| 1. |
- Gonzalez Bosca, Alejandra, et al.
(författare)
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Thermodynamic model of gene regulation for the Or59b olfactory receptor in Drosophila
- 2019
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Ingår i: PloS Computational Biology. - : PUBLIC LIBRARY SCIENCE. - 1553-734X .- 1553-7358. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Complex eukaryotic promoters normally contain multiple cis-regulatory sequences for different transcription factors (TFs). The binding patterns of the TFs to these sites, as well as the way the TFs interact with each other and with the RNA polymerase (RNAp), lead to combinatorial problems rarely understood in detail, especially under varying epigenetic conditions. The aim of this paper is to build a model describing how the main regulatory cluster of the olfactory receptor Or59b drives transcription of this gene in Drosophila. The cluster-driven expression of this gene is represented as the equilibrium probability of RNAp being bound to the promoter region, using a statistical thermodynamic approach. The RNAp equilibrium probability is computed in terms of the occupancy probabilities of the single TFs of the cluster to the corresponding binding sites, and of the interaction rules among TFs and RNAp, using experimental data of Or59b expression to tune the model parameters. The model reproduces correctly the changes in RNAp binding probability induced by various mutation of specific sites and epigenetic modifications. Some of its predictions have also been validated in novel experiments.
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| 2. |
- Jafari, Shadi, et al.
(författare)
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Cis-Regulatory Mechanisms for Robust Olfactory Sensory Neuron Class-restricted Odorant Receptor Gene Expression in Drosophila
- 2015
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Ingår i: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Odor perception requires that each olfactory sensory neuron (OSN) class continuously express a single odorant receptor (OR) regardless of changes in the environment. However, little is known about the control of the robust, class-specific OR expression involved. Here, we investigate the cis-regulatory mechanisms and components that generate robust and OSN class-specific OR expression in Drosophila. Our results demonstrate that the spatial restriction of expression to a single OSN class is directed by clusters of transcription-factor DNA binding motifs. Our dissection of motif clusters of differing complexity demonstrates that structural components such as motif overlap and motif order integrate transcription factor combinations and chromatin status to form a spatially restricted pattern. We further demonstrate that changes in metabolism or temperature perturb the function of complex clusters. We show that the cooperative regulation between motifs around and within the cluster generates robust, class-specific OR expression.
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| 3. |
- Jafari, Shadi, et al.
(författare)
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Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression
- 2012
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Ingår i: PLoS biology. - : Public Library of Science. - 1544-9173 .- 1545-7885. ; 10:3, s. e1001280-
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Tidskriftsartikel (refereegranskat)abstract
- The mechanism that specifies olfactory sensory neurons to express only one odorant receptor (OR) from a large repertoire is critical for odor discrimination but poorly understood. Here, we describe the first comprehensive analysis of OR expression regulation in Drosophila. A systematic, RNAi-mediated knock down of most of the predicted transcription factors identified an essential function of acj6, E93, Fer1, onecut, sim, xbp1, and zf30c in the regulation of more than 30 ORs. These regulatory factors are differentially expressed in antennal sensory neuron classes and specifically required for the adult expression of ORs. A systematic analysis reveals not only that combinations of these seven factors are necessary for receptor gene expression but also a prominent role for transcriptional repression in preventing ectopic receptor expression. Such regulation is supported by bioinformatics and OR promoter analyses, which uncovered a common promoter structure with distal repressive and proximal activating regions. Thus, our data provide insight into how combinatorial activation and repression can allow a small number of transcription factors to specify a large repertoire of neuron classes in the olfactory system.
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| 4. |
- Jafari, Shadi, et al.
