SETDB1 regulates short interspersed nuclear elements and chromatin loop organization in mouse neural precursor cells
Daijing SunYueyan ZhuWenzhu PengShenghui ZhengJie WengShulong DongJiaqi LiQi ChenChuanhui GeLiyong LiaoYuhao DongYun LiuWeida MengYan Jiang
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Abstract Background Transposable elements play a critical role in maintaining genome architecture during neurodevelopment. Short Interspersed Nuclear Elements (SINEs), a major subtype of transposable elements, are known to harbor binding sites for the CCCTC-binding factor (CTCF) and pivotal in orchestrating chromatin organization. However, the regulatory mechanisms controlling the activity of SINEs in the developing brain remains elusive. Results In our study, we conduct a comprehensive genome-wide epigenetic analysis in mouse neural precursor cells using ATAC-seq, ChIP-seq, whole genome bisulfite sequencing, in situ Hi-C, and RNA-seq. Our findings reveal that the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1)-mediated H3K9me3, in conjunction with DNA methylation, restricts chromatin accessibility on a selective subset of SINEs in neural precursor cells. Mechanistically, loss of Setdb1 increases CTCF access to these SINE elements and contributes to chromatin loop reorganization. Moreover, de novo loop formation contributes to differential gene expression, including the dysregulation of genes enriched in mitotic pathways. This leads to the disruptions of cell proliferation in the embryonic brain after genetic ablation of Setdb1 both in vitro and in vivo . Conclusions In summary, our study sheds light on the epigenetic regulation of SINEs in mouse neural precursor cells, suggesting their role in maintaining chromatin organization and cell proliferation during neurodevelopment.Keywords:
CTCF
CTCF-mediated chromatin interactions influence organization and function of mammalian genome in diverse ways. We analyzed the interactions among CTCF binding sites (CBS) at the murine TCRb locus to discern the role of CTCF-mediated interactions in the regulation of transcription and VDJ recombination. Chromosome conformation capture analysis revealed thymocyte-specific long-range intrachromosomal interactions among various CBS across the locus that were relevant for defining the limit of the enhancer Eb-regulated recombination center (RC) and for facilitating the spatial proximity of TCRb variable (V) gene segments to the RC. Ectopic CTCF binding in the RC region, effected via genetic manipulation, altered CBS-directed chromatin loops, interfered with RC establishment, and reduced the spatial proximity of the RC with Trbv segments. Changes in chromatin loop organization by ectopic CTCF binding were relatively modest but influenced transcription and VDJ recombination dramatically. Besides revealing the importance of CTCF-mediated chromatin organization for TCRb regulation, the observed chromatin loops were consistent with the emerging idea that CBS orientations influence chromatin loop organization and underscored the importance of CBS orientations for defining chromatin architecture that supports VDJ recombination. Further, our study suggests that in addition to mediating long-range chromatin interactions, CTCF influences intricate configuration of chromatin loops that govern functional interactions between elements.
CTCF
Bivalent chromatin
Ectopic expression
ChIA-PET
Chromosome conformation capture
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DNA demethylation
Epigenomics
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It was shown that after treatment by Ca2+- and Mg2+-dependent DNAses and subsequent dosed ultrasonication the fractions of active and relatively inactive chromatins isolated from liver cell nuclei of rats differing in age contain all main types of histones, but differ considerably in the relative amounts of individual fractions of these proteins. In all age groups studied the proteins of relatively inactive chromatin are largely histones, while the amount of non-histone proteins is higher in active chromatin. In the course of postnatal development the amount of histones in both chromatin fractions is increased and that of non-histone proteins is decreased. This is probably due to heterochromatization of the chromatin complex in liver cells with ageing. In the course of postnatal ontogenesis the spectrum of non-histone proteins in both chromatin fractions is changed.
