Tet1 regulates epigenetic remodeling of the pericentromeric heterochromatin and chromocenter organization in DNA hypomethylated cells.
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ABSTRACT:
SUBMITTER: Hagihara Y
PROVIDER: S-EPMC8263065 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Many repetitive DNA elements are packaged in heterochromatin, but depend on occasional transcription to maintain long-term silencing. The factors that promote transcription of repeat elements in heterochromatin are largely unknown. Here, we show that DOT1L, a histone methyltransferase that modifies lysine 79 of histone H3 (H3K79), is required for transcription of major satellite repeats to maintain pericentromeric heterochromatin (PCH), and that this function is essential for preimplantation development. DOT1L is a transcriptional activator at single-copy genes but does not have a known role in repeat element transcription. We show that H3K79me3 is specifically enriched at repetitive elements, that loss of DOT1L compromises pericentromeric major satellite transcription, and that this function depends on interaction between DOT1L and the chromatin remodeler SMARCA5. DOT1L inhibition causes chromosome breaks and cell cycle defects, and leads to embryonic lethality. Together, our findings uncover a vital new role for DOT1L in transcriptional activation of heterochromatic repeats.
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Project description:Pericentromeric heterochromatin is maintained in a condensed structure by repressive epigenetic control mechanisms and perturbation of these may cause diseases. The chromosome 1q12 region harbors the largest pericentromeric heterochromatin domain in the genome and is among the most common breakpoints in both solid and hematopoietic cancers. Furthermore, the 1q arm is frequently amplified in cancer and this may support tumorigenesis by increasing the dosage of the many oncogenes of this genomic region. Recent studies have provided insight into the mechanisms leading to loss of 1q12 stability and 1q amplification and DNA hypomethylation seems to play a prominent role. This may be the result of decreased activity of DNA methyltransferases and instrumental for 1q12 destabilization or arise secondary to perturbation of other important epigenetic mechanisms that control repression of pericentromeric heterochromatin. Polycomb proteins were recently demonstrated to epigenetically reprogram demethylated 1q12 pericentromeric heterochromatin in premalignant and malignant cells to form large subnuclear structures known as polycomb bodies. This may influence the regulation and stability of 1q12 pericentromeric heterochromatin and/or the distribution of polycomb factors to support tumorigenesis. This review will discuss recent insight into the epigenetic perturbations causing the destabilization of 1q12 pericentromeric heterochromatin and its possible implications for tumor biology.
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Project description:Heterochromatic regions render the replication process particularly difficult due to the high level of chromatin compaction and the presence of repeated DNA sequences. In humans, replication through pericentromeric heterochromatin requires the binding of a complex formed by the telomeric factor TRF2 and the helicase RTEL1 in order to relieve topological barriers blocking fork progression. Since TRF2 is known to bind the Origin Replication Complex (ORC), we hypothesized that this factor could also play a role at the replication origins (ORI) of these heterochromatin regions. By performing DNA combing analysis, we found that the ORI density is higher within pericentromeric satellite DNA repeats than within bulk genomic DNA and decreased upon TRF2 downregulation. Moreover, we showed that TRF2 and ORC2 interact in pericentromeric DNA, providing a mechanism by which TRF2 is involved in ORI activity. Altogether, our findings reveal an essential role for TRF2 in pericentromeric heterochromatin replication by regulating both replication initiation and elongation.
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Project description:Pericentric heterochromatin (PCH) is a particular form of constitutive heterochromatin that is localized to both sides of centromeres and that forms silent compartments enriched in repressive marks. These genomic regions contain species-specific repetitive satellite DNA that differs in terms of nucleotide sequences and repeat lengths. In spite of this sequence diversity, PCH is involved in many biological phenomena that are conserved among species, including centromere function, the preservation of genome integrity, the suppression of spurious recombination during meiosis, and the organization of genomic silent compartments in the nucleus. PCH organization and maintenance of its repressive state is tightly regulated by a plethora of factors, including enzymes (e.g., DNA methyltransferases, histone deacetylases, and histone methyltransferases), DNA and histone methylation binding factors (e.g., MECP2 and HP1), chromatin remodeling proteins (e.g., ATRX and DAXX), and non-coding RNAs. This evidence helps us to understand how PCH organization is crucial for genome integrity. It then follows that alterations to the molecular signature of PCH might contribute to the onset of many genetic pathologies and to cancer progression. Here, we describe the most recent updates on the molecular mechanisms known to underlie PCH organization and function.