(författare)
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Drosophila olfactory sensory neurons have two phases of gene expression regulation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Here, we investigate the gene regulatory mechanisms that buffer environmental challenges and are required for Drosophila OSNs to maintain their fate. Each OSN expresses one odorant receptor (OR) gene from a large OR gene repertoire and the expression is maintained throughout the life of the neuron. We demonstrate that OSNs transit from a permissive gene regulatory state at the end of development to a robust continuous regulatory state in mature OSNs that secure the expression of a single OR gene. We provide evidence that the switch is associated to a change in the H3K9 methylation state. We show that the H3K9 demetylase su(var)3-3 is required for the permissive phase and the robust phase require the H3K9 methylase, su(var) 3-9. We further show that H3K9 methylation status has a role in the regulation of gene expression during the environmental challenges. Thus, our data demonstrate that OSNs go through two separate phases that compensate the environmental fluctuations differently.
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| 5. |
- Jafari, Shadi
(författare)
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Mechanisms of Olfactory sensory neuron class maintenance in Drosophila : It is all about design and equilibrium
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- How the cellular diversity of our body is generated and maintained is still a great mystery regardless of the wealth of research that has been done on this issue. The greatest complexity is found in the nervous system that contains a vast number of neurons and displays a great diversity in cell types and classes. For example the Drosophila olfactory system is a complex but defined set of neurons with extremely high specificity and sensitivity. The 34 OSN classes are each defined by their expression of a specific odorant receptor (OR). During development each OSN chooses one OR from 60 different OR genes in the genome to express. Furthermore, a cell is subject to immense challenges during its life cycle. Confronting each challenge the cell needs to perform its function and maintain its fate. OSNs continue to express the same OR during their whole life regardless of fluctuations in the environment.Although the olfactory system is remarkably conserved across the phyla, it is still unclear how an OSN chooses to express a particular OR from a large genomic repertoire. In this thesis the final steps of the specification and diversification for establishing an OSN identity is addressed. We find seven transcription factors that are continuously required in different combinations for the expression of the Drosophila ORs. The TFs can in different background context both activate and repress OR expression, making the regulation more economical. We also imply that repression is crucial for correct OR gene expression. We further show that short DNA sequences from OR gene promoters are sufficient to drive OSN class specific expression. These regions contain clusters of TF binding motifs, which we show to be sensitive to any change in their composition or to changes of the internal or external environment. We demonstrate that the chromatin state is responsible for the clusters response to environmental challenges. We reveal that Su(var)3-9 controls the OSN response to environmental stresses. We address the epigenetic mechanisms that initiate and pertain the single OR expression to a single OSN class. Our results show that OSNs have an epigenetic switch marking the end of development and the transition to mature OSNs. This switch supplies the expression of a single OR gene.
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| 6. |
- Jafari, Shadi, et al.
(författare)
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Odor response adaptation in Drosophila : a continuous individualization process
- 2021
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Ingår i: Cell and Tissue Research. - : Springer. - 0302-766X .- 1432-0878. ; 83:1, s. 143-148
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Tidskriftsartikel (refereegranskat)abstract
- Olfactory perception is very individualized in humans and also in Drosophila. The process that individualize olfaction is adaptation that across multiple time scales and mechanisms shape perception and olfactory-guided behaviors. Olfactory adaptation occurs both in the central nervous system and in the periphery. Central adaptation occurs at the level of the circuits that process olfactory inputs from the periphery where it can integrate inputs from other senses, metabolic states, and stress. We will here focus on the periphery and how the fast, slow, and persistent (lifelong) adaptation mechanisms in the olfactory sensory neurons individualize the Drosophila olfactory system.
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| 7. |
- Jafari, Shadi, et al.
(författare)
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Stress and odorant receptor feedback during a critical period after hatching regulates olfactory sensory neuron differentiation in Drosophila
- 2021
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Ingår i: PLoS biology. - : Public Library of Science. - 1544-9173 .- 1545-7885. ; 19:4
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Tidskriftsartikel (refereegranskat)abstract
- Here, we reveal that the regulation of Drosophila odorant receptor (OR) expression during the pupal stage is permissive and imprecise. We found that directly after hatching an OR feedback mechanism both directs and refines OR expression. We demonstrate that, as in mice, dLsd1 and Su(var)3-9 balance heterochromatin formation to direct OR expression. We show that the expressed OR induces dLsd1 and Su(var)3-9 expression, linking OR level and possibly function to OR expression. OR expression refinement shows a restricted duration, suggesting that a gene regulatory critical period brings olfactory sensory neuron differentiation to an end. Consistent with a change in differentiation, stress during the critical period represses dLsd1 and Su(var)3-9 expression and makes the early permissive OR expression permanent. This induced permissive gene regulatory state makes OR expression resilient to stress later in life. Hence, during a critical period OR feedback, similar to in mouse OR selection, defines adult OR expression in Drosophila.
