Cancer is a complex disease caused by genetic and epigenetic alterations in the control of cell division. Findings from the field of cancer genomics and epigenomics have increased our understanding ...of the origin and evolution of tumorigenic processes, greatly advancing our knowledge of the molecular etiology of cancer. Consequently, any contemporary view of cancer research must consider tumorigenesis as a cellular phenomenon that is a result of the interplay between genetic and epigenetic mutations and their interaction with environmental factors, including our microbiome, that influences cellular metabolism and proliferation rates. The integration and better knowledge of these processes will help us to improve diagnosis, prognosis, and future genetic and epigenetic therapies. Here, I present an overview of the epigenetic processes that are affected in cancer and how they contribute to the onset and progression of the disease. Finally, I discuss how the development of sophisticated experimental approaches and computational tools, including novel ways to exploit large data sets, could contribute to the better understanding and treatment of cancer.
CTCF is a highly conserved zinc-finger DNA-binding protein that mediates interactions between distant sequences in the genome. As a consequence, CTCF regulates enhancer-promoter interactions and ...contributes to the three-dimensional organization of the genome. Recent studies indicate that CTCF is developmentally regulated, suggesting that it plays a role in cell type-specific genome organization. Here, we review these studies and discuss how CTCF functions during the development of various cell and tissue types, ranging from embryonic stem cells and gametes, to neural, muscle and cardiac cells. We propose that the lineage-specific control of CTCF levels, and its partnership with lineage-specific transcription factors, allows for the control of cell type-specific gene expression via chromatin looping.
In mammals, DNA methylation is a crucial epigenetic modification with key functions during development. Cellular processes that are regulated by DNA methylation comprise X chromosome inactivation, ...gene imprinting, genomic stability and transcriptional regulation. Generally, the methylation status of the majority of target sites is reliably propagated during mitosis. However, advances in genome-wide DNA methylation analysis at base-resolution have discovered a substantial amount of differential DNA methylation between normal cells of different tissue-origin. Moreover, aberrant DNA methylation changes are linked with a significant number of human diseases, particularly with cancer. Sites of differential and aberrant DNA methylation include regulatory DNA sequences, such as CpG islands in promoters and distal
-regulatory elements, like enhancers. In this review, we will discuss novel aspects of DNA methylation dynamics, during normal development and in association with diseases.
The multifunctional CCCTC-binding factor (CTCF) protein exhibits a broad range of functions, including that of insulator and higher-order chromatin organizer. We found that CTCF comprises a ...previously unrecognized region that is necessary and sufficient to bind RNA (RNA-binding region RBR) and is distinct from its DNA-binding domain. Depletion of cellular CTCF led to a decrease in not only levels of p53 mRNA, as expected, but also those of Wrap53 RNA, an antisense transcript originated from the p53 locus. PAR-CLIP-seq (photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation PAR-CLIP combined with deep sequencing) analyses indicate that CTCF binds a multitude of transcripts genome-wide as well as to Wrap53 RNA. Apart from its established role at the p53 promoter, CTCF regulates p53 expression through its physical interaction with Wrap53 RNA. Cells harboring a CTCF mutant in its RBR exhibit a defective p53 response to DNA damage. Moreover, the RBR facilitates CTCF multimerization in an RNA-dependent manner, which may bear directly on its role in establishing higher-order chromatin structures in vivo.
Chronic hypoxia is a major contributor to Chronic Kidney Disease (CKD) after Acute Kidney Injury (AKI). However, the temporal relation between the acute insult and maladaptive renal response to ...hypoxia remains unclear. In this study, we analyzed the time-course of renal hemodynamics, oxidative stress, inflammation, and fibrosis, as well as epigenetic modifications, with focus on HIF1α/VEGF signaling, in the AKI to CKD transition. Sham-operated, right nephrectomy (UNx), and UNx plus renal ischemia (IR + UNx) groups of rats were included and studied at 1, 2, 3, or 4 months. The IR + UNx group developed CKD characterized by progressive proteinuria, renal dysfunction, tubular proliferation, and fibrosis. At first month post-ischemia, there was a twofold significant increase in oxidative stress and reduction in global DNA methylation that was maintained throughout the study. Hif1α and Vegfa expression were depressed in the first and second-months post-ischemia, and then Hif1α but not Vegfa expression was recovered. Interestingly, hypermethylation of the Vegfa promoter gene at the HIF1α binding site was found, since early stages of the CKD progression. Our findings suggest that renal hypoperfusion, inefficient hypoxic response, increased oxidative stress, DNA hypomethylation, and, Vegfa promoter gene hypermethylation at HIF1α binding site, are early determinants of AKI-to-CKD transition.
