Olfactory receptor genes make the case for inter-chromosomal interactions

Bashkirova, Elizaveta; Lomvardas, Stavros

doi:10.1016/j.gde.2019.07.004

Cited by 55 publications

(59 citation statements)

References 71 publications

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“…Single cell transcriptome analysis during mouse olfactory neurogenesis in early development reveals that expression of olfactory receptor (OR) genes becomes progressively restricted to one gene per neuron in each mature neuron instead of several receptor genes that express in immature neurons [115,116]. Expression of a single OR allele in olfactory sensory neurons is the outcome of coalescence of multiple intergenic enhancers to a multi-chromosomal hub that allows the expression of a single OR allele while the remaining OR genes converge into few heterochromatic compartments leading to effective transcriptional silencing [117]. Age associated chromosomal breakage and DNA damage lead to an increase in markers of genome instability [118] and requires many layers of regulatory functions such as inducing senescence [48], reducing accumulation of DNA damage and enhancing DNA repair pathways [119].…”

Section: Discussionmentioning

confidence: 99%

“…Naina Bhatia-Dey and Thomas Heinbockel* Department of Anatomy, Howard University College of Medicine, Washington, DC, USA *Address all correspondence to: theinbockel@howard.edu aging effects is also an effective strategy to minimize risk factor for neurodegeneration [119]. This is likely to retain olfactory acuity and ability based on the model proposed by Bashkirova and Lomvardas [117].…”

Section: Author Detailsmentioning

confidence: 99%

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Neurological and Neuropsychiatric Disorders in Relation to Olfactory Dysfunction

Bhatia‐Dey¹,

Heinbockel²

2020

Sino-Nasal and Olfactory System Disorders [Working Title]

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Olfaction is an underestimated sensory modality in terms of its predictive value as an indicator of disorders. It is a well-known phenomenon that a significant percentage of people afflicted with certain prevalent disorders causing degenerative neuropathology, progressive loss of memory and communication function, normal age-based decline of physiological functions, intellectual challenges, depressive and anxiety disorders as well as post-traumatic stress disorders, present with a range of olfactory deficits. Here, we review our understanding of these deficits and their relation to various clinical manifestations such as neurological and neuropsychiatric diseases and disorders. At the outset, we will briefly describe the olfactory pathway from olfactory sensory neurons in the nasal epithelium to the olfactory bulb and on to olfactory cortical and subcortical structures involved in olfaction such as the amygdala.

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Section: Discussionmentioning

confidence: 99%

Section: Author Detailsmentioning

confidence: 99%

Neurological and Neuropsychiatric Disorders in Relation to Olfactory Dysfunction

Bhatia‐Dey¹,

Heinbockel²

2020

Sino-Nasal and Olfactory System Disorders [Working Title]

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“…Here we focus on enhancer regulation in cis, which, at least in vertebrates, seems to be the most prevalent regulatory mechanism. Nevertheless, enhancer regulation can also occur in trans, with some interesting examples of interchromosomal enhancer-gene interactions being described in both flies and mammals (Müller and Schaffner, 1990;Bashkirova and Lomvardas, 2019;Monahan et al, 2019). Although several mechanisms have been proposed to explain the long-range regulatory activity of enhancers, the most accepted one is the so-called looping model, whereby enhancers and their targets become close to each other in 3-D nuclear space due to the formation of chromatin loops (Palstra et al, 2003).…”

Section: Long-range Gene Expression Control: Far In the Genome But CLmentioning

confidence: 99%

Rare or Overlooked? Structural Disruption of Regulatory Domains in Human Neurocristopathies

2020

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In the last few years, the role of non-coding regulatory elements and their involvement in human disease have received great attention. Among the non-coding regulatory sequences, enhancers are particularly important for the proper establishment of cell type-specific gene-expression programs. Furthermore, the disruption of enhancers can lead to human disease through two main mechanisms: (i) Mutations or copy number variants can directly alter the enhancer sequences and thereby affect expression of their target genes; (ii) structural variants can provoke changes in 3-D chromatin organization that alter neither the enhancers nor their target genes, but rather the physical communication between them. In this review, these pathomechanisms are mostly discussed in the context of neurocristopathies, congenital disorders caused by defects that occur during neural crest development. We highlight why, due to its contribution to multiple tissues and organs, the neural crest represents an important, yet understudied, cell type involved in multiple congenital disorders. Moreover, we discuss currently available resources and experimental models for the study of human neurocristopathies. Last, we provide some practical guidelines that can be followed when investigating human neurocristopathies caused by structural variants. Importantly, these guidelines can be useful not only to uncover the etiology of human neurocristopathies, but also of other human congenital disorders in which enhancer disruption is involved.

