Long-Range Regulatory Synergy Is Required to Allow Control of the TAC1 Locus by MEK/ERK Signalling in Sensory Neurones

Lynne Shanley, Scott Davidson, Marissa Lear, Anil Kumar Thotakura, Iain Joseph McEwan, Ruth Alexandra Ross, Alasdair Mackenzie

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)173-185
Number of pages13
JournalNeuro-Signals
Volume18
Issue number3
DOIs
Publication statusPublished - 2010

Fingerprint

Internal-External Control
Mitogen-Activated Protein Kinase Kinases
Sensory Receptor Cells
Substance P
Genomics
Primary Cell Culture
Hyperalgesia
Neuropeptides
Transgenic Mice
Signal Transduction
Chronic Disease
Anti-Inflammatory Agents
Gene Expression
Population
Genes

Cite this

Long-Range Regulatory Synergy Is Required to Allow Control of the TAC1 Locus by MEK/ERK Signalling in Sensory Neurones. / Shanley, Lynne; Davidson, Scott; Lear, Marissa; Thotakura, Anil Kumar; McEwan, Iain Joseph; Ross, Ruth Alexandra; Mackenzie, Alasdair.

In: Neuro-Signals, Vol. 18, No. 3, 2010, p. 173-185.

Research output: Contribution to journalArticle

Shanley, Lynne ; Davidson, Scott ; Lear, Marissa ; Thotakura, Anil Kumar ; McEwan, Iain Joseph ; Ross, Ruth Alexandra ; Mackenzie, Alasdair. / Long-Range Regulatory Synergy Is Required to Allow Control of the TAC1 Locus by MEK/ERK Signalling in Sensory Neurones. In: Neuro-Signals. 2010 ; Vol. 18, No. 3. pp. 173-185.
@article{41bb1e3b89004683943f28042c13cdd2,
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.",
author = "Lynne Shanley and Scott Davidson and Marissa Lear and Thotakura, {Anil Kumar} and McEwan, {Iain Joseph} and Ross, {Ruth Alexandra} and Alasdair Mackenzie",
note = "Copyright {\circledC} 2010 S. Karger AG, Basel.",
year = "2010",
doi = "10.1159/000322010",
language = "English",
volume = "18",
pages = "173--185",
journal = "Neuro-Signals",
issn = "1424-862X",
publisher = "S. Karger AG",
number = "3",

}

TY - JOUR

T1 - Long-Range Regulatory Synergy Is Required to Allow Control of the TAC1 Locus by MEK/ERK Signalling in Sensory Neurones

AU - Shanley, Lynne

AU - Davidson, Scott

AU - Lear, Marissa

AU - Thotakura, Anil Kumar

AU - McEwan, Iain Joseph

AU - Ross, Ruth Alexandra

AU - Mackenzie, Alasdair

N1 - Copyright © 2010 S. Karger AG, Basel.

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

U2 - 10.1159/000322010

DO - 10.1159/000322010

M3 - Article

C2 - 21160161

VL - 18

SP - 173

EP - 185

JO - Neuro-Signals

JF - Neuro-Signals

SN - 1424-862X

IS - 3

ER -