scholarly journals WOMEN IN CANCER THEMATIC REVIEW: Diverse functions of DNA methylation: implications for prostate cancer and beyond

2016 ◽  
Vol 23 (11) ◽  
pp. T169-T178 ◽  
Author(s):  
Thomas J Sweet ◽  
Angela H Ting
Keyword(s):  
Prostate Cancer ◽  
Dna Methylation ◽  
Transcription Initiation ◽  
Alternative Polyadenylation ◽  
Regulatory Elements ◽  
Gene Promoters ◽  
Prostate Tumorigenesis ◽  
Cpg Dinucleotides ◽  
Molecular Features ◽  
Cancer Aggressiveness

Prostate cancer is one of the most common malignancies in men worldwide. Current clinical screening ensures that most prostate cancers are diagnosed while still organ confined, but disease outcome is highly variable. Thus, a better understanding of the molecular features contributing to prostate cancer aggressiveness is being sought. For many cancers, aberrant genome-wide patterns of cytosine DNA methylation in CpG dinucleotides distinguish tumor from normal tissue and contribute to disease progression by altering the transcriptome. In prostate cancer, recent genomic studies identified cancer and high grade-specific differential DNA methylation in gene promoters, gene bodies, gene 3′ ends and at distal regulatory elements. Using examples from developmental and disease systems, we will discuss how DNA methylation in each of these genomic contexts can contribute to transcriptome diversity by modulating transcription initiation, alternative transcription start site selection, alternative pre-mRNA splicing and alternative polyadenylation. Alternative transcripts from the same gene often exhibit altered protein-coding potential, translatability, stability and/or localization. All of these can have functional consequences in cells. In future work, it will be important to determine if DNA methylation abnormalities in prostate cancer modify the transcriptome through some or all of these mechanisms and if these DNA methylation-mediated transcriptome alterations impact prostate tumorigenesis and aggressiveness.

Androgen receptor: acting in the three-dimensional chromatin landscape of prostate cancer cells

2011 ◽  
Vol 5 (1) ◽  
Author(s):  
Harri Makkonen ◽  
Jorma J. Palvimo
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Binding Sites ◽  
Target Genes ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Gene Promoters ◽  
Loop Formation ◽  
Prostate Cancer Cells

AbstractAndrogen receptor (AR) acts as a hormone-controlled transcription factor that conveys the messages of both natural and synthetic androgens to the level of genes and gene programs. Defective AR signaling leads to a wide array of androgen insensitivity disorders, and deregulated AR function, in particular overexpression of AR, is involved in the growth and progression of prostate cancer. Classic models of AR action view AR-binding sites as upstream regulatory elements in gene promoters or their proximity. However, recent wider genomic screens indicate that AR target genes are commonly activated through very distal chromatin-binding sites. This highlights the importance of long-range chromatin regulation of transcription by the AR, shifting the focus from the linear gene models to three-dimensional models of AR target genes and gene programs. The capability of AR to regulate promoters from long distances in the chromatin is particularly important when evaluating the role of AR in the regulation of genes in malignant prostate cells that frequently show striking genomic aberrations, especially gene fusions. Therefore, in addition to the mechanisms of DNA loop formation between the enhancer bound ARs and the transcription apparatus at the target core promoter, the mechanisms insulating distally bound ARs from promiscuously making contacts and activating other than their normal target gene promoters are critical for proper physiological regulation and thus currently under intense investigation. This review discusses the current knowledge about the AR action in the context of gene aberrations and the three-dimensional chromatin landscape of prostate cancer cells.

scholarly journals DNA methylation marks inter-nucleosome linker regions throughout the human genome

2013 ◽  
Author(s):  
Benjamin P. Berman ◽  
Yaping Liu ◽  
Theresa K. Kelly
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Sequencing Technologies ◽  
Nucleosome Organization ◽  
Genome Wide ◽  
A Genome ◽  
Sequencing Studies

