title: Long-range regulatory synergy is required to allow control of the TAC1 locus by MEK/ERK signalling in sensory neurones.
abstract: Changes in the expression of the neuropeptide substance P (SP) in different populations of sensory neurones are associated with the progression of chronic inflammatory disease. Thus, understanding the genomic and cellular mechanisms driving the expression of the TAC1 gene, which encodes SP, in sensory neurones is essential to understanding its role in inflammatory disease. We used a novel combination of computational genomics, primary-cell culture and mouse transgenics to determine the genomic and cellular mechanisms that control the expression of TAC1 in sensory neurones. Intriguingly, we demonstrated that the promoter of the TAC1 gene must act in synergy with a remote enhancer, identified using comparative genomics, to respond to MAPK signalling that modulates the expression of TAC1 in sensory neurones. We also reveal that noxious stimulation of sensory neurones triggers this synergy in larger diameter sensory neurones--an expression of SP associated with hyperalgesia. This noxious stimulation of TAC1 enhancer-promotor synergy could be strongly blocked by antagonism of the MEK pathway. This study provides a unique insight into the role of long-range enhancer-promoter synergy and selectivity in the tissue-specific response of promoters to specific signal transduction pathways and suggests a possible new avenue for the development of novel anti-inflammatory therapies.
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Lynne
authors.initials: L
authors.lastname: Shanley
authors.forename: Scott
authors.initials: S
authors.lastname: Davidson
authors.forename: Marissa
authors.initials: M
authors.lastname: Lear
authors.forename: Anil Kumar
authors.initials: AK
authors.lastname: Thotakura
authors.forename: Iain Joseph
authors.initials: IJ
authors.lastname: McEwan
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Ross
authors.forename: Alasdair
authors.initials: A
authors.lastname: MacKenzie
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002642:Chick Embryo; D004285:Dogs; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology*; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008253:Macaca mulatta; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011984:Sensory Receptor Cells / Q000201:enzymology* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D015320:Tachykinins / Q000235:genetics* / Q000502:physiology
chemical_list: D015320:Tachykinins