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“…Monogenic expression, the expression of a single gene from a large gene family, is essential for several important biological processes. One of the most striking examples of such regulation is the expression of a single odorant receptor from more than 1400 genes in mammalian olfactory sensory neurons 1 . Likewise, monogenic expression is a key feature of antigenic variation, an immune evasion strategy used by pathogens such as Plasmodium falciparum or Trypanosoma brucei .…”

Section: Main Textmentioning

confidence: 99%

Antigenic variation by switching inter-chromosomal interactions with an RNA splicing locus in trypanosomes

Faria

Luzak

Mueller

et al. 2020

Preprint

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24Highly selective gene expression is a key requirement for antigenic variation in several 25 pathogens, allowing evasion of host immune responses and maintenance of persistent 26 infections. African trypanosomes, parasites that cause lethal diseases in humans and 27 livestock, employ an antigenic variation mechanism that involves monogenic antigen 28 expression from a pool of >2500 antigen coding genes. In other eukaryotes, the expression of 29 individual genes can be enhanced by mechanisms involving the juxtaposition of otherwise 30 distal chromosomal loci in the three-dimensional nuclear space. However, trypanosomes lack 31 classical enhancer sequences or regulated transcription initiation and the monogenic 32 expression mechanism has remained enigmatic. Here, we show that the single expressed 33 antigen coding gene displays a specific inter-chromosomal interaction with a major mRNA 34 splicing locus. Chromosome conformation capture (Hi-C), revealed a dynamic reconfiguration 35 of this inter-chromosomal interaction upon activation of another antigen. Super-resolution 36 microscopy showed the interaction to be heritable and splicing dependent. We find that the 37 two genomic loci are connected by the antigen exclusion complex, whereby VEX1 associated 38 with the splicing locus and VEX2 with the antigen coding locus. Following VEX2 depletion, 39 loss of monogenic antigen expression was accompanied by increased interactions between 40 previously silent antigen genes and the splicing locus. Our results reveal a novel mechanism 41 to ensure monogenic expression, requiring the spatial integration of antigen transcription and 42 mRNA splicing in a dedicated compartment. These findings suggest a new means of post-43 transcriptional gene regulation. 44 45 3 Main Text: 46 Monogenic expression, the expression of a single gene from a large gene family, is 47 essential for several important biological processes. One of the most striking examples of such 48 regulation is the expression of a single odorant receptor from more than 1400 genes in 49 mammalian olfactory sensory neurons 1 . Likewise, monogenic expression is a key feature of 50 antigenic variation, an immune evasion strategy used by pathogens such as Plasmodium 51 falciparum or Trypanosoma brucei. Antigenic variation refers to the capacity of an infecting 52 organism to systematically alter the identity of proteins displayed to the host immune system 53 2 . How pathogens ensure the exclusive expression of only one antigen from a large pool of 54 antigen coding genes remains one of the most intriguing questions in infection biology. 55 In T. brucei, a unicellular parasite responsible for lethal and debilitating diseases in 56 humans and animals, 10 million copies of a single variant surface glycoprotein (VSG) isoform 57 are exposed on the surface of the parasite. The exclusive expression of only one VSG gene 58 per cell and the periodic switching of the expressed VSG gene allow the parasite to evade the 59 host immune system and to maintain persistent infecti...

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Olfactory receptor genes make the case for inter-chromosomal interactions

Cited by 55 publications

References 71 publications

Neurological and Neuropsychiatric Disorders in Relation to Olfactory Dysfunction

Neurological and Neuropsychiatric Disorders in Relation to Olfactory Dysfunction

Rare or Overlooked? Structural Disruption of Regulatory Domains in Human Neurocristopathies

Antigenic variation by switching inter-chromosomal interactions with an RNA splicing locus in trypanosomes

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