysis reveals no evidence of trans chromosomal regulation of mammalian immune development (bioRxiv, 2017)

Tags: 3d genome, chromatin, epigenetics, neurons, nuclear architecture

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