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Project description:Introduction and resultsImmunodeficiency, centromeric instability and facial anomalies syndrome (ICF) is a rare autosomal recessive disease, characterized by severe hypomethylation in pericentromeric regions of chromosomes (1, 16 and 9), marked immunodeficiency and facial anomalies. The majority of ICF patients present mutations in the DNMT3B gene, affecting the DNA methyltransferase activity of the protein. In the present study, we have used the Infinium 450K DNA methylation array to evaluate the methylation level of 450,000 CpGs in lymphoblastoid cell lines and untrasformed fibroblasts derived from ICF patients and healthy donors. Our results demonstrate that ICF-specific DNMT3B variants A603T/STP807ins and V699G/R54X cause global DNA hypomethylation compared to wild-type protein. We identified 181 novel differentially methylated positions (DMPs) including subtelomeric and intrachromosomic regions, outside the classical ICF-related pericentromeric hypomethylated positions. Interestingly, these sites were mainly located in intergenic regions and inside the CpG islands. Among the identified hypomethylated CpG-island associated genes, we confirmed the overexpression of three selected genes, BOLL, SYCP2 and NCRNA00221, in ICF compared to healthy controls, which are supposed to be expressed in germ line and silenced in somatic tissues.ConclusionsIn conclusion, this study contributes in clarifying the direct relationship between DNA methylation defect and gene expression impairment in ICF syndrome, identifying novel direct target genes of DNMT3B. A high percentage of the DMPs are located in the subtelomeric regions, indicating a specific role of DNMT3B in methylating these chromosomal sites. Therefore, we provide further evidence that hypomethylation in specific non-pericentromeric regions of chromosomes might be involved in the molecular pathogenesis of ICF syndrome. The detection of DNA hypomethylation at BOLL, SYCP2 and NCRNA00221 may pave the way for the development of specific clinical biomarkers with the aim to facilitate the identification of ICF patients.
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Project description:One key aspect of epigenetic inheritance is that chromatin structures can be stably inherited through generations after the removal of the signals that establish such structures. In fission yeast, the RNA interference (RNAi) pathway is critical for the targeting of histone methyltransferase Clr4 to pericentric repeats to establish heterochromatin. However, pericentric heterochromatin cannot be properly inherited in the absence of RNAi, suggesting the existence of mechanisms that counteract chromatin structure inheritance. Here, we show that mutations of components of the INO80 chromatin-remodeling complex allow pericentric heterochromatin inheritance in RNAi mutants. The ability of INO80 to counter heterochromatin inheritance is attributed to one subunit, Iec5, which promotes histone turnover at heterochromatin but has little effects on nucleosome positioning at heterochromatin, gene expression, or the DNA damage response. These analyses demonstrate the importance of the INO80 chromatin-remodeling complex in controlling heterochromatin inheritance and maintaining the proper heterochromatin landscape of the genome.
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Project description:BackgroundGene promoters in vertebrate genomes show distinct chromatin features such as stably positioned nucleosome array and DNA hypomethylation. The nucleosomes are known to have certain sequence preferences, and the prediction of nucleosome positioning from DNA sequence has been successful in some organisms such as yeast. However, at gene promoters where nucleosomes are much more stably positioned than in other regions, the sequence-based model has failed to work well, and sequence-independent mechanisms have been proposed.ResultsUsing DNase I-seq in medaka embryos, we demonstrated that hypomethylated domains (HMDs) specifically possess accessible nucleosome organization with longer linkers, and we reassessed the DNA sequence preference for nucleosome positioning in these specific regions. Remarkably, we found with a supervised machine learning algorithm, k-mer SVM, that nucleosome positioning in HMDs is accurately predictable from DNA sequence alone. Specific short sequences (6-mers) that contribute to the prediction are specifically enriched in HMDs and distribute periodically with approximately 200-bp intervals which prepattern the position of accessible linkers. Surprisingly, the sequence preference of the nucleosome and linker in HMDs is opposite from that reported previously. Furthermore, the periodicity of specific motifs at hypomethylated promoters was conserved in zebrafish.ConclusionThis study reveals strong link between nucleosome positioning and DNA sequence at vertebrate promoters, and we propose hypomethylated DNA-specific regulation of nucleosome positioning.
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Project description:Glioblastomas are the most aggressive of malignant brain cancers with a median patient survival of approximately 18?months. We recently demonstrated that Tet methylcytosine dioxygenase 1(TET1) is involved in cellular responses to ionizing radiation (IR) in glial-, glioblastoma-, and non-tumor-derived cells. This study used a lentiviral-mediated knockdown of TET1 to further dissect the contribution of TET1 to the DNA damage response in glial cell lines by evaluating its role in DNA repair. TET1-deficient glial cell lines displayed attenuated cytotoxicity compared to non-targeted knockdown after treatment with IR but these differences were not observed between control and TET1 deficient in response to inhibitors of Na+/K+-ATPase. Additionally, the percentage of glial cells displaying ?H2A.x foci was greatly reduced in TET1-deficient glial cells compared to non-targeted knockdown conditions in response to IR and topoisomerase inhibitors. We also observed a lower percentage and a delay in 53BP1 foci formation, a marker of non-homologous end-joining, in response to IR and topoisomerase inhibitors in TET1-deficient glial cells. DNA-PK, another marker of non-homologous end-joining, was also lower in TET1-deficient glial cell lines. Interestingly, TET1-deficient glial cells displayed higher numbers of DNA strand breaks compared to control cells and repaired DNA breaks less efficiently in Comet assays. We suggest that attenuated DNA repair in TET1 deficient gliomas leads to genomic instability, which underlies poor patient survival.
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