Chromatin-Mediated Reversible Silencing of Sense-Antisense Gene Pairs in Embryonic Stem Cells Is Consolidated upon Differentiation

Loos, Friedemann; Loda, Agnese; Wijk, L. van; Grootegoed, J. Anton; Gribnau, Joost

doi:10.1128/mcb.00029-15

Cited by 8 publications

(10 citation statements)

References 46 publications

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“…The formation of triplexes can generate CpG methylation, as shown for PARTICLE and MAT2A SAGP in cells exposed to radiation 20 . Recent data also strongly support a role of antisense transcription of SAGP in the generation of H3K36me3 marks, in the developmental mechanisms of yeast, and in the Igf2r promoter of mouse embryonic stem cells (ESC) 21 . The H3K36me3 mark could play a major role in the de novo methylation of the CpG island.…”

Section: Discussionmentioning

confidence: 82%

A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients

et al. 2018

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To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B12 metabolism that we name “epi-cblC”. The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios.

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Section: Discussionmentioning

confidence: 82%

A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients

et al. 2018

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“…The antisense-mediated repression may involve transcriptional perturbation of the sense partner but may also include engagement of chromatin remodeling complexes, with local accumulation of histone modifications and DNA methylation. Alternatively, chromatin modulation based on the process of transcription per se might be involved ( 73 ). This model is supported by the association of Pol II with chromatin remodelers like Set2, which catalyzes the deposition of H3K36me3 in transcribed regions ( 74 ).…”

Section: Discussionmentioning

confidence: 99%

ICF-specific DNMT3B dysfunction interferes with intragenic regulation of mRNA transcription and alternative splicing

Gatto

Gagliardi

Franzese

et al. 2017

Nucleic Acids Research

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Hypomorphic mutations in DNA-methyltransferase DNMT3B cause majority of the rare disorder Immunodeficiency, Centromere instability and Facial anomalies syndrome cases (ICF1). By unspecified mechanisms, mutant-DNMT3B interferes with lymphoid-specific pathways resulting in immune response defects. Interestingly, recent findings report that DNMT3B shapes intragenic CpG-methylation of highly-transcribed genes. However, how the DNMT3B-dependent epigenetic network modulates transcription and whether ICF1-specific mutations impair this process remains unknown. We performed a transcriptomic and epigenomic study in patient-derived B-cell lines to investigate the genome-scale effects of DNMT3B dysfunction. We highlighted that altered intragenic CpG-methylation impairs multiple aspects of transcriptional regulation, like alternative TSS usage, antisense transcription and exon splicing. These defects preferentially associate with changes of intragenic H3K4me3 and at lesser extent of H3K27me3 and H3K36me3. In addition, we highlighted a novel DNMT3B activity in modulating the self-regulatory circuit of sense-antisense pairs and the exon skipping during alternative splicing, through interacting with RNA molecules. Strikingly, altered transcription affects disease relevant genes, as for instance the memory-B cell marker CD27 and PTPRC genes, providing us with biological insights into the ICF1-syndrome pathogenesis. Our genome-scale approach sheds light on the mechanisms still poorly understood of the intragenic function of DNMT3B and DNA methylation in gene expression regulation.

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“…But a recent report exhibited that transcriptional interference of the sense gene of a sense-antisense convergent gene reporter was coupled with H3K36me3, which was enriched by the antisense promoter activation. 27 The maintain system of this transcriptional interference of the sense gene changes depending on the state of the cell. H3K36me3 is promptly removed by the inactivation of the antisense promoter in ES cells, but it is maintained even after the inactivation of the antisense promoter to repress the transcription from the sense strand as a transcriptional memory in differentiating cells.…”

Section: Set2-dependent H3k36mementioning

confidence: 99%

“…H3K36me3 is promptly removed by the inactivation of the antisense promoter in ES cells, but it is maintained even after the inactivation of the antisense promoter to repress the transcription from the sense strand as a transcriptional memory in differentiating cells. 27 In fission yeast, Set2 is the sole methyltransferase that produces all methylation states of H3K36. We found that in set2DSRI cells, H3K36me3 was abolished while H3K36me2 was unaffected.…”

Section: Set2-dependent H3k36mementioning

confidence: 99%