Background: Nucleosome organization and DNA methylation are two mechanisms that are important for proper control of mammalian transcription, as well as epigenetic dysregulation associated with cancer. Whole-genome DNA methylation sequencing studies have found that methylation levels in the human genome show periodicities of approximately 190 bp, suggesting a genome-wide relationship between the two marks. A recent report (Chodavarapu et al., 2010) attributed this to higher methylation levels of DNA within nucleosomes. Here, we analyzed a number of published datasets and found a more compelling alternative explanation, namely that methylation levels are highest in linker regions between nucleosomes. Results: Reanalyzing the data from (Chodavarapu et al., 2010), we found that nucleosome-associated methylation could be strongly confounded by known sequence-related biases of the next-generation sequencing technologies. By accounting for these biases and using an unrelated nucleosome profiling technology, NOMe-seq, we found that genome-wide methylation was actually highest within linker regions occurring between nucleosomes in multi-nucleosome arrays. This effect was consistent among several methylation datasets generated independently using two unrelated methylation assays. Linker-associated methylation was most prominent within long Partially Methylated Domains (PMDs) and the positioned nucleosomes that flank CTCF binding sites. CTCF adjacent nucleosomes retained the correct positioning in regions completely devoid of CpG dinucleotides, suggesting that DNA methylation is not required for proper nucleosomes positioning. Conclusions: The biological mechanisms responsible for DNA methylation patterns outside of gene promoters remain poorly understood. We identified a significant genome-wide relationship between nucleosome organization and DNA methylation, which can be used to more accurately analyze and understand the epigenetic changes that accompany cancer and other diseases.

scholarly journals Transcription start site analysis reveals widespread divergent transcription in D. melanogaster and core promoter-encoded enhancer activities

2017 ◽  
Author(s):  
Sarah Rennie ◽  
Maria Dalby ◽  
Marta Lloret-Llinares ◽  
Stylianos Bakoulis ◽  
Christian Dalager Vaagensø ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
Core Promoter ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Chromatin Interaction ◽  
Promoter Strength ◽  
Gene Promoters ◽  
Core Promoters ◽  
Promoter Architecture ◽  
Regulatory Functions

ABSTRACTMammalian gene promoters and enhancers share many properties. They are composed of a unified promoter architecture of divergent transcripton initiation and gene promoters may exhibit enhancer function. However, it is currently unclear how expression strength of a regulatory element relates to its enhancer strength and if the unifying architecture is conserved across Metazoa. Here we investigate the transcription initiation landscape and its associated RNA decay in D. melanogaster. Surprisingly, we find that the majority of active gene-distal enhancers and a considerable fraction of gene promoters are divergently transcribed. We observe quantitative relationships between enhancer potential, expression level and core promoter strength, providing an explanation for indirectly related histone modifications that are reflecting expression levels. Lowly abundant unstable RNAs initiated from weak core promoters are key characteristics of gene-distal developmental enhancers, while the housekeeping enhancer strengths of gene promoters reflect their expression strengths. The different layers of regulation mediated by gene-distal enhancers and gene promoters are also reflected in chromatin interaction data. Our results suggest a unified promoter architecture of many D. melanogaster regulatory elements, that is universal across Metazoa, whose regulatory functions seem to be related to their core promoter elements.

scholarly journals Frequent DNA Hypermethylation at the RASSF1A and APC Gene Loci in Prostate Cancer Patients of Pakistani Origin

ISRN Urology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Ahmed Yaqinuddin ◽  
Sohail A. Qureshi ◽  
Shahid Pervez ◽  
Mohammed Umair Bashir ◽  
Ressam Nazir ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Methylation ◽  
Cancer Patients ◽  
Methylation Status ◽  
Transurethral Resection Of Prostate ◽  
Gene Promoters ◽  
Dna Hypermethylation ◽  
Pakistani Population ◽  
Specific Pcr ◽  
Pakistani Origin

DNA methylation has emerged as a potentially robust biomarker for prostate cancer (PCa). Since DNA methylomes appear to be disease as well as population specific, we have assessed the DNA methylation status of RASSF1A, APC, and p16 (potential biomarkers of PCa) in Pakistani population. Primary prostate cancer tissues were obtained from 27 formalin-fixed paraffin-embedded blocks (FFPE) of cancer patients who underwent radical prostatectomy and transurethral resection of prostate (TURP) during 2003–2008. As controls, twenty-four benign prostatic FFPE tissues were obtained from patients who underwent TURP for benign prostatic hyperplasia during 2008. DNA was extracted, and methylation-specific PCR was used to assess the methylation status for RASSF1A, APC, and p16 gene promoters. Our results revealed that the RASSF1A promoter was hypermethylated in all the tested cancer samples but was also hypermethylated in 3 out of 24 control tissues. The APC promoter was hypermethylated in 15 out of 27 cancer samples and in none of the control samples. Strikingly, none of the samples showed methylation at the p16 promoter. Our findings suggest that RASSF1A and APC gene promoters are frequently hypermethylated in the Pakistani population and therefore have the potential to develop into universally dependable biomarkers for detecting PCa.

scholarly journals DNA methylation marks inter-nucleosome linker regions throughout the human genome

2013 ◽  
Author(s):  
Benjamin P. Berman ◽  
Yaping Liu ◽  
Theresa K. Kelly
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Sequencing Technologies ◽  
Nucleosome Organization ◽  
Genome Wide ◽  
A Genome ◽  
Sequencing Studies

Background: Nucleosome organization and DNA methylation are two mechanisms that are important for proper control of mammalian transcription, as well as epigenetic dysregulation associated with cancer. Whole-genome DNA methylation sequencing studies have found that methylation levels in the human genome show periodicities of approximately 190 bp, suggesting a genome-wide relationship between the two marks. A recent report (Chodavarapu et al., 2010) attributed this to higher methylation levels of DNA within nucleosomes. Here, we analyzed a number of published datasets and found a more compelling alternative explanation, namely that methylation levels are highest in linker regions between nucleosomes. Results: Reanalyzing the data from (Chodavarapu et al., 2010), we found that nucleosome-associated methylation could be strongly confounded by known sequence-related biases of the next-generation sequencing technologies. By accounting for these biases and using an unrelated nucleosome profiling technology, NOMe-seq, we found that genome-wide methylation was actually highest within linker regions occurring between nucleosomes in multi-nucleosome arrays. This effect was consistent among several methylation datasets generated independently using two unrelated methylation assays. Linker-associated methylation was most prominent within long Partially Methylated Domains (PMDs) and the positioned nucleosomes that flank CTCF binding sites. CTCF adjacent nucleosomes retained the correct positioning in regions completely devoid of CpG dinucleotides, suggesting that DNA methylation is not required for proper nucleosomes positioning. Conclusions: The biological mechanisms responsible for DNA methylation patterns outside of gene promoters remain poorly understood. We identified a significant genome-wide relationship between nucleosome organization and DNA methylation, which can be used to more accurately analyze and understand the epigenetic changes that accompany cancer and other diseases.

scholarly journals BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

2020 ◽  
Author(s):  
Nadezda A. Fursova ◽  
Anne H. Turberfield ◽  
Neil P. Blackledge ◽  
Emma L. Findlater ◽  
Anna Lastuvkova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Modifications ◽  
Transcription Initiation ◽  
Target Genes ◽  
Regulatory Elements ◽  
Polycomb Group ◽  
Gene Promoters ◽  
Histone H2a ◽  
Gene Regulatory Elements ◽  
Gene Regulatory

AbstractHistone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications that are found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A mono-ubiquitylation (H2AK119ub1) which is enriched at Polycomb-repressed gene promoters, but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we discover that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 represses gene expression by counteracting transcription initiation from gene regulatory elements, causing reductions in transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes leading to their derepression, therefore explaining the original genetic characterisation of BAP1 as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification, without the need for elaborate gene-specific targeting mechanisms.

Fraction genome altered (FGA) to regulate both cell autonomous and non-cell autonomous functions in prostate cancer and its effect on prostate cancer aggressiveness.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 347-347
Author(s):  
Goutam Chakraborty ◽  
Arnab Ghosh ◽  
Subhiksha Nandakumar ◽  
Joshua Armenia ◽  
Ying Zhang Mazzu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
High Risk ◽  
Signaling Pathway ◽  
Management Strategies ◽  
Disease Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Effector ◽  
Molecular Features ◽  
Cancer Aggressiveness

