Dynamic epigenetic states of ribosomal RNA promoters during the cell cycle

Brown, Shelley E.; Szyf, Moshe

doi:10.4161/cc.7.3.5283

Cited by 23 publications

(15 citation statements)

References 49 publications

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“…Different studies have used various reference genes, TBP and ACTB being among the most common, to determine rRNA expression levels in cancer (23,24,35). We used TBP (a RNA polymerase II transcribed gene) to normalize rRNA gene expression and found no significant differences between the breast tumor and matched normal samples.…”

Section: Discussionmentioning

confidence: 92%

“…TBP, GAPDH and ACTB have been used as reference genes to determine rRNA expression levels in several studies (23,24,35) but these RNA polymerase II (Pol II) transcribed genes are variably expressed in numerous types of cancer (36,37). However, several studies advise against using rRNA levels to determine mRNA levels (26,27).…”

Section: S Rdna Promoter Is Highly Methylated In Breast Cancer Cellmentioning

confidence: 99%

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Relative expression of rRNA transcripts and 45S rDNA promoter methylation status are dysregulated in tumors in comparison with matched-normal tissues in breast cancer

et al. 2015

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Abstract. Ribosomal RNA (rRNA) expression, one of the most important factors regulating ribosome production, is primarily controlled by a CG-rich 45S rDNA promoter. However, the DNA methylation state of the 45S rDNA promoter, as well as its effect on rRNA gene expression in types of human cancers is controversial. In the present study we analyzed the methylation status of the rDNA promoter (-380 to +53 bp) as well as associated rRNA expression levels in breast cancer cell lines and breast tumor-normal tissue pairs. We found that the aforementioned regulatory region was extensively methylated (74-96%) in all cell lines and in 68% (13/19 tumor-normal pairs) of the tumors. Expression levels of rRNA transcripts 18S, 28S, 5.8S and 45S external transcribed spacer (45S ETS) greatly varied in the breast cancer cell lines regardless of their methylation status. Analyses of rRNA transcript expression levels in the breast tumor and normal matched tissues showed no significant difference when normalized with TBP. On the other hand, using the geometric mean of the rRNA expression values (GM-rRNA) as reference enabled us to identify significant changes in the relative expression of rRNAs in the tissue samples. We propose GM-rRNA normalization as a novel strategy to analyze expression differences between rRNA transcripts. Accordingly, the 18S rRNA/GM-rRNA ratio was significantly higher whereas the 5.8S rRNA/GM-rRNA ratio was significantly lower in breast tumor samples than this ratio in the matched normal samples. Moreover, the 18S rRNA/GM-rRNA ratio was negatively correlated with the 45S rDNA promoter methylation level in the normal breast tissue samples, yet not in the breast tumors. Significant correlations observed between the expression levels of rRNA transcripts in the normal samples were lost in the tumor samples. We showed that the expression of rRNA transcripts may not be based solely on promoter methylation. Carcinogenesis may cause dysregulation of the correlation between spliced rRNA expression levels, possibly due to changes in rRNA processing, which requires further investigation. IntroductionBreast cancer, the most common type of cancer among women, was also the primary and secondary cause of cancer-related deaths among women living in less developed (14.3% of all cancer-related deaths) and more developed regions (15.4% after lung cancer) in 2012, respectively (1). Familial or somatic mutations of BRCA1, BRCA2 and TP53 (alias p53) are wellknown high risk factors for breast cancer formation while others (PALB2, BRIP1, ATM, CHEK2, PTEN and CDH1) have been estimated to have moderate or weak effects (2).Contrary to mutations that modify the DNA sequence itself, epigenetic alterations affect gene expression via DNA methylation, histone modifications and chromatin remodeling. DNA methylation, the frequently studied epigenetic modification in the context of embryogenesis, X chromosome inactivation and imprinting (3-5), is also important for the protection of genome integrity and hence cancer. Global hypomethylation of ...

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Section: Discussionmentioning

confidence: 92%

Section: S Rdna Promoter Is Highly Methylated In Breast Cancer Cellmentioning

confidence: 99%

Relative expression of rRNA transcripts and 45S rDNA promoter methylation status are dysregulated in tumors in comparison with matched-normal tissues in breast cancer

et al. 2015

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“…The procedure for methylated DNA immunoprecipitation was adapted from previously published work (27)(28)(29). The amplification (Whole Genome Amplification kit; Sigma) and labeling reaction (CGH labeling kit; Invitrogen), and all of the steps of hybridization including washing and scanning were performed according to the Agilent protocol for chip-on-chip analysis.…”

Section: Methodsmentioning

confidence: 99%

Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus

Suderman

McGowan

Sasaki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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284

