Densely methylated DNA traps Methyl-CpG–binding domain protein 2 but permits free diffusion by Methyl-CpG–binding domain protein 3

Leighton, Gage O.; Irvin, Elizabeth Marie; Kaur, Parminder; Liu, Ming; You, Changjiang; Bhattaram, Dhruv; Piehler, Jacob; Riehn, Robert; Wang, Hong; Pan, Hai; Williams, David C.

doi:10.1016/j.jbc.2022.102428

Cited by 11 publications

(6 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unlike MBD2, MBD3 cannot make a strong contact with methylated cytosines, instead it binds unmethylated or hydroxymethylated cytosines 31,37 . For this reason, we assessed MBD3 as a reader of E7‐induced hydroxymethylation in cells.…”

Section: Resultsmentioning

confidence: 99%

“…Unlike MBD2, MBD3 cannot make a strong contact with methylated cytosines, instead it binds unmethylated or hydroxymethylated cytosines. 31,37 For this reason, we assessed MBD3 as a reader of E7-induced hydroxymethylation in cells. Surprisingly, MBD3 mRNA expression was unaffected by the presence of E7 (wildtype and mutant) in C33A cells but not in keratinocytes (Figure 4A).…”

Section: Mbd2 Downregulation Modifies Global Hydroxymethylation In Ce...mentioning

confidence: 99%

See 1 more Smart Citation

A paradigm for post‐embryonic Oct4 re‐expression: E7‐induced hydroxymethylation regulates Oct4 expression in cervical cancer

Panayiotou,

Eftychiou,

Patera

et al. 2023

Journal of Medical Virology

View full text Add to dashboard Cite

The Octamer‐binding transcription factor‐4 (Oct4) is upregulated in different malignancies, yet a paradigm for mechanisms of Oct4 post‐embryonic re‐expression is inadequately understood. In cervical cancer, Oct4 expression is higher in human papillomavirus (HPV)‐related than HPV‐unrelated cervical cancers and this upregulation correlates with the expression of the E7 oncogene. We have reported that E7 affects the Oct4‐transcriptional output and Oct4‐related phenotypes in cervical cancer, however, the underlying mechanism remains elusive. Here, we characterize the Oct4‐protein interactions in cervical cancer cells via computational analyses and Mass Spectrometry and reveal that Methyl‐binding proteins (MBD2 and MBD3), are determinants of Oct4‐driven transcription. E7 triggers MBD2 downregulation and TET1 upregulation, thereby disrupting the methylation status of the Oct4 gene. This coincides with an increase in the total DNA hydroxymethylation leading to the re‐expression of Oct4 in cervical cancer and likely affecting broader transcriptional patterns. Our findings reveal a previously unreported mechanism by which the E7 oncogene can regulate Oct4 re‐expression and global transcriptional patterns by increasing DNA hydroxymethylation and lowering the barrier to cellular plasticity during carcinogenesis.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Mbd2 Downregulation Modifies Global Hydroxymethylation In Ce...mentioning

confidence: 99%

A paradigm for post‐embryonic Oct4 re‐expression: E7‐induced hydroxymethylation regulates Oct4 expression in cervical cancer

Panayiotou,

Eftychiou,

Patera

et al. 2023

Journal of Medical Virology

View full text Add to dashboard Cite

show abstract

“…Although it is unclear how phased nucleosomes may contribute to DUX4 repression, we can speculate that the preferentially methylated CpGs near position 1700 may participate in positioning of nucleosomes by localizing NuRD complexes through their methyl-CpG-binding protein domain 2 (MBD2) subunits to specific methyl-CpGs. Recent studies indicate that MBD2 has high affinity for large and densely methylated CpG islands, allowing recruitment of NuRD to facilitate nucleosome positioning, histone deacetylation, and chromatin compaction ( Leighton et al 2022 ). Further investigation is required to determine whether the fine-scale methylation pattern observed within each D4Z4 repeat is established during development or whether it arises from the dynamic turnover of methyl-CpGs, reflecting changes in the underlying chromatin state.…”

Section: Discussionmentioning

confidence: 99%

Deciphering D4Z4 CpG methylation gradients in fascioscapulohumeral muscular dystrophy using nanopore sequencing

Butterfield,

Dunn,

Duval

et al. 2023

Genome Res.

View full text Add to dashboard Cite

Fascioscapulohumeral muscular dystrophy (FSHD) is caused by a unique genetic mechanism that relies on contraction and hypomethylation of the D4Z4 macrosatellite array on the Chromosome 4q telomere allowing ectopic expression of theDUX4gene in skeletal muscle. Genetic analysis is difficult because of the large size and repetitive nature of the array, a nearly identical array on the 10q telomere, and the presence of divergent D4Z4 arrays scattered throughout the genome. Here, we combine nanopore long-read sequencing with Cas9-targeted enrichment of 4q and 10q D4Z4 arrays for comprehensive genetic analysis including determination of the length of the 4q and 10q D4Z4 arrays with base-pair resolution. In the same assay, we differentiate 4q from 10q telomeric sequences, determine A/B haplotype, identify paralogous D4Z4 sequences elsewhere in the genome, and estimate methylation for all CpGs in the array. Asymmetric, length-dependent methylation gradients were observed in the 4q and 10q D4Z4 arrays that reach a hypermethylation point at approximately 10 D4Z4 repeat units, consistent with the known threshold of pathogenic D4Z4 contractions. High resolution analysis of individual D4Z4 repeat methylation revealed areas of low methylation near the CTCF/insulator region and areas of high methylation immediately preceding theDUX4transcriptional start site. Within theDUX4exons, we observed a waxing/waning methylation pattern with a 180-nucleotide periodicity, consistent with phased nucleosomes. Targeted nanopore sequencing complements recently developed molecular combing and optical mapping approaches to genetic analysis for FSHD by adding precision of the length measurement, base-pair resolution sequencing, and quantitative methylation analysis.

show abstract

“…Evidence suggests a role for circRNAs in the epigenetic modification of nucleic acids in ALS [94]. Methyl-CpG binding domain protein 2 (MDB2) binds to a fraction of hypomethylated genes and plays a pivotal role in methylation-related transcription regulation [95]. Knockdown of circKCNN2 (has_circ_0127664), a circular form of potassium calcium-activated channel subfamily N member 2 (KCNN2), leads to the downregulation of MDB2 [96].…”

Section: Als-related Circrnamentioning

confidence: 99%

Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets

Hosaka

Toda

Kwak

2023

Cells

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, age-related molecular changes may provide clues for the development of new therapeutic strategies. Dysregulation of age-dependent RNA metabolism plays a pivotal role in the pathogenesis of ALS. In addition, failure of RNA editing at the glutamine/arginine (Q/R) site of GluA2 mRNA causes excitotoxicity due to excessive Ca2+ influx through Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, which is recognized as an underlying mechanism of motor neuron death in ALS. Circular RNAs (circRNAs), a circular form of cognate RNA generated by back-splicing, are abundant in the brain and accumulate with age. Hence, they are assumed to play a role in neurodegeneration. Emerging evidence has demonstrated that age-related dysregulation of RNA editing and changes in circRNA expression are involved in ALS pathogenesis. Herein, we review the potential associations between age-dependent changes in circRNAs and RNA editing, and discuss the possