Epigenetic reprogramming of pericentromeric satellite DNA in premalignant and malignant lesions

Nadine Heidi Brückmann, Christina Bøg Pedersen, Henrik Jørn Ditzel, Morten Frier Gjerstorff*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Repression of repetitive DNA is important for maintaining genomic stability, but is often perturbed in cancer. For instance, the megabase satellite domain at chromosome 1q12 is a common site of genetic rearrangements, such as translocations and deletions. Polycomb-group proteins can be observed as large subnuclear domains called polycomb bodies, the composition and cellular function of which has remained elusive. This study demonstrates that polycomb bodies are canonical subunits of the multiprotein polycomb repressive complex 1 deposited on 1q12 pericentromeric satellite DNA, which are normally maintained as constitutive heterochromatin by other mechanisms. Furthermore, the data reveal that polycomb bodies are exclusive to premalignant and malignant cells, being absent in normal cells. For instance, polycomb bodies are present in melanocytic cells of nevi and conserved in primary and metastatic melanomas. Deposition of polycomb on the 1q12 satellite DNA in melanoma development correlated with reduced DNA methylation levels. In agreement with this, inhibition of DNA methyltransferases, with the hypomethylating agent guadecitabine (SGI-110), was sufficient for polycomb body formation on pericentromeric satellites in primary melanocytes. This suggests that polycomb bodies form in cancer cells with global DNA demethylation to control the stability of pericentromeric satellite DNA. These results reveal a novel epigenetic perturbation specific to premalignant and malignant cells that may be used as an early diagnostic marker for detection of precancerous changes and a new therapeutic entry point. Implications: Pericentromeric satellite DNA is epigenetically reprogrammed into polycomb bodies as a premalignant event with implications for transcriptional activity and genomic stability. Mol Cancer Res; 16(3); 417-27. ©2018 AACR.

OriginalsprogEngelsk
TidsskriftMolecular Cancer Research
Vol/bind16
Udgave nummer3
Sider (fra-til)417-427
ISSN1541-7786
DOI
StatusUdgivet - mar. 2018

Fingeraftryk

Satellite DNA
Epigenomics
Polycomb Repressive Complex 1
Melanoma
DNA
Pigmented Nevus
Neoplasms
Melanocytes
DNA Methylation

Bibliografisk note

©2018 American Association for Cancer Research.

Citer dette

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title = "Epigenetic reprogramming of pericentromeric satellite DNA in premalignant and malignant lesions",
abstract = "Repression of repetitive DNA is important for maintaining genomic stability, but is often perturbed in cancer. For instance, the megabase satellite domain at chromosome 1q12 is a common site of genetic rearrangements, such as translocations and deletions. Polycomb-group proteins can be observed as large subnuclear domains called polycomb bodies, the composition and cellular function of which has remained elusive. This study demonstrates that polycomb bodies are canonical subunits of the multiprotein polycomb repressive complex 1 deposited on 1q12 pericentromeric satellite DNA, which are normally maintained as constitutive heterochromatin by other mechanisms. Furthermore, the data reveal that polycomb bodies are exclusive to premalignant and malignant cells, being absent in normal cells. For instance, polycomb bodies are present in melanocytic cells of nevi and conserved in primary and metastatic melanomas. Deposition of polycomb on the 1q12 satellite DNA in melanoma development correlated with reduced DNA methylation levels. In agreement with this, inhibition of DNA methyltransferases, with the hypomethylating agent guadecitabine (SGI-110), was sufficient for polycomb body formation on pericentromeric satellites in primary melanocytes. This suggests that polycomb bodies form in cancer cells with global DNA demethylation to control the stability of pericentromeric satellite DNA. These results reveal a novel epigenetic perturbation specific to premalignant and malignant cells that may be used as an early diagnostic marker for detection of precancerous changes and a new therapeutic entry point. Implications: Pericentromeric satellite DNA is epigenetically reprogrammed into polycomb bodies as a premalignant event with implications for transcriptional activity and genomic stability. Mol Cancer Res; 16(3); 417-27. {\circledC}2018 AACR.",
keywords = "DNA, Satellite/genetics, Epigenesis, Genetic, Humans, Neoplasms/genetics, Precancerous Conditions/genetics, Transfection",
author = "Br{\"u}ckmann, {Nadine Heidi} and Pedersen, {Christina B{\o}g} and Ditzel, {Henrik J{\o}rn} and Gjerstorff, {Morten Frier}",
note = "{\circledC}2018 American Association for Cancer Research.",
year = "2018",
month = "3",
doi = "10.1158/1541-7786.MCR-17-0477",
language = "English",
volume = "16",
pages = "417--427",
journal = "Molecular Cancer Research",
issn = "1541-7786",
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Epigenetic reprogramming of pericentromeric satellite DNA in premalignant and malignant lesions. / Brückmann, Nadine Heidi; Pedersen, Christina Bøg; Ditzel, Henrik Jørn; Gjerstorff, Morten Frier.