347 Background: Our ability to distinguish lethal from non-lethal forms of prostate cancer (PC) is limited. Given prostate tumors’ genetic heterogeneity, is it unlikely that a single somatic variant is prognostic. Herein we investigated fraction of genome altered (FGA; percentage of copy number altered chromosome regions out of measured regions; cBioportal) and tumor mutational count (TMC; number of mutational events per case) harbored by the primary tumor as two tumor-specific factors posited to influence disease aggressiveness or responsiveness to certain therapeutic agents. Methods: We used the TCGA data (n= 490 primary PC) and MSKCC-IMPACT (n=717, Zehir et al 2017) PC datasets to analyze the correlation between FGA and TMC in PC. GSEA was performed with transcriptomes used to identify signaling pathways associated with these two measures. We then categorized 490 primary PC patients from TCGA dataset into 4 groups based on FGA and TMC levels (based on the median values) to assess associations with outcomes. Results: Primary PC patients who harbor FGAhighTMClow exhibited shorter disease-free survival (High Risk). We observed attenuation of the androgen signaling pathway and induction of cell proliferation pathways associated with this aggressive form of disease. We used results from CIBERSORT algorithm and deep learning methods of TCGA data and observed that quantities of tumor infiltrating lymphocytes was higher in the FGAhighTMClow group (p=0.038). However, we also observed significantly reduced immune effector signaling-pathway signaling in this high-risk FGAhighTMClow group suggesting the presence of immune-suppressive networks in primary disease associated with a high risk of progression. Conclusions: A greater understanding of molecular features of aggressive primary PC (FGA/TMC) will be important in developing management strategies. Based on our preliminary analyses, we hypothesize that patients whose primary PC harbors FGAhighTMClow have a higher likelihood of aggressive disease due to their impact on PC cell proliferation and dedifferentiation (cell autonomous), and subdued immune responses (non-cell-autonomous).

scholarly journals Lsh Is Essential for Maintaining Global DNA Methylation Levels in Amphibia and Fish and Interacts Directly with Dnmt1

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Donncha S. Dunican ◽  
Sari Pennings ◽  
Richard R. Meehan
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Repetitive Sequences ◽  
Global Dna Methylation ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Mouse Cells ◽  
Eukaryotic Genomes

Eukaryotic genomes are methylated at cytosine bases in the context of CpG dinucleotides, a pattern which is maintained through cell division by the DNA methyltransferase Dnmt1. Dramatic methylation losses are observed in plant and mouse cells lacking Lsh (lymphoid specific helicase), predominantly at repetitive sequences and gene promoters. However, the mechanism by which Lsh contributes to the maintenance of DNA methylation is unknown. Here we show that DNA methylation is lost in Lsh depleted frog and fish embryos, both of which exhibit developmental delay. Additionally, we show that both Lsh and Dnmt1 are associated with chromatin and that Lsh knockdown leads to a decreased Dnmt1-chromatin association. Coimmunoprecipitation experiments reveal that Lsh and Dnmt1 are found in the same protein complex, and pulldowns show this interaction is direct. Our data indicate that Lsh is usually diffuse in the nucleus but can be recruited to heterochromatin in a HP1α-dependent manner. These data together (a) show that the role of Lsh in DNA methylation is conserved in plants, amphibian, fish, and mice and (b) support a model in which Lsh contributes to Dnmt1 binding to chromatin, explaining how its loss can potentially lead to perturbations in DNA methylation maintenance.

scholarly journals Ligand-induced native G-quadruplex stabilization impairs transcription initiation

2021 ◽  
Author(s):  
Conghui Li ◽  
Honghong Wang ◽  
Zhinang Yin ◽  
Pingping Fang ◽  
Ruijing Xiao ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Gene Transcription ◽  
Transcription Initiation ◽  
Regulatory Elements ◽  
Gene Promoters ◽  
Drug Induced ◽  
Transcriptional Regulatory Elements ◽  
Genome Wide ◽  
Self Association

G-quadruplexes (G4s) are noncanonical DNA secondary structures formed through the self-association of guanines, and G4s are distributed widely across the genome. G4 participates in multiple biological processes including gene transcription, and G4-targeted ligands serve as potential therapeutic agents for DNA-targeted therapies. However, genome-wide studies of the exact roles of G4s in transcriptional regulation are still lacking. Here, we establish a sensitive G4-CUT&Tag method for genome-wide profiling of native G4s with high resolution and specificity. We find that native G4 signals are cell type–specific and are associated with transcriptional regulatory elements carrying active epigenetic modifications. Drug-induced promoter-proximal RNA polymerase II pausing promotes nearby G4 formation. In contrast, G4 stabilization by G4-targeted ligands globally reduces RNA polymerase II occupancy at gene promoters as well as nascent RNA synthesis. Moreover, ligand-induced G4 stabilization modulates chromatin states and impedes transcription initiation via inhibition of general transcription factors loading to promoters. Together, our study reveals a reciprocal genome-wide regulation between native G4 dynamics and gene transcription, which will deepen our understanding of G4 biology toward therapeutically targeting G4s in human diseases.

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