The Function of the Conserved Regulatory Element within the Second Intron of the Mammalian Csf1r Locus

Kristin A Sauter; M Amine Bouhlel; Julie O'Neal; David P Sester; Hiromi Tagoh; Richard M Ingram; Clare Pridans; Constanze Bonifer; David A Hume

doi:10.1371/journal.pone.0054935

The Function of the Conserved Regulatory Element within the Second Intron of the Mammalian Csf1r Locus

Kristin A Sauter, M Amine Bouhlel, Julie O'Neal, David P Sester, Hiromi Tagoh, Richard M Ingram, Clare Pridans, Constanze Bonifer, David A Hume

Royal (Dick) School of Veterinary Studies

Research output: Contribution to journal › Article › peer-review

Abstract

The gene encoding the receptor for macrophage colony-stimulating factor (CSF-1R) is expressed exclusively in cells of the myeloid lineages as well as trophoblasts. A conserved element in the second intron, Fms-Intronic Regulatory Element (FIRE), is essential for macrophage-specific transcription of the gene. However, the molecular details of how FIRE activity is regulated and how it impacts the Csf1r promoter have not been characterised. Here we show that agents that down-modulate Csf1r mRNA transcription regulated promoter activity altered the occupancy of key FIRE cis-acting elements including RUNX1, AP1, and Sp1 binding sites. We demonstrate that FIRE acts as an anti-sense promoter in macrophages and reversal of FIRE orientation within its native context greatly reduced enhancer activity in macrophages. Mutation of transcription initiation sites within FIRE also reduced transcription. These results demonstrate that FIRE is an orientation-specific transcribed enhancer element.

Original language	English
Pages (from-to)	e54935
Journal	PLoS ONE
Volume	8
Issue number	1
DOIs	https://doi.org/10.1371/journal.pone.0054935
Publication status	Published - 31 Jan 2013

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10.1371/journal.pone.0054935

The Function of the Conserved Regulatory Element within the Second Intron of the Mammalian Csf1r Locus
Copyright: © 2013 Sauter et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054935

Innate immunity and endemic diseases in livestock species
Collie, D. (Principal Investigator), Beard, P. (Co-investigator), Bishop, S. (Co-investigator), Bronsvoort, M. (Co-investigator), Burt, D. (Co-investigator), Fitzgerald, R. (Co-investigator), Freeman, T. (Co-investigator), Gally, D. (Co-investigator), Gill, A. (Co-investigator), Glass, E. (Co-investigator), Hocking, P. (Co-investigator), Hope, J. (Co-investigator), Hume, D. (Co-investigator), Kaiser, P. (Co-investigator), Mabbott, N. (Co-investigator), McLachlan, G. (Co-investigator), Morrison, L. (Co-investigator), Stevens, J. (Co-investigator), Stevens, M. (Co-investigator) & Watson, M. (Co-investigator)
Biotechnology and Biological Sciences Research Council
1/04/12 → 31/03/17
Project: Research
Csf1 and the control of postnatal growth and organ development in the rat
Hume, D. (Principal Investigator), Burdon, T. (Co-investigator), Farquharson, C. (Co-investigator) & Whitelaw, B. (Co-investigator)
MRC
12/07/10 → 11/06/14
Project: Research

Cite this

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title = "The Function of the Conserved Regulatory Element within the Second Intron of the Mammalian Csf1r Locus",

abstract = "The gene encoding the receptor for macrophage colony-stimulating factor (CSF-1R) is expressed exclusively in cells of the myeloid lineages as well as trophoblasts. A conserved element in the second intron, Fms-Intronic Regulatory Element (FIRE), is essential for macrophage-specific transcription of the gene. However, the molecular details of how FIRE activity is regulated and how it impacts the Csf1r promoter have not been characterised. Here we show that agents that down-modulate Csf1r mRNA transcription regulated promoter activity altered the occupancy of key FIRE cis-acting elements including RUNX1, AP1, and Sp1 binding sites. We demonstrate that FIRE acts as an anti-sense promoter in macrophages and reversal of FIRE orientation within its native context greatly reduced enhancer activity in macrophages. Mutation of transcription initiation sites within FIRE also reduced transcription. These results demonstrate that FIRE is an orientation-specific transcribed enhancer element.",

author = "Sauter, \{Kristin A\} and Bouhlel, \{M Amine\} and Julie O'Neal and Sester, \{David P\} and Hiromi Tagoh and Ingram, \{Richard M\} and Clare Pridans and Constanze Bonifer and Hume, \{David A\}",

note = "This work was supported by the Medical Research Council (http://www.mrc.ac.uk/index.htm) Grant G0901193 and a Roslin Foundation Grant (http://www.roslin.ed.ac.uk/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",

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AU - Sester, David P

AU - Tagoh, Hiromi

AU - Ingram, Richard M

AU - Pridans, Clare

AU - Bonifer, Constanze

AU - Hume, David A

N1 - This work was supported by the Medical Research Council (http://www.mrc.ac.uk/index.htm) Grant G0901193 and a Roslin Foundation Grant (http://www.roslin.ed.ac.uk/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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N2 - The gene encoding the receptor for macrophage colony-stimulating factor (CSF-1R) is expressed exclusively in cells of the myeloid lineages as well as trophoblasts. A conserved element in the second intron, Fms-Intronic Regulatory Element (FIRE), is essential for macrophage-specific transcription of the gene. However, the molecular details of how FIRE activity is regulated and how it impacts the Csf1r promoter have not been characterised. Here we show that agents that down-modulate Csf1r mRNA transcription regulated promoter activity altered the occupancy of key FIRE cis-acting elements including RUNX1, AP1, and Sp1 binding sites. We demonstrate that FIRE acts as an anti-sense promoter in macrophages and reversal of FIRE orientation within its native context greatly reduced enhancer activity in macrophages. Mutation of transcription initiation sites within FIRE also reduced transcription. These results demonstrate that FIRE is an orientation-specific transcribed enhancer element.

AB - The gene encoding the receptor for macrophage colony-stimulating factor (CSF-1R) is expressed exclusively in cells of the myeloid lineages as well as trophoblasts. A conserved element in the second intron, Fms-Intronic Regulatory Element (FIRE), is essential for macrophage-specific transcription of the gene. However, the molecular details of how FIRE activity is regulated and how it impacts the Csf1r promoter have not been characterised. Here we show that agents that down-modulate Csf1r mRNA transcription regulated promoter activity altered the occupancy of key FIRE cis-acting elements including RUNX1, AP1, and Sp1 binding sites. We demonstrate that FIRE acts as an anti-sense promoter in macrophages and reversal of FIRE orientation within its native context greatly reduced enhancer activity in macrophages. Mutation of transcription initiation sites within FIRE also reduced transcription. These results demonstrate that FIRE is an orientation-specific transcribed enhancer element.

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The Function of the Conserved Regulatory Element within the Second Intron of the Mammalian Csf1r Locus

Abstract

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Projects

Innate immunity and endemic diseases in livestock species

Csf1 and the control of postnatal growth and organ development in the rat

Cite this