I: Molecular Cancer Research, Bind 16, Nr. 3, 03.2018, s. 417-427.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Epigenetic reprogramming of pericentromeric satellite DNA in premalignant and malignant lesions

AU - Brückmann, Nadine Heidi

AU - Pedersen, Christina Bøg

AU - Ditzel, Henrik Jørn

AU - Gjerstorff, Morten Frier

N1 - ©2018 American Association for Cancer Research.

PY - 2018/3

Y1 - 2018/3

N2 - Repression of repetitive DNA is important for maintaining genomic stability, but is often perturbed in cancer. For instance, the megabase satellite domain at chromosome 1q12 is a common site of genetic rearrangements, such as translocations and deletions. Polycomb-group proteins can be observed as large subnuclear domains called polycomb bodies, the composition and cellular function of which has remained elusive. This study demonstrates that polycomb bodies are canonical subunits of the multiprotein polycomb repressive complex 1 deposited on 1q12 pericentromeric satellite DNA, which are normally maintained as constitutive heterochromatin by other mechanisms. Furthermore, the data reveal that polycomb bodies are exclusive to premalignant and malignant cells, being absent in normal cells. For instance, polycomb bodies are present in melanocytic cells of nevi and conserved in primary and metastatic melanomas. Deposition of polycomb on the 1q12 satellite DNA in melanoma development correlated with reduced DNA methylation levels. In agreement with this, inhibition of DNA methyltransferases, with the hypomethylating agent guadecitabine (SGI-110), was sufficient for polycomb body formation on pericentromeric satellites in primary melanocytes. This suggests that polycomb bodies form in cancer cells with global DNA demethylation to control the stability of pericentromeric satellite DNA. These results reveal a novel epigenetic perturbation specific to premalignant and malignant cells that may be used as an early diagnostic marker for detection of precancerous changes and a new therapeutic entry point. Implications: Pericentromeric satellite DNA is epigenetically reprogrammed into polycomb bodies as a premalignant event with implications for transcriptional activity and genomic stability. Mol Cancer Res; 16(3); 417-27. ©2018 AACR.

AB - Repression of repetitive DNA is important for maintaining genomic stability, but is often perturbed in cancer. For instance, the megabase satellite domain at chromosome 1q12 is a common site of genetic rearrangements, such as translocations and deletions. Polycomb-group proteins can be observed as large subnuclear domains called polycomb bodies, the composition and cellular function of which has remained elusive. This study demonstrates that polycomb bodies are canonical subunits of the multiprotein polycomb repressive complex 1 deposited on 1q12 pericentromeric satellite DNA, which are normally maintained as constitutive heterochromatin by other mechanisms. Furthermore, the data reveal that polycomb bodies are exclusive to premalignant and malignant cells, being absent in normal cells. For instance, polycomb bodies are present in melanocytic cells of nevi and conserved in primary and metastatic melanomas. Deposition of polycomb on the 1q12 satellite DNA in melanoma development correlated with reduced DNA methylation levels. In agreement with this, inhibition of DNA methyltransferases, with the hypomethylating agent guadecitabine (SGI-110), was sufficient for polycomb body formation on pericentromeric satellites in primary melanocytes. This suggests that polycomb bodies form in cancer cells with global DNA demethylation to control the stability of pericentromeric satellite DNA. These results reveal a novel epigenetic perturbation specific to premalignant and malignant cells that may be used as an early diagnostic marker for detection of precancerous changes and a new therapeutic entry point. Implications: Pericentromeric satellite DNA is epigenetically reprogrammed into polycomb bodies as a premalignant event with implications for transcriptional activity and genomic stability. Mol Cancer Res; 16(3); 417-27. ©2018 AACR.

KW - DNA, Satellite/genetics

KW - Epigenesis, Genetic

KW - Humans

KW - Neoplasms/genetics

KW - Precancerous Conditions/genetics

KW - Transfection

U2 - 10.1158/1541-7786.MCR-17-0477

DO - 10.1158/1541-7786.MCR-17-0477

M3 - Journal article

C2 - 29330295

AN - SCOPUS:85045413180

VL - 16

SP - 417

EP - 427

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 3

ER -