Maternal gametic transmission of translocations or inversions of human chromosome 11p15.5 results in regional DNA hypermethylation and downregulation of CDKN1C expression

Adam C. Smith, Masako Suzuki, Reid Thompson, Sanaa Choufani, Michael J. Higgins, Idy W. Chiu, Jeremy A. Squire, John M. Greally, Rosanna Weksberg

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with genetic or epigenetic alterations in one of two imprinted domains on chromosome 11p15.5. Rarely, chromosomal translocations or inversions of chromosome 11p15.5 are associated with BWS but the molecular pathophysiology in such cases is not understood. In our series of 3 translocation and 2 inversion patients with BWS, the chromosome 11p15.5 breakpoints map within the centromeric imprinted domain, 2. We hypothesized that either microdeletions/microduplications adjacent to the breakpoints could disrupt genomic sequences important for imprinted gene regulation. An alternate hypothesis was that epigenetic alterations of as yet unknown regulatory DNA sequences, result in the BWS phenotype. A high resolution Nimblegen custom microarray was designed representing all non-repetitive sequences in the telomeric 33. Mb of the short arm of human chromosome 11. For the BWS-associated chromosome 11p15.5 translocations and inversions, we found no evidence of microdeletions/microduplications. DNA methylation was also tested on this microarray using the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay. This high-resolution DNA methylation microarray analysis revealed a gain of DNA methylation in the translocation/inversion patients affecting the p-ter segment of chromosome 11p15, including both imprinted domains. BWS patients that inherited a maternal translocation or inversion also demonstrated reduced expression of the growth suppressing imprinted gene, CDKN1C in Domain 2. In summary, our data demonstrate that translocations and inversions involving imprinted domain 2 on chromosome 11p15.5, alter regional DNA methylation patterns and imprinted gene expression in cis, suggesting that these epigenetic alterations are generated by an alteration in "chromatin context".

Original languageEnglish (US)
Pages (from-to)25-35
Number of pages11
JournalGenomics
Volume99
Issue number1
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

Fingerprint

Beckwith-Wiedemann Syndrome
Human Chromosomes
Down-Regulation
Mothers
DNA Methylation
DNA
Chromosomes
Epigenomics
Chromosome Breakpoints
Genetic Translocation
Chromosomes, Human, Pair 11
Chromosomes, Human, Pair 2
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Genes
Chromatin
Ligation
Phenotype
Gene Expression
Polymerase Chain Reaction

Keywords

  • Balanced chromosome translocation
  • Beckwith-Wiedemann syndrome
  • Chromosome 11p15.5
  • DNA methylation microarray
  • Genomic imprinting

ASJC Scopus subject areas

  • Genetics

Cite this

Maternal gametic transmission of translocations or inversions of human chromosome 11p15.5 results in regional DNA hypermethylation and downregulation of CDKN1C expression. / Smith, Adam C.; Suzuki, Masako; Thompson, Reid; Choufani, Sanaa; Higgins, Michael J.; Chiu, Idy W.; Squire, Jeremy A.; Greally, John M.; Weksberg, Rosanna.

In: Genomics, Vol. 99, No. 1, 01.01.2012, p. 25-35.

Research output: Contribution to journalArticle

Smith, Adam C. ; Suzuki, Masako ; Thompson, Reid ; Choufani, Sanaa ; Higgins, Michael J. ; Chiu, Idy W. ; Squire, Jeremy A. ; Greally, John M. ; Weksberg, Rosanna. / Maternal gametic transmission of translocations or inversions of human chromosome 11p15.5 results in regional DNA hypermethylation and downregulation of CDKN1C expression. In: Genomics. 2012 ; Vol. 99, No. 1. pp. 25-35.
@article{c84501ef52154a9d82cd87a8168cc0f1,
title = "Maternal gametic transmission of translocations or inversions of human chromosome 11p15.5 results in regional DNA hypermethylation and downregulation of CDKN1C expression",
abstract = "Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with genetic or epigenetic alterations in one of two imprinted domains on chromosome 11p15.5. Rarely, chromosomal translocations or inversions of chromosome 11p15.5 are associated with BWS but the molecular pathophysiology in such cases is not understood. In our series of 3 translocation and 2 inversion patients with BWS, the chromosome 11p15.5 breakpoints map within the centromeric imprinted domain, 2. We hypothesized that either microdeletions/microduplications adjacent to the breakpoints could disrupt genomic sequences important for imprinted gene regulation. An alternate hypothesis was that epigenetic alterations of as yet unknown regulatory DNA sequences, result in the BWS phenotype. A high resolution Nimblegen custom microarray was designed representing all non-repetitive sequences in the telomeric 33. Mb of the short arm of human chromosome 11. For the BWS-associated chromosome 11p15.5 translocations and inversions, we found no evidence of microdeletions/microduplications. DNA methylation was also tested on this microarray using the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay. This high-resolution DNA methylation microarray analysis revealed a gain of DNA methylation in the translocation/inversion patients affecting the p-ter segment of chromosome 11p15, including both imprinted domains. BWS patients that inherited a maternal translocation or inversion also demonstrated reduced expression of the growth suppressing imprinted gene, CDKN1C in Domain 2. In summary, our data demonstrate that translocations and inversions involving imprinted domain 2 on chromosome 11p15.5, alter regional DNA methylation patterns and imprinted gene expression in cis, suggesting that these epigenetic alterations are generated by an alteration in {"}chromatin context{"}.",
keywords = "Balanced chromosome translocation, Beckwith-Wiedemann syndrome, Chromosome 11p15.5, DNA methylation microarray, Genomic imprinting",
author = "Smith, {Adam C.} and Masako Suzuki and Reid Thompson and Sanaa Choufani and Higgins, {Michael J.} and Chiu, {Idy W.} and Squire, {Jeremy A.} and Greally, {John M.} and Rosanna Weksberg",
year = "2012",
month = "1",
day = "1",
doi = "10.1016/j.ygeno.2011.10.007",
language = "English (US)",
volume = "99",
pages = "25--35",
journal = "Genomics",
issn = "0888-7543",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Maternal gametic transmission of translocations or inversions of human chromosome 11p15.5 results in regional DNA hypermethylation and downregulation of CDKN1C expression