As phosphorus is one of the most limiting nutrients in many natural and agricultural ecosystems, plants have evolved strategies that cope with its scarcity. Genetic approaches have facilitated the ...identification of several molecular elements that regulate the phosphate (Pi) starvation response (PSR) of plants, including the master regulator of the transcriptional response to phosphate starvation PHOSPHATE STARVATION RESPONSE1 (PHR1). However, the chromatin modifications underlying the plant transcriptional response to phosphate scarcity remain largely unknown. Here, we present a detailed analysis of changes in chromatin accessibility during phosphate starvation in
root cells. Root cells undergo a genome-wide remodeling of chromatin accessibility in response to Pi starvation that is often associated with changes in the transcription of neighboring genes. Analysis of chromatin accessibility in the
double mutant revealed that the transcription factors PHR1 and PHL2 play a key role in remodeling chromatin accessibility in response to Pi limitation. We also discovered that PHR1 and PHL2 play an important role in determining chromatin accessibility and the associated transcription of many genes under optimal Pi conditions, including genes involved in the PSR. We propose that a set of transcription factors directly activated by PHR1 in Pi-starved root cells trigger a second wave of epigenetic changes required for the transcriptional activation of the complete set of low-Pi-responsive genes.
Chromosomes are organized into high-frequency chromatin interaction domains called topologically associating domains (TADs), which are separated from each other by domain boundaries. The molecular ...mechanisms responsible for TAD formation are not yet fully understood. In Drosophila, it has been proposed that transcription is fundamental for TAD organization while the participation of genetic sequences bound by architectural proteins (APs) remains controversial. Here, we investigate the contribution of domain boundaries to TAD organization and the regulation of gene expression at the Notch gene locus in Drosophila. We find that deletion of domain boundaries results in TAD fusion and long-range topological defects that are accompanied by loss of APs and RNA Pol II chromatin binding as well as defects in transcription. Together, our results provide compelling evidence of the contribution of discrete genetic sequences bound by APs and RNA Pol II in the partition of the genome into TADs and in the regulation of gene expression in Drosophila.
The p53 tumor suppressor is one of the most studied molecules in cancer research. Despite the fact that there is a detailed understanding involving multiple aspects of the p53-associated biology, ...many aspects of its transcriptional regulation are still not well clarified. Limited information is available on how the p53 gene is transcriptional and epigenetically regulated. The p53 gene expression is tightly controlled through a variety of transcription factors, miRNAs, its anti-sense RNA Wrap53, the insulator protein CTCF and very likely by other genetic and epigenetic mechanisms. It's the intent of this article to review in depth important aspects concerning the transcriptional regulation of the p53 gene and perhaps serve as a stepping-stone to begin a conceptual change on how future p53 research can be approached.
DNA methylation is a key epigenetic modification to regulate gene expression in mammalian cells. Abnormal DNA methylation in gene promoters is common across human cancer types. DNMT3B is the main de ...novo methyltransferase enhanced in several primary tumors. How de novo methylation is established in genes related to cancer is poorly understood. CpG islands (CGIs), common sequences, and transcription factors (TFs) that interact with DNMT3B have been associated with abnormal de novo methylation. We initially identified cis elements associated with DNA methylation to investigate the contribution of DNMT3B overexpression to the deregulation of its possible target genes in an epithelial cell model. In a set of downregulated genes (n = 146) from HaCaT cells with DNMT3B overexpression, we found CGI, common sequences, and TFs Binding Sites that interact with DNMT3B (we called them P-down-3B). PPL1, VAV3, IRF1, and BRAF are P-down-3B genes that are downregulated and increased their methylation in DNMT3B presence. Together these findings suggest that methylated promoters aberrantly have some cis elements that could conduce de novo methylation by DNMT3B.
Thousands of long noncoding RNAs (lncRNAs) are actively transcribed in mammalian genomes. This class of RNAs has important regulatory functions in a broad range of cellular processes and diseases. ...Numerous lncRNAs have been demonstrated to mediate gene regulation through RNA-based mechanisms. Simultaneously, non-functional lncRNA transcripts derived from the activity of lncRNA loci have been identified, which underpin the notion that a considerable fraction of lncRNA loci exert regulatory functions through mechanisms associated with the production or the activity of lncRNA loci beyond the synthesized transcripts. We particularly distinguish two main RNA-independent components associated with regulatory effects; the act of transcription and the activity of DNA regulatory elements. We describe the experimental approaches to distinguish and understand the functional mechanisms derived from lncRNA loci. These scenarios reveal emerging mechanisms important to understanding the lncRNA implications in genome biology.
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