186

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Early life experience is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCOR-TICOID RECEPTOR) gene in the hippocampus of both rats and humans. However, it is unlikely that such effects completely capture the evolutionarily conserved epigenetic mechanisms of early adaptation to environment. Here we present DNA methylation profiles spanning 6.5 million base pairs centered at the NR3C1 gene in the hippocampus of humans who experienced abuse as children and nonabused controls. We compare these profiles to corresponding DNA methylation profiles in rats that received differential levels of maternal care. The profiles of both species reveal hundreds of DNA methylation differences associated with early life experience distributed across the entire region in nonrandom patterns. For instance, methylation differences tend to cluster by genomic location, forming clusters covering as many as 1 million bases. Even more surprisingly, these differences seem to specifically target regulatory regions such as gene promoters, particularly those of the protocadherin α, β, and γ gene families. Beyond these high-level similarities, more detailed analyses reveal methylation differences likely stemming from the significant biological and environmental differences between species. These results provide support for an analogous cross-species epigenetic regulatory response at the level of the genomic region to early life experience.conservation | neuronal plasticity V ariation in early life experience is associated with differences in life-long health and behavioral trajectories in animals as well as humans. For example, differences in maternal care in rats during the first week of life are associated with long-term effects on behavior and brain function that persist into adulthood, including alterations in the stress response (1). In humans, similar effects are observed. For instance, childhood maltreatment associates with development of both externalizing and internalizing personality traits and psychopathology in adulthood (2). The association in both rats and humans of stable developmental phenotypes with early life experience suggests that molecular mechanisms may serve as a memory of these early life experiences in both species. In fact, there is evidence that these long-term effects are, at least in part, mediated by epigenetic alterations in the brain. In particular, recent studies have found aberrant DNA methylation in the NR3C1 (GLUCOCORTICOID RECEPTOR) gene promoter of the hippocampi of both rats and humans associated with differential early life experience (3, 4). Exposure of infant rats to stressed caretakers displaying abusive behavior produced persisting changes in methylation of the BDNF gene promoter in the adult prefrontal cortex (5). Early life stress in mice caused sustained DNA hypomethylation of an important regulatory region of the AVP gene (6).Although explanations involving a single site are appealing, it is unlikely that the broad systemic response to early life experien...

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“…Indeed, there is increasing evidence that aberrant gene transcription resulting from altered epigenetic regulation is associated with the pathophysiology of suicide. Ribosomal RNA (r RNA) promoter methylation [167,168] has been shown to be increased in the hippocampus (but not the cerebellum) of suicide victims who were victims of abuse during childhood compared to controls [169]. Thus, it is tempting to speculate that there is an epigenetically determined reduced capacity for protein synthesis (required for learning and memory) in the brains of suicide victims.…”

Section: Influence Of Chromatin Plasticity On Major Neuropsychiatric mentioning

confidence: 99%

Epigenetics: Integrating Genetic Programs, Brain Development and Emergent Phenotypes

Weaver¹

2014

Cell Dev Biol

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Adaptation to environmental changes is based on the perpetual generation of new phenotypes. Modern biology has focused on the role of epigenetic mechanisms in facilitating the adaptation of organisms to changing environments through alterations in gene expression. Inherited and/or acquired epigenetic factors are relatively stable and have regulatory roles in numerous genomic activities that translate into phenotypic outcomes. Evidence that dietary and pharmacological interventions have the potential to reverse environment-induced modification of epigenetic states (e.g., early life experience, nutrition, medication, infection etc.) has provided an additional stimulus for understanding the biological basis of individual differences in cognitive abilities and disorders of the brain. It has been suggested that the accurate quantification of the relative contribution of heritable genetic and epigenetic variation is essential for understanding phenotypic divergence and adaptation in changing environments, a process requiring stable modulation of gene expression. The main challenge for epigenetics in psychology and psychiatry is to determine how experiences and environmental cues influence the expression of neuronal genes to produce long-term individual differences in behavior, cognition, personality and mental health. To this end, focusing on DNA and histone modifications and their initiators, mediators and readers may provide new inroads for understanding the molecular basis phenotypic plasticity and disorders of the brain. In this review, we survey recent developments revealing epigenetic aspects of mental illness, as well as review some of the challenges of current approaches and some future directions in the field of behavioral epigenetics. Early Life Development and Transmission of PhenotypeHuman development not only involves the biological and physical aspects of growth, but also the cognitive and social aspects. Early in life, neuronal circuits are created and connections between neurons undergo remodeling as they develop their adult functional properties in response to intrinsic (genomic) and extrinsic (environmental) cues. The capacity of a single genotype to exhibit variable phenotypes in different environments is common across all species and is often highly adaptive and forms the basis for 'phenotypic plasticity'. Historically, the relationship between the genome and the environment has been presented under the framework of gene-environment interaction (or genotype-environment interaction, G×E). The challenge for developmental psychology and psychiatry has been to integrate findings from genetics into the study of personality and our understanding of the pathophysiology of mental illness. For example: (1) common genetic risk factors and rare mutations such as Single-Nucleotide Polymorphisms (SNPs) and variation in the number of nucleotide repeats such as Copy-Number Variants (CNVs) mapped in GenomeWide Association Studies (GWAS) account for only a small fraction (1-2%) of the total risk for comple...

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Dynamic epigenetic states of ribosomal RNA promoters during the cell cycle

Cited by 23 publications

References 49 publications

Relative expression of rRNA transcripts and 45S rDNA promoter methylation status are dysregulated in tumors in comparison with matched-normal tissues in breast cancer

Relative expression of rRNA transcripts and 45S rDNA promoter methylation status are dysregulated in tumors in comparison with matched-normal tissues in breast cancer

Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus

Epigenetics: Integrating Genetic Programs, Brain Development and Emergent Phenotypes

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