AU - Smith, Adam C.

AU - Suzuki, Masako

AU - Thompson, Reid

AU - Choufani, Sanaa

AU - Higgins, Michael J.

AU - Chiu, Idy W.

AU - Squire, Jeremy A.

AU - Greally, John M.

AU - Weksberg, Rosanna

PY - 2012/1/1

Y1 - 2012/1/1

N2 - Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with genetic or epigenetic alterations in one of two imprinted domains on chromosome 11p15.5. Rarely, chromosomal translocations or inversions of chromosome 11p15.5 are associated with BWS but the molecular pathophysiology in such cases is not understood. In our series of 3 translocation and 2 inversion patients with BWS, the chromosome 11p15.5 breakpoints map within the centromeric imprinted domain, 2. We hypothesized that either microdeletions/microduplications adjacent to the breakpoints could disrupt genomic sequences important for imprinted gene regulation. An alternate hypothesis was that epigenetic alterations of as yet unknown regulatory DNA sequences, result in the BWS phenotype. A high resolution Nimblegen custom microarray was designed representing all non-repetitive sequences in the telomeric 33. Mb of the short arm of human chromosome 11. For the BWS-associated chromosome 11p15.5 translocations and inversions, we found no evidence of microdeletions/microduplications. DNA methylation was also tested on this microarray using the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay. This high-resolution DNA methylation microarray analysis revealed a gain of DNA methylation in the translocation/inversion patients affecting the p-ter segment of chromosome 11p15, including both imprinted domains. BWS patients that inherited a maternal translocation or inversion also demonstrated reduced expression of the growth suppressing imprinted gene, CDKN1C in Domain 2. In summary, our data demonstrate that translocations and inversions involving imprinted domain 2 on chromosome 11p15.5, alter regional DNA methylation patterns and imprinted gene expression in cis, suggesting that these epigenetic alterations are generated by an alteration in "chromatin context".

AB - Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with genetic or epigenetic alterations in one of two imprinted domains on chromosome 11p15.5. Rarely, chromosomal translocations or inversions of chromosome 11p15.5 are associated with BWS but the molecular pathophysiology in such cases is not understood. In our series of 3 translocation and 2 inversion patients with BWS, the chromosome 11p15.5 breakpoints map within the centromeric imprinted domain, 2. We hypothesized that either microdeletions/microduplications adjacent to the breakpoints could disrupt genomic sequences important for imprinted gene regulation. An alternate hypothesis was that epigenetic alterations of as yet unknown regulatory DNA sequences, result in the BWS phenotype. A high resolution Nimblegen custom microarray was designed representing all non-repetitive sequences in the telomeric 33. Mb of the short arm of human chromosome 11. For the BWS-associated chromosome 11p15.5 translocations and inversions, we found no evidence of microdeletions/microduplications. DNA methylation was also tested on this microarray using the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay. This high-resolution DNA methylation microarray analysis revealed a gain of DNA methylation in the translocation/inversion patients affecting the p-ter segment of chromosome 11p15, including both imprinted domains. BWS patients that inherited a maternal translocation or inversion also demonstrated reduced expression of the growth suppressing imprinted gene, CDKN1C in Domain 2. In summary, our data demonstrate that translocations and inversions involving imprinted domain 2 on chromosome 11p15.5, alter regional DNA methylation patterns and imprinted gene expression in cis, suggesting that these epigenetic alterations are generated by an alteration in "chromatin context".

KW - Balanced chromosome translocation

KW - Beckwith-Wiedemann syndrome

KW - Chromosome 11p15.5

KW - DNA methylation microarray

KW - Genomic imprinting

UR - http://www.scopus.com/inward/record.url?scp=84855190073&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84855190073&partnerID=8YFLogxK

U2 - 10.1016/j.ygeno.2011.10.007

DO - 10.1016/j.ygeno.2011.10.007

M3 - Article

C2 - 22079941

AN - SCOPUS:84855190073

VL - 99

SP - 25

EP - 35

JO - Genomics

JF - Genomics

SN - 0888-7543

IS - 1

ER -