Maintenance of genome stability requires control over the expression of transposable elements (TEs), whose activity can have substantial deleterious effects on the host. Chemical modification of DNA is a commonly used strategy to achieve this, and it has long been argued that the emergence of 5-methylcytosine (5mC) in many species was driven by the requirement to silence TEs. Potential roles in TE regulation have also been suggested for other DNA modifications, such as N6-methyladenine and oxidation derivatives of 5mC, although the underlying mechanistic relationships are poorly understood. Here, we discuss current evidence implicating DNA modifications and DNA modifying enzymes in TE regulation across different species. 100 LINE-1 elements account for virtually all of the transposition activity observed today 18 , including retrotransposition of non-autonomous short interspersed nuclear elements (SINEs), which depend on proteins encoded by LINE-1 elements 19. Although many TEs are neutral in their effect on the host, some insertions can disrupt gene function or lead to harmful chromosomal rearrangements, as demonstrated by over 120 disease-causing TE insertions in humans 20. Additionally, exacerbated TE expression in the germline can lead to sterility in mice and fruit flies 21,22. The resulting selective pressure has driven the evolution of numerous transcriptional and posttranscriptional host defence mechanisms that repress TE expression (Figure 2), which have been recently reviewed by Molaro and Malik 22. Small RNAs, including PIWI-interacting RNAs [G] (piRNAs), are the
There is increasing evidence for the presence of an alternative code imprinted in the genome that might contribute to gene expression regulation through an indirect reading mechanism. In mammals, components of this coarse-grained regulatory mechanism include chromatin structure and epigenetic signatures, where d(CpG) nucleotide steps are key players. We report a comprehensive experimental and theoretical study of d(CpG) steps that provides a detailed description of their physical characteristics and the impact of cytosine methylation on these properties. We observed that methylation changes the physical properties of d(CpG) steps, having a dramatic effect on enriched CpG segments, such as CpG islands. We demonstrate that methylation reduces the affinity of DNA to assemble into nucleosomes, and can affect nucleosome positioning around transcription start sites. Overall, our results suggest a mechanism by which the basic physical properties of the DNA fiber can explain parts of the cellular epigenetic regulatory mechanisms.
Transposable elements (TEs) are thought to have helped establish gene regulatory networks. Both the embryonic and extraembryonic lineages of the early mouse embryo have seemingly co-opted TEs as enhancers, but there is little evidence that they play significant roles in gene regulation. Here we tested a set of long terminal repeat TE families for roles as enhancers in mouse embryonic and trophoblast stem cells. Epigenomic and transcriptomic data suggested that a large number of TEs helped to establish tissue-specific gene expression programmes. Genetic editing of individual TEs confirmed a subset of these regulatory relationships. However, a wider survey via CRISPR interference of RLTR13D6 elements in embryonic stem cells revealed that only a minority play significant roles in gene regulation. Our results suggest that a subset of TEs are important for gene regulation in early mouse development, and highlight the importance of functional experiments when evaluating gene regulatory roles of TEs.
Acute myeloid leukemia (AML) is characterised by a series of genetic and epigenetic alterations that result in deregulation of transcriptional networks. One understudied source of transcriptional regulators are transposable elements (TEs), whose aberrant usage could contribute to oncogenic transcriptional circuits. However, the regulatory influence of TEs and their links to AML pathogenesis remain unexplored. Here we identify six endogenous retrovirus (ERV) families with AML-associated enhancer chromatin signatures that are enriched in binding of key regulators of hematopoiesis and AML pathogenesis. Using both locus-specific genetic editing and simultaneous epigenetic silencing of multiple ERVs, we demonstrate that ERV deregulation directly alters the expression of adjacent genes in AML. Strikingly, deletion or epigenetic silencing of an ERV-derived enhancer suppresses cell growth by inducing apoptosis in leukemia cell lines. This work reveals that ERVs are a previously unappreciated source of AML enhancers that may be exploited by cancer cells to help drive tumour heterogeneity and evolution.
BackgroundTen-eleven translocation (TET) enzymes oxidise DNA methylation as part of an active demethylation pathway. Despite extensive research into the role of TETs in genome regulation, little is known about their effect on transposable elements (TEs), which make up nearly half of the mouse and human genomes. Epigenetic mechanisms controlling TEs have the potential to affect their mobility and to drive the co-adoption of TEs for the benefit of the host.ResultsWe performed a detailed investigation of the role of TET enzymes in the regulation of TEs in mouse embryonic stem cells (ESCs). We find that TET1 and TET2 bind multiple TE classes that harbour a variety of epigenetic signatures indicative of different functional roles. TETs co-bind with pluripotency factors to enhancer-like TEs that interact with highly expressed genes in ESCs whose expression is partly maintained by TET2-mediated DNA demethylation. TETs and 5-hydroxymethylcytosine (5hmC) are also strongly enriched at the 5′ UTR of full-length, evolutionarily young LINE-1 elements, a pattern that is conserved in human ESCs. TETs drive LINE-1 demethylation, but surprisingly, LINE-1s are kept repressed through additional TET-dependent activities. We find that the SIN3A co-repressive complex binds to LINE-1s, ensuring their repression in a TET1-dependent manner.ConclusionsOur data implicate TET enzymes in the evolutionary dynamics of TEs, both in the context of exaptation processes and of retrotransposition control. The dual role of TET action on LINE-1s may reflect the evolutionary battle between TEs and the host.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1096-8) contains supplementary material, which is available to authorized users.
Graphical Abstract Highlights d TET2 is upregulated in microglia cells upon various inflammatory stimuli d TET2 regulates TLR-4-induced type I IFN response and LPSinduced aerobic glycolysis d TET2 regulates the proinflammatory response induced by LPS in vitro and in vivo d TET2 is expressed by amyloid b plaque-associated microglia in AD brains SUMMARY Epigenomic mechanisms regulate distinct aspects of the inflammatory response in immune cells. Despite the central role for microglia in neuroinflammation and neurodegeneration, little is known about their epigenomic regulation of the inflammatory response.Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-kBdependent pathway. We found that TET2 regulates early gene transcriptional changes, leading to early metabolic alterations, as well as a later inflammatory response independently of its enzymatic activity. We further show that TET2 regulates the proinflammatory response in microglia of mice intraperitoneally injected with LPS. We observed that microglia associated with amyloid b plaques expressed TET2 in brain tissue from individuals with Alzheimer's disease (AD) and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response and suggest TET2 as a potential target to combat neurodegenerative brain disorders.
BackgroundIn eukaryotic organisms, DNA is packaged into chromatin structure, where most of DNA is wrapped into nucleosomes. DNA compaction and nucleosome positioning have clear functional implications, since they modulate the accessibility of genomic regions to regulatory proteins. Despite the intensive research effort focused in this area, the rules defining nucleosome positioning and the location of DNA regulatory regions still remain elusive.ResultsNaked (histone-free) and nucleosomal DNA from yeast were digested by microccocal nuclease (MNase) and sequenced genome-wide. MNase cutting preferences were determined for both naked and nucleosomal DNAs. Integration of their sequencing profiles with DNA conformational descriptors derived from atomistic molecular dynamic simulations enabled us to extract the physical properties of DNA on a genomic scale and to correlate them with chromatin structure and gene regulation. The local structure of DNA around regulatory regions was found to be unusually flexible and to display a unique pattern of nucleosome positioning. Ab initio physical descriptors derived from molecular dynamics were used to develop a computational method that accurately predicts nucleosome enriched and depleted regions.ConclusionsOur experimental and computational analyses jointly demonstrate a clear correlation between sequence-dependent physical properties of naked DNA and regulatory signals in the chromatin structure. These results demonstrate that nucleosome positioning around TSS (Transcription Start Site) and TTS (Transcription Termination Site) (at least in yeast) is strongly dependent on DNA physical properties, which can define a basal regulatory mechanism of gene expression.
Endogenous retroviruses (ERVs) and other transposons can act as tissue-specific regulators of gene expression in cis, with potential to affect biological processes. In cancer, epigenetic alterations and transcription factor misregulation may uncover the regulatory potential of typically repressed ERVs, which could contribute to tumour evolution and progression. Here, we asked whether transposons help to rewire oncogenic transcriptional circuits in acute myeloid leukemia (AML). Using epigenomic data from both primary cells and cell lines, we have identified six ERV families that are frequently found in an open chromatin state in AML when compared to differentiated healthy myeloid cells. A subset of these AML-associated ERVs harbour enhancerspecific histone modifications, and are bound by hematopoiesis-associated transcription factors that play key roles in haematopoiesis and in the pathogenesis of AML. Using CRISPR-mediated genetic editing and simultaneous epigenetic silencing of multiple ERV copies, we have established causal links between ERV deregulation in AML and expression changes of adjacent genes. Finally, we show that deletion and epigenetic silencing of an ERV, through modulating expression of APOC1 gene, leads to growth suppression by inducing apoptosis in leukemia cell lines. Our results suggest that ERV derepression provides an additional layer of gene regulation in AML that may be exploited by cancer cells to help drive oncogenic phenotypes. 10% or more of the AML samples ( Figure 1B). Five of these families were highly enriched across all samples, including macrophages and monocytes, as well as mobilized CD34+ cells (data from the Roadmap epigenomics project), suggesting little cell specificity. The remaining seven families displayed more variability between AML samples and, notably, tended to display little to no enrichment in differentiated myeloid cells ( Figure 1B). Nearly all families were also DHS-enriched in CD34+ cells, suggesting an association with a stem cell state. The exception was the LTR2B family, whose DHS enrichment appeared to be AML-specific. Analysis of an independent
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