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Human-specific epigenetic variation in the immunological Leukotriene B4 Receptor (LTB4R/BLT1) implicated in common inflammatory diseases.

Human-specific epigenetic variation in the immunological Leukotriene B4 Receptor (LTB4R/BLT1) implicated in common inflammatory diseases.
Human-specific epigenetic variation in the immunological Leukotriene B4 Receptor (LTB4R/BLT1) implicated in common inflammatory diseases.
Background: Common human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors. Due to the environment’s influence on the epigenome, and therefore genome function, as well as conversely the genome’s facilitative effect on the epigenome, analysis of this level of regulation may increase our knowledge of disease pathogenesis.

Methods: In order to identify human-specific epigenetic influences, we have performed a novel genome-wide DNA methylation analysis comparing human, chimpanzee and rhesus macaque.

Results: We have identified that the immunological Leukotriene B4 receptor (LTB4R, BLT1 receptor) is the most epigenetically divergent human gene in peripheral blood in comparison with other primates. This difference is due to the co-ordinated active state of human-specific hypomethylation in the promoter and human-specific increased gene body methylation. This gene is significant in innate immunity and the LTB4/LTB4R pathway is involved in the pathogenesis of the spectrum of human inflammatory diseases. This finding was confirmed by additional neutrophil-only DNA methylome and lymphoblastoid H3K4me3 chromatin comparative data. Additionally we show through functional analysis that this receptor has increased expression and a higher response to the LTB4 ligand in human versus rhesus macaque peripheral blood mononuclear cells. Genome-wide we also find human species-specific differentially methylated regions (human s-DMRs) are more prevalent in CpG island shores than within the islands themselves, and within the latter are associated with the CTCF motif.

Conclusions: This result further emphasises the exclusive nature of the human immunological system, its divergent adaptation even from very closely related primates, and the power of comparative epigenomics to identify and understand human uniqueness.
1-18
Wilson, Gareth A.
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Butcher, Lee M.
7744895f-2b21-42e3-80fe-17272f22c75e
Foster, Holly R.
57d2838c-01ad-435a-b1c6-789a02ef100b
Feber, Andrew
cdc62c70-e4c3-4a70-8eff-515a6eaf895b
Roos, Christian
d270f68b-2c11-41f3-b10b-a2fe6d4d8ddc
Walter, Lutz
edc3e97f-af3d-4f90-9f45-fd4be013ccb9
Woszczek, Grzegorz
7da060b5-b7ab-49c8-a24f-bb6b98d5de25
Beck, Stephan
50f0c07a-19a8-4bca-adbc-af41a3800412
Bell, Christopher G.
44982df7-0746-4cdb-bed1-0bdfe68f1a64
Wilson, Gareth A.
6af36a85-7d05-4989-9ab3-d8adac4d5eb8
Butcher, Lee M.
7744895f-2b21-42e3-80fe-17272f22c75e
Foster, Holly R.
57d2838c-01ad-435a-b1c6-789a02ef100b
Feber, Andrew
cdc62c70-e4c3-4a70-8eff-515a6eaf895b
Roos, Christian
d270f68b-2c11-41f3-b10b-a2fe6d4d8ddc
Walter, Lutz
edc3e97f-af3d-4f90-9f45-fd4be013ccb9
Woszczek, Grzegorz
7da060b5-b7ab-49c8-a24f-bb6b98d5de25
Beck, Stephan
50f0c07a-19a8-4bca-adbc-af41a3800412
Bell, Christopher G.
44982df7-0746-4cdb-bed1-0bdfe68f1a64

Wilson, Gareth A., Butcher, Lee M., Foster, Holly R., Feber, Andrew, Roos, Christian, Walter, Lutz, Woszczek, Grzegorz, Beck, Stephan and Bell, Christopher G. (2014) Human-specific epigenetic variation in the immunological Leukotriene B4 Receptor (LTB4R/BLT1) implicated in common inflammatory diseases. Genome Medicine, 6 (19), 1-18. (doi:10.1186/gm536). (PMID:24598577)

Record type: Article

Abstract

Background: Common human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors. Due to the environment’s influence on the epigenome, and therefore genome function, as well as conversely the genome’s facilitative effect on the epigenome, analysis of this level of regulation may increase our knowledge of disease pathogenesis.

Methods: In order to identify human-specific epigenetic influences, we have performed a novel genome-wide DNA methylation analysis comparing human, chimpanzee and rhesus macaque.

Results: We have identified that the immunological Leukotriene B4 receptor (LTB4R, BLT1 receptor) is the most epigenetically divergent human gene in peripheral blood in comparison with other primates. This difference is due to the co-ordinated active state of human-specific hypomethylation in the promoter and human-specific increased gene body methylation. This gene is significant in innate immunity and the LTB4/LTB4R pathway is involved in the pathogenesis of the spectrum of human inflammatory diseases. This finding was confirmed by additional neutrophil-only DNA methylome and lymphoblastoid H3K4me3 chromatin comparative data. Additionally we show through functional analysis that this receptor has increased expression and a higher response to the LTB4 ligand in human versus rhesus macaque peripheral blood mononuclear cells. Genome-wide we also find human species-specific differentially methylated regions (human s-DMRs) are more prevalent in CpG island shores than within the islands themselves, and within the latter are associated with the CTCF motif.

Conclusions: This result further emphasises the exclusive nature of the human immunological system, its divergent adaptation even from very closely related primates, and the power of comparative epigenomics to identify and understand human uniqueness.

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More information

Accepted/In Press date: 24 February 2014
e-pub ahead of print date: 5 March 2014
Published date: 5 March 2014
Organisations: Human Development & Health, Centre for Biological Sciences, MRC Life-Course Epidemiology Unit

Identifiers

Local EPrints ID: 400984
URI: http://eprints.soton.ac.uk/id/eprint/400984
PURE UUID: 94573ad1-dfad-4132-9bd2-793c11a14665
ORCID for Christopher G. Bell: ORCID iD orcid.org/0000-0003-4601-1242

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Date deposited: 03 Oct 2016 09:07
Last modified: 20 Jul 2019 00:34

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