Chromosomes Come Together to Help Mice Distinguish Odors
A study shows that a multi-chromosomal hub assembles in the mouse’s olfactory neurons to ensure that only one odor-sensing receptor is expressed in each neuron, a feature essential to odor discrimination. Come to think of it, what chromosomes are really capable of, as the body’s genetic material, is yet to be discovered. Olfactory Sensory Neurons (OSNs) are receptor neurons for odorant detection. Each of these neurons has the ability to distinguish between specific odors or, in other words, they express odorant detection specificity.
Mammals can easily discriminate between a large variety of volatile compound (probably more than a trillion!). This kind of extraordinary capacity is encoded by a plethora of olfactory-receptor genes that are literally present on almost all the chromosomes. As the response to different odors is specific, this ensures that each olfactory sensory neuron expresses a single, randomly selected olfactory-receptor gene. In the nuclei of the mice’s OSNs, certain regions of multiple chromosomes assemble in such a way that it controls the expression of the full repertoire of olfactory-receptor genes that reside in the nose, at the same time ensuring that each cell expresses only one specific gene. These findings provide solid evidence that inter-chromosomal interactions can have persuading role in expressing certain genes.
The expression of vertebrate genes is regulated by activating genomic elements called Enhancers. Enhancers can be found far away from the genes themselves but they are present on the same chromosome of the gene they regulate, forming cis-interactions. These regulatory interactions are mediated by transcription factors, supported by various proteins and require participating proteins and DNA elements to be interconnected in the nucleus.
Molecular techniques like Hi-C5 that capture the 3-D folding of chromatin(DNA and associated proteins) have actually revealed that the interactions between the genes and their enhancers occur in compact structures called Topologically Associating Domains(TADs) that categorize chromosomes into distinct cis-neighborhoods. Regarding Hi-C analyses, it has been used to uncover specific interactions between genes and genomic elements that have quite the distance between them in different TADs and even on different chromosomes which can be named as Trans-interactions. After observation, it has been seen that these particular interactions raised the possibility of trans-interactions influencing gene expression. However, because the prevalence of the trans-interactions is so much lower than the cis-interactions, their functional relevance still remains debatable.
Olfactory receptor genes were reported to form interchromosomal clusters more than a decade ago. Still, the role of these clusters was speculative because deletion of potential (trans) enhancers affected only the expression of the respective olfactory-genes on the same chromosome. A little while back, researchers from the same group known as Monahan et Al. identified 63 prospective olfactory-receptor-genes enhancers, which they named as Greek Islands, scattered across 16 to 20 chromosomes of mice cells. In the current paper, Monahan and colleagues provided an inclusive and functional high-resolution analysis of the 3-D organization of olfactory-receptor-gene clusters and the Greek Islands while differentiating mice OSNs.
The researchers used Hi-C to monitor the structural conformation of chromosomes in mature OSNs, the immediate instigators of OSNs and stem cells that give rise to these neurons. They observed interactions between olfactory-receptor gene clusters from different chromosomes in OSNs and their immediate instigators but these same interactions were absent in stem cells. The interactions involved in the entire gene clusters, which might correspond to the convoy of olfactory-receptor-genes in an area of dense chromatin that is seen by means of microscopy.
Monahan and colleagues, while working, also reported the presence of powerful and focal reciprocal cis and trans interactions in between Greek Islands present in mature OSNs, the specific reports directing towards using cells efficiently in transgenic mice. The Greek-Island hub appends the active olfactory-receptor gene expressed in the OSNs, but not the other silenced olfactory receptor genes. They deduced that the aggregation of olfactory-receptor-genes in a compartment of hetero-chromatin brings the Greek-Islands from specific chromosomes altogether. Deletion of the specific gene that encodes for the protein LHX2, a transcription factor bound to Greek Islands or another gene that encodes for LDB1( a co-factor of LHX2) effectively reduced interactions between Greek Islands which paved the way to the loss of olfactory-receptor gene expression.
Remarkably, Greek Islands normally act as structural organizers throughout the process, folding chromosomes into a compact, despotic and functioning structures and directing olfactory genes to the specific structures. Furthermore, they may be working as textbook enhancers that activate transcriptional machinery at the start of gene transcription only in the final step of selection and activation of olfactory-receptor genes, at the same time keeping the specific olfactory-gene robustly expressed.
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