Hydroxymethylation of DNA influences nucleosomal conformation and stability in vitro

Mendonca, Agnes; Chang, En Hyung; Liu, Wenjie; Yuan, Ching

doi:10.1016/j.bbagrm.2014.09.014

Cited by 44 publications

(34 citation statements)

References 54 publications

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“…4A), chromatin opening could be directly triggered by the presence of 5hmC itself and not by the loss of 5mC. This hypothesis is supported by data indicating that nucleosomes formed in vitro on a hydroxymethylated DNA template are unstable due to a lower interaction of DNA with H2A-H2B dimers (Mendonca et al 2014). In order to compare the data obtained with DMOG, a compound affecting the enzymatic activity of TETs, and the effects of a reduction in TET proteins, P19 cells were transfected with siRNA targeting all three Tets (Supplemental Fig.…”

Section: Cytosine Modifications Control Enhancer Primingmentioning

confidence: 66%

Cytosine modifications modulate the chromatin architecture of transcriptional enhancers

Mahé¹,

Madigou²,

Sérandour³

et al. 2017

Genome Res.

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Epigenetic mechanisms are believed to play key roles in the establishment of cell-specific transcription programs. Accordingly, the modified bases 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) have been observed in DNA of genomic regulatory regions such as enhancers, and oxidation of 5mC into 5hmC by Ten-eleven translocation (TET) proteins correlates with enhancer activation. However, the functional relationship between cytosine modifications and the chromatin architecture of enhancers remains elusive. To gain insights into their function, 5mC and 5hmC levels were perturbed by inhibiting DNA methyltransferases and TETs during differentiation of mouse embryonal carcinoma cells into neural progenitors, and chromatin characteristics of enhancers bound by the pioneer transcription factors FOXA1, MEIS1, and PBX1 were interrogated. In a large fraction of the tested enhancers, inhibition of DNA methylation was associated with a significant increase in monomethylation of H3K4, a characteristic mark of enhancer priming. In addition, at some specific enhancers, 5mC oxidation by TETs facilitated chromatin opening, a process that may stabilize MEIS1 binding to these genomic regions.

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Section: Cytosine Modifications Control Enhancer Primingmentioning

confidence: 66%

Cytosine modifications modulate the chromatin architecture of transcriptional enhancers

Mahé¹,

Madigou²,

Sérandour³

et al. 2017

Genome Res.

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“…In glioblastoma cells, 5hmC recruits a complex that methylates arginine 3 of histone 4, thus activating the expression of genes involved in glioblastomagenesis (37). Another recent report by Mendonca et al showed that 5hmC-modified DNA may convert chromatin to a more open and active state by weakening the DNA-H2A-H2B dimer interaction (38).…”

Section: Discussionmentioning

confidence: 99%

5-hydroxymethylation of the EBV genome regulates the latent to lytic switch

Wille

Nawandar

Henning

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Latent Epstein-Barr virus (EBV) infection and cellular hypermethylation are hallmarks of undifferentiated nasopharyngeal carcinoma (NPC). However, EBV infection of normal oral epithelial cells is confined to differentiated cells and is lytic. Here we demonstrate that the EBV genome can become 5-hydroxymethylated and that this DNA modification affects EBV lytic reactivation. We show that global 5-hydroxymethylcytosine (5hmC)-modified DNA accumulates during normal epithelial-cell differentiation, whereas EBV+ NPCs have little if any 5hmC-modified DNA. Furthermore, we find that increasing cellular ten-eleven translocation (TET) activity [which converts methylated cytosine (5mC) to 5hmC] decreases methylation, and increases 5hmC modification, of lytic EBV promoters in EBV-infected cell lines containing highly methylated viral genomes. Conversely, inhibition of endogenous TET activity increases lytic EBV promoter methylation in an EBV-infected telomerase-immortalized normal oral keratinocyte (NOKs) cell line where lytic viral promoters are largely unmethylated. We demonstrate that these cytosine modifications differentially affect the ability of the two EBV immediateearly proteins, BZLF1 (Z) and BRLF1 (R), to induce the lytic form of viral infection. Although methylation of lytic EBV promoters increases Z-mediated and inhibits R-mediated lytic reactivation, 5hmC modification of lytic EBV promoters has the opposite effect. We also identify a specific CpG-containing Z-binding site on the BRLF1 promoter that must be methylated for Z-mediated viral reactivation and show that TET-mediated 5hmC modification of this site in NOKs prevents Z-mediated viral reactivation. Decreased 5-hydroxymethylation of cellular and viral genes may contribute to NPC formation.EBV | 5hmC | lytic reactivation | NPC

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“…Mendonca et al recently demonstrated that DNA modified with 5hmC generally exhibits an open chromatin configuration. 28 In addition, 5hmC was reported to accumulate at DNA damage foci induced by irradiation and colocalize with major DNA damage response proteins 53BP1 and gH2AX, indicating that the TET family members and 5hmC play essential roles in ensuring genome integrity. 29 Given that Tet2 loss causes decreased 5hmC whereas Aid loss induces accumulation of 5hmC ( Figure 1D), it is possible that Tet2 loss and Aid loss demonstrate a different effect on hematopoiesis through the unique and specific biological role of 5hmC independent of DNA demethylation.…”

Section: Discussionmentioning

confidence: 99%

Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

Kunimoto¹,

McKenney

Meydan

et al. 2017

Blood

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• Aid loss leads to altered differentiation, transcription, and methylation in specific genetic loci in hematopoietic stem/progenitor cells.• Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD in myeloid leukemogenesis.Recent studies have reported that activation-induced cytidine deaminase (AID) and teneleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies, and hematopoietic-specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating TET2 as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of AID loss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing of AID in human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast to Tet2 loss, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD to induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation. (Blood. 2017;129(13):1779-1790

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Hydroxymethylation of DNA influences nucleosomal conformation and stability in vitro

Cited by 44 publications

References 54 publications

Cytosine modifications modulate the chromatin architecture of transcriptional enhancers

Cytosine modifications modulate the chromatin architecture of transcriptional enhancers

5-hydroxymethylation of the EBV genome regulates the latent to lytic switch

Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

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