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Human non-CpG methylation patterns display both tissue-specific and inter-individual differences suggestive of underlying function

Human non-CpG methylation patterns display both tissue-specific and inter-individual differences suggestive of underlying function
Human non-CpG methylation patterns display both tissue-specific and inter-individual differences suggestive of underlying function
DNA methylation (DNAm) in mammals is mostly examined within the context of CpG dinucleotides. Non-CpG DNAm is also widespread across the human genome, but the functional relevance, tissue-specific disposition, and inter-individual variability has not been widely studied. Our aim was to examine non-CpG DNAm in the wider methylome across multiple tissues from the same individuals to better understand non-CpG DNAm distribution within different tissues and individuals, and in relation to known genomic regulatory features. DNA methylation in umbilical cord and cord blood at birth, and peripheral venous blood at age 12-13 years from twenty individuals from the Southampton Women’s Survey cohort was assessed by Agilent SureSelect methyl-seq. Hierarchical cluster analysis (HCA) was performed on CpG and non-CpG sites, and stratified by specific cytosine environment. Analysis of tissue and inter-individual variation was then conducted in a second dataset of twelve samples: eight muscle tissue, and four aliquots of cord blood pooled from two individuals. HCA using methylated non-CpG sites showed different clustering patterns specific to the three base pair triplicate (CNN) sequence. Analysis of CAC sites with non-zero methylation showed that samples clustered first by tissue type, then by individual (as observed for CpG methylation), while analysis using non-zero methylation at CAT sites showed samples grouped predominantly by individual. These clustering patterns were validated in an independent dataset using cord blood and muscle tissue. This research suggests that CAC methylation can have tissue-specific patterns, and that individual effects, either genetic or unmeasured environmental factors, can influence CAT methylation.
CAC, CAT, CHG, CHH, CNN, CpG, DNA methylation, HCA, cluster, comparison, hierarchical clustering analysis, human, individual-specific, methylation, methylation patterns, muscle, non-CpG, peripheral blood, tissue-specific, umbilical cord, umbilical cord blood
1559-2294
Titcombe, Philip
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Murray, Robert
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Hewitt, Matthew
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Antoun, Elie
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Cooper, Cyrus
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Inskip, Hazel
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Holbrook, Joanna D
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Godfrey, Keith
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Lillycrop, Karen
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Hanson, Mark
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Barton, Sheila
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Titcombe, Philip
a84c9fad-0580-42f9-8bb6-db0fe20435aa
Murray, Robert
c3e973b5-525c-49b3-96ee-af60a666a0f4
Hewitt, Matthew
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Antoun, Elie
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Cooper, Cyrus
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Inskip, Hazel
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Holbrook, Joanna D
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Godfrey, Keith
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Lillycrop, Karen
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Hanson, Mark
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Barton, Sheila
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Titcombe, Philip, Murray, Robert, Hewitt, Matthew, Antoun, Elie, Cooper, Cyrus, Inskip, Hazel, Holbrook, Joanna D, Godfrey, Keith, Lillycrop, Karen, Hanson, Mark and Barton, Sheila (2021) Human non-CpG methylation patterns display both tissue-specific and inter-individual differences suggestive of underlying function. Epigenetics. (doi:10.1080/15592294.2021.1950990).

Record type: Article

Abstract

DNA methylation (DNAm) in mammals is mostly examined within the context of CpG dinucleotides. Non-CpG DNAm is also widespread across the human genome, but the functional relevance, tissue-specific disposition, and inter-individual variability has not been widely studied. Our aim was to examine non-CpG DNAm in the wider methylome across multiple tissues from the same individuals to better understand non-CpG DNAm distribution within different tissues and individuals, and in relation to known genomic regulatory features. DNA methylation in umbilical cord and cord blood at birth, and peripheral venous blood at age 12-13 years from twenty individuals from the Southampton Women’s Survey cohort was assessed by Agilent SureSelect methyl-seq. Hierarchical cluster analysis (HCA) was performed on CpG and non-CpG sites, and stratified by specific cytosine environment. Analysis of tissue and inter-individual variation was then conducted in a second dataset of twelve samples: eight muscle tissue, and four aliquots of cord blood pooled from two individuals. HCA using methylated non-CpG sites showed different clustering patterns specific to the three base pair triplicate (CNN) sequence. Analysis of CAC sites with non-zero methylation showed that samples clustered first by tissue type, then by individual (as observed for CpG methylation), while analysis using non-zero methylation at CAT sites showed samples grouped predominantly by individual. These clustering patterns were validated in an independent dataset using cord blood and muscle tissue. This research suggests that CAC methylation can have tissue-specific patterns, and that individual effects, either genetic or unmeasured environmental factors, can influence CAT methylation.

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KEPI-2021-0060_R1 (00000002) - Accepted Manuscript
Restricted to Repository staff only until 29 June 2022.
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More information

Accepted/In Press date: 29 June 2021
Published date: 30 August 2021
Keywords: CAC, CAT, CHG, CHH, CNN, CpG, DNA methylation, HCA, cluster, comparison, hierarchical clustering analysis, human, individual-specific, methylation, methylation patterns, muscle, non-CpG, peripheral blood, tissue-specific, umbilical cord, umbilical cord blood

Identifiers

Local EPrints ID: 450168
URI: http://eprints.soton.ac.uk/id/eprint/450168
ISSN: 1559-2294
PURE UUID: 050f4c65-4647-434e-ae49-0b45d5662b59
ORCID for Philip Titcombe: ORCID iD orcid.org/0000-0002-7797-8571
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709
ORCID for Hazel Inskip: ORCID iD orcid.org/0000-0001-8897-1749
ORCID for Joanna D Holbrook: ORCID iD orcid.org/0000-0003-1791-6894
ORCID for Keith Godfrey: ORCID iD orcid.org/0000-0002-4643-0618
ORCID for Karen Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489
ORCID for Mark Hanson: ORCID iD orcid.org/0000-0002-6907-613X
ORCID for Sheila Barton: ORCID iD orcid.org/0000-0003-4963-4242

Catalogue record

Date deposited: 14 Jul 2021 16:45
Last modified: 26 Nov 2021 03:02

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Contributors

Author: Philip Titcombe ORCID iD
Author: Robert Murray
Author: Matthew Hewitt
Author: Elie Antoun
Author: Cyrus Cooper ORCID iD
Author: Hazel Inskip ORCID iD
Author: Joanna D Holbrook ORCID iD
Author: Keith Godfrey ORCID iD
Author: Karen Lillycrop ORCID iD
Author: Mark Hanson ORCID iD
Author: Sheila Barton ORCID iD

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