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| 8. |
- Jafari, Shadi, 1973-, et al.
(författare)
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Stress and odorant receptor feedback during a critical period after hatching regulates olfactory sensory neuron differentiation in Drosophila
- 2021
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Ingår i: PLoS biology. - : Public Library of Science. - 1544-9173 .- 1545-7885. ; 19:4
-
Tidskriftsartikel (refereegranskat)abstract
- Here, we reveal that the regulation of Drosophila odorant receptor (OR) expression during the pupal stage is permissive and imprecise. We found that directly after hatching an OR feedback mechanism both directs and refines OR expression. We demonstrate that, as in mice, dLsd1 and Su(var)3-9 balance heterochromatin formation to direct OR expression. We show that the expressed OR induces dLsd1 and Su(var)3-9 expression, linking OR level and possibly function to OR expression. OR expression refinement shows a restricted duration, suggesting that a gene regulatory critical period brings olfactory sensory neuron differentiation to an end. Consistent with a change in differentiation, stress during the critical period represses dLsd1 and Su(var)3-9 expression and makes the early permissive OR expression permanent. This induced permissive gene regulatory state makes OR expression resilient to stress later in life. Hence, during a critical period OR feedback, similar to in mouse OR selection, defines adult OR expression in Drosophila.
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| 9. |
- Sanchez, Gonzalo Manuel, et al.
(författare)
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Hedgehog Signaling Regulates the Ciliary Transport of Odorant Receptors in Drosophila
- 2016
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Ingår i: Cell Reports. - : CELL PRESS. - 2211-1247. ; 14:3, s. 464-470
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Tidskriftsartikel (refereegranskat)abstract
- Hedgehog (Hh) signaling is a key regulatory pathway during development and also has a functional role in mature neurons. Here, we show that Hh signaling regulates the odor response in adult Drosophila olfactory sensory neurons (OSNs). We demonstrate that this is achieved by regulating odorant receptor (OR) transport to and within the primary cilium in OSN neurons. Regulation relies on ciliary localization of the Hh signal transducer Smoothened (Smo). We further demonstrate that the Hh- and Smo-dependent regulation of the kinesin-like protein Cos2 acts in parallel to the intraflagellar transport system (IFT) to localize ORs within the cilium compartment. These findings expand our knowledge of Hh signaling to encompass chemosensory modulation and receptor trafficking.
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| 10. |
- Yan, Hua, et al.
(författare)
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Evolution, developmental expression and function of odorant receptors in insects
- 2020
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Ingår i: Journal of Experimental Biology. - : Company biologists LTD. - 0022-0949 .- 1477-9145. ; 223
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Forskningsöversikt (refereegranskat)abstract
- Animals rely on their chemosensory system to discriminate among a very large number of attractive or repulsive chemical cues in the environment, which is essential to respond with proper action. The olfactory sensory systems in insects share significant similarities with those of vertebrates, although they also exhibit dramatic differences, such as the molecular nature of the odorant receptors (ORs): insect ORs function as heteromeric ion channelswith a commonOrco subunit, unlike the G-protein-coupled olfactory receptors found in vertebrates. Remarkable progress has recently been made in understanding the evolution, development and function of insect odorant receptor neurons (ORNs). These studies have uncovered the diversity of olfactory sensory systems among insect species, including in eusocial insects that rely extensively on olfactory sensing of pheromones for social communication. However, further studies, notably functional analyses, are needed to improve our understanding of the origins of the Orco-OR system, the mechanisms of ORN fate determination, and the extraordinary diversity of behavioral responses to chemical cues.
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