Page 39 - 2014 Printable Abstract Book
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differentiation, proliferation and self-renewal. Numerous studies report alterations in bone marrow DNA
methylation, including loss or gain of global, repetitive elements- and gene-specific DNA methylation in
response to exposure to both low- and high-LET radiation. These alterations may lead to the reactivation
of oncogenes and repetitive DNA sequences and to the silencing of tumor-suppressor genes, leading to
development of genomic instability and cancer. Indeed, aberrant DNA methylation has been reported in
leukemia patients with a history of exposure to IR and has been suggested as a potential driving
mechanism of carcinogenesis. Understanding the effects of irradiation on DNA methylation will aid in
deciphering the mechanisms of radiation-induced hematological malignancies and can potentially lead to
the development of novel therapeutic strategies.
(S403) Epigenetic responses to high and low LET radiations: Effect of dose and radiation quality. Janet
E. Baulch, University of California, Irvine, Irvine, CA
Epigenetic changes are mitotically and meiotically heritable stable, alterations in gene expression
that include DNA methylation, histone modification and RNA-associated gene silencing. In mammals, 5-
methylcytosine in DNA occurs at CpG dinucliotides and is normally associated with an inactive chromatin
state and repressed gene activity. Recently it has also been shown that other cytosine modifications play
a key role in regulating gene expression and cellular phenotype. These other modifications include 5-
hydroxymethylcytosine, which has been found primarily in the brain and CNS. While DNA methylation is
important for normal development, cell proliferation and genome maintenance, alterations in DNA
methylation have emerged as one of the most consistent molecular alterations in multiple cancers. It has
also been acknowledged that radiation exposure induces changes in DNA methylation. We have used in
vitro irradiated cultured cells and in vivo irradiated mice to describe the effect of varied linear energy
transfer (LET) radiations on tissue-specific DNA methylation profiles in the radiation response at delayed
times after exposure. Differences in methylation profiles between cell lines or tissues, or over time
following exposure provides mechanistic information regarding the radiation response and allows for the
development of functional biomarkers for exposure and for carcinogenesis.
(S404) DNA Methylation and the Radiation Response. Steven P. Zielske, Wayne State University, Detroit,
MI
The cellular response to radiation-induced DNA damage is diverse and involves pathways leading
to DNA repair, alteration of cell cycle, and modulation of cell survival, among many others. DNA
methylation is an epigenetic mechanism that affects gene expression and potentially cellular response to
environmental factors including radiation. We have begun to investigate epigenetic changes (DNA
methylation) that occur following exposure to therapeutic levels of radiation as well as potential
epigenetic therapies that may influence the cellular response. New DNA methylation profiling
technologies has allowed us to assess whole genome DNA methylation changes. Utilizing this technology,
we determined DNA methylation at 0, 2, and 6 Gy and over up to 3 days post-exposure. The major finding
was that among the pathways which were enriched for DNA methylation changes, these included DNA
repair, cell cycle, and apoptotic pathways. Therapeutic radiation thus induces epigenetic changes in
prototypical radiation response pathways. DNA methylation can be modulated in the cell using various
inhibitors of DNMT1, the main enzyme responsible for methylating newly synthesized DNA. We assessed
37 | P a g e
methylation, including loss or gain of global, repetitive elements- and gene-specific DNA methylation in
response to exposure to both low- and high-LET radiation. These alterations may lead to the reactivation
of oncogenes and repetitive DNA sequences and to the silencing of tumor-suppressor genes, leading to
development of genomic instability and cancer. Indeed, aberrant DNA methylation has been reported in
leukemia patients with a history of exposure to IR and has been suggested as a potential driving
mechanism of carcinogenesis. Understanding the effects of irradiation on DNA methylation will aid in
deciphering the mechanisms of radiation-induced hematological malignancies and can potentially lead to
the development of novel therapeutic strategies.
(S403) Epigenetic responses to high and low LET radiations: Effect of dose and radiation quality. Janet
E. Baulch, University of California, Irvine, Irvine, CA
Epigenetic changes are mitotically and meiotically heritable stable, alterations in gene expression
that include DNA methylation, histone modification and RNA-associated gene silencing. In mammals, 5-
methylcytosine in DNA occurs at CpG dinucliotides and is normally associated with an inactive chromatin
state and repressed gene activity. Recently it has also been shown that other cytosine modifications play
a key role in regulating gene expression and cellular phenotype. These other modifications include 5-
hydroxymethylcytosine, which has been found primarily in the brain and CNS. While DNA methylation is
important for normal development, cell proliferation and genome maintenance, alterations in DNA
methylation have emerged as one of the most consistent molecular alterations in multiple cancers. It has
also been acknowledged that radiation exposure induces changes in DNA methylation. We have used in
vitro irradiated cultured cells and in vivo irradiated mice to describe the effect of varied linear energy
transfer (LET) radiations on tissue-specific DNA methylation profiles in the radiation response at delayed
times after exposure. Differences in methylation profiles between cell lines or tissues, or over time
following exposure provides mechanistic information regarding the radiation response and allows for the
development of functional biomarkers for exposure and for carcinogenesis.
(S404) DNA Methylation and the Radiation Response. Steven P. Zielske, Wayne State University, Detroit,
MI
The cellular response to radiation-induced DNA damage is diverse and involves pathways leading
to DNA repair, alteration of cell cycle, and modulation of cell survival, among many others. DNA
methylation is an epigenetic mechanism that affects gene expression and potentially cellular response to
environmental factors including radiation. We have begun to investigate epigenetic changes (DNA
methylation) that occur following exposure to therapeutic levels of radiation as well as potential
epigenetic therapies that may influence the cellular response. New DNA methylation profiling
technologies has allowed us to assess whole genome DNA methylation changes. Utilizing this technology,
we determined DNA methylation at 0, 2, and 6 Gy and over up to 3 days post-exposure. The major finding
was that among the pathways which were enriched for DNA methylation changes, these included DNA
repair, cell cycle, and apoptotic pathways. Therapeutic radiation thus induces epigenetic changes in
prototypical radiation response pathways. DNA methylation can be modulated in the cell using various
inhibitors of DNMT1, the main enzyme responsible for methylating newly synthesized DNA. We assessed
37 | P a g e