Non-histone protein
Histone-modifying enzymes
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Epigenetics describes the study of cellular modifications that can modify the expression of genes without changing the DNA sequence. DNA methylation is one of the most stable and prevalent epigenetic mechanisms. Twin studies have been a valuable model for unraveling the genetic and epigenetic epidemiology of complex traits, and now offer a potential to dissect the factors that impact DNA methylation variability and its biomedical significance. The twin design specifically allows for the study of genetic, environmental and lifestyle factors, and their potential interactions, on epigenetic profiles. Furthermore, genetically identical twins offer a unique opportunity to assess nongenetic impacts on epigenetic profiles. Here, we summarize recent findings from twin studies of DNA methylation profiles across tissues, to define current knowledge regarding the genetic and nongenetic factors that influence epigenetic variation.
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TOBACCO AND DNA METHYLATION THE CASE FOR EPIGENETIC ALTERATIONS The mechanisms of the long-term impacts of exposure to chemical substances remain poorly understood. While genotoxic and mutagenic effects have been well characterized, epigenetic mechanisms such as DNA methylation could also account for the delayed effects of exposures. It is in the case of tobacco that the strongest arguments for a role of these mechanisms have been obtained in human populations. This text presents recent data on this issue demonstrating the plausibility of epigenetic mechanisms to explain the persistence of biological signals long after stopping exposure.
Epigenesis
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Inducer
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The human genome is not just a simple string of DNA, it is a complex and dynamic entity intricately folded within the cell's nucleus. This three-dimensional organization of chromatin, the combination of DNA and proteins in the nucleus, is crucial for many biological processes and has been prominently studied for its intricate relationship to gene expression. Indeed, the transcriptional machinery does not operate in isolation but interacts intimately with the folded chromatin structure. Techniques for chromatin conformation capture, including genome-wide sequencing approaches, have revealed key organizational features of chromatin, such as the formation of loops by CCCTC-binding factor (CTCF) and the division of loci into chromatin compartments. While much of the recent research and reviews have focused on CTCF loops, we discuss several new revelations that have emerged concerning chromatin compartments, with a particular focus on what is known about mechanistic drivers of compartmentalization. These insights challenge the traditional views of chromatin organization and reveal the complexity behind the formation and maintenance of chromatin compartments.
CTCF
Scaffold/matrix attachment region
ChIA-PET
Compartmentalization (fire protection)
Genomic Organization
Bivalent chromatin
Histone-modifying enzymes
ChIP-sequencing
Chromosome conformation capture
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Transient nutritional exposures during critical ontogenic periods can cause persistent changes in gene expression, metabolism, and risk of various diseases. We have been investigating whether such ‘developmental programming’ occurs via nutritional influences on developmental epigenetics. Our studies in agouti viable yellow and axin-fused mice showed that developmental establishment of DNA methylation at ‘metastable epialleles’ is especially sensitive to maternal nutritional status around the time of conception. At metastable epialleles, DNA methylation is established stochastically in the early embryo and subsequently maintained during differentiation of diverse lineages, resulting in systemic interindividual epigenetic variation that is not genetically mediated. Lately, using a multiple-tissue screen for interindividual variation in DNA methylation, we have identified human genomic regions that appear to be metastable epialleles. Stochastic establishment of DNA methylation at these loci is affected by maternal nutrition around the time of conception, consistent across multiple tissues, and stable for many years. Most recently, our studies using genome-wide bisulfite sequencing have identified candidate metastable epialleles that are associated with human disease, providing exciting opportunities for epigenetic epidemiology.
Epigenesis
Epigenomics
Genomic Imprinting
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CTCF is a nuclear protein initially discovered for its role in enhancer-promoter insulation. It has been shown to play a role in genome architecture and in fact, its DNA binding sites are enriched at the borders of chromatin domains. Recently, we showed that depletion of CTCF impairs the DNA damage response to ionizing radiation. To investigate the relationship between chromatin domains and DNA damage repair, we present here clonogenic survival assays in different cell lines upon CTCF knockdown and ionizing irradiation. The application of a wide range of ionizing irradiation doses (0-10 Gy) allowed us to investigate the survival response through a biophysical model that accounts for the double-strand breaks' probability distribution onto chromatin domains. We demonstrate that the radiosensitivity of different cell lines is increased upon lowering the amount of the architectural protein. Our model shows that the deficiency in the DNA repair ability is related to the changes in the size of chromatin domains that occur when different amounts of CTCF are present in the nucleus.
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Radiosensitivity
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Histone-modifying enzymes
ChIA-PET
Histone code
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