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Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes

Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes
Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes
Background

Genomic imprinting is allelic restriction of gene expression potential depending on parent of origin, maintained by epigenetic mechanisms including parent of origin-specific DNA methylation. Among approximately 70 known imprinted genes are some causing disorders affecting growth, metabolism and cancer predisposition. Some imprinting disorder patients have hypomethylation of several imprinted loci (HIL) throughout the genome and may have atypically severe clinical features. Here we used array analysis in HIL patients to define patterns of aberrant methylation throughout the genome.

Design

We developed a novel informatic pipeline capable of small sample number analysis, and profiled 10 HIL patients with two clinical presentations (Beckwith–Wiedemann syndrome and neonatal diabetes) using the Illumina Infinium Human Methylation450 BeadChip array to identify candidate imprinted regions. We used robust statistical criteria to quantify DNA methylation.

Results

We detected hypomethylation at known imprinted loci, and 25 further candidate imprinted regions (nine shared between patient groups) including one in the Down syndrome critical region (WRB) and another previously associated with bipolar disorder (PPIEL). Targeted analysis of three candidate regions (NHP2L1, WRB and PPIEL) showed allelic expression, methylation patterns consistent with allelic maternal methylation and frequent hypomethylation among an additional cohort of HIL patients, including six with Silver–Russell syndrome presentations and one with pseudohypoparathyroidism 1B.

Conclusions

This study identified novel candidate imprinted genes, revealed remarkable epigenetic convergence among clinically divergent patients, and highlights the potential of epigenomic profiling to expand our understanding of the normal methylome and its disruption in human disease.
0022-2593
229-238
Docherty, L.E.
4accb565-e53b-400f-8d62-83935e2ae410
Rezwan, F.I.
203f8f38-1f5d-485b-ab11-c546b4276338
Poole, R.L.
d8fe00fa-9deb-4a34-a7d8-4b7f57ce82fa
Jagoe, H.
ef4394b4-cc5e-4992-b038-54d4a70719f0
Lake, H.
cf7a1d88-09c4-4377-9157-503f79b05149
Lockett, G.A.
4d92a28c-f54c-431b-81f6-e82ad9057d7a
Arshad, H.
917e246d-2e60-472f-8d30-94b01ef28958
Wilson, D.I.
1500fca1-7082-4271-95f4-691f1d1252a2
Holloway, J.W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Temple, I.K.
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Mackay, D.J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Docherty, L.E.
4accb565-e53b-400f-8d62-83935e2ae410
Rezwan, F.I.
203f8f38-1f5d-485b-ab11-c546b4276338
Poole, R.L.
d8fe00fa-9deb-4a34-a7d8-4b7f57ce82fa
Jagoe, H.
ef4394b4-cc5e-4992-b038-54d4a70719f0
Lake, H.
cf7a1d88-09c4-4377-9157-503f79b05149
Lockett, G.A.
4d92a28c-f54c-431b-81f6-e82ad9057d7a
Arshad, H.
917e246d-2e60-472f-8d30-94b01ef28958
Wilson, D.I.
1500fca1-7082-4271-95f4-691f1d1252a2
Holloway, J.W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Temple, I.K.
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Mackay, D.J.G.
588a653e-9785-4a00-be71-4e547850ee4a

Docherty, L.E., Rezwan, F.I., Poole, R.L., Jagoe, H., Lake, H., Lockett, G.A., Arshad, H., Wilson, D.I., Holloway, J.W., Temple, I.K. and Mackay, D.J.G. (2014) Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes. Journal of Medical Genetics, 51 (4), 229-238. (doi:10.1136/jmedgenet-2013-102116).

Record type: Article

Abstract

Background

Genomic imprinting is allelic restriction of gene expression potential depending on parent of origin, maintained by epigenetic mechanisms including parent of origin-specific DNA methylation. Among approximately 70 known imprinted genes are some causing disorders affecting growth, metabolism and cancer predisposition. Some imprinting disorder patients have hypomethylation of several imprinted loci (HIL) throughout the genome and may have atypically severe clinical features. Here we used array analysis in HIL patients to define patterns of aberrant methylation throughout the genome.

Design

We developed a novel informatic pipeline capable of small sample number analysis, and profiled 10 HIL patients with two clinical presentations (Beckwith–Wiedemann syndrome and neonatal diabetes) using the Illumina Infinium Human Methylation450 BeadChip array to identify candidate imprinted regions. We used robust statistical criteria to quantify DNA methylation.

Results

We detected hypomethylation at known imprinted loci, and 25 further candidate imprinted regions (nine shared between patient groups) including one in the Down syndrome critical region (WRB) and another previously associated with bipolar disorder (PPIEL). Targeted analysis of three candidate regions (NHP2L1, WRB and PPIEL) showed allelic expression, methylation patterns consistent with allelic maternal methylation and frequent hypomethylation among an additional cohort of HIL patients, including six with Silver–Russell syndrome presentations and one with pseudohypoparathyroidism 1B.

Conclusions

This study identified novel candidate imprinted genes, revealed remarkable epigenetic convergence among clinically divergent patients, and highlights the potential of epigenomic profiling to expand our understanding of the normal methylome and its disruption in human disease.

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More information

e-pub ahead of print date: 5 February 2014
Published date: April 2014
Organisations: Human Development & Health, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 361983
URI: https://eprints.soton.ac.uk/id/eprint/361983
ISSN: 0022-2593
PURE UUID: 01aff567-5628-4c8d-bc7e-0f6c881207d5
ORCID for F.I. Rezwan: ORCID iD orcid.org/0000-0001-9921-222X
ORCID for J.W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464
ORCID for I.K. Temple: ORCID iD orcid.org/0000-0002-6045-1781
ORCID for D.J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

Catalogue record

Date deposited: 10 Feb 2014 14:33
Last modified: 01 Jun 2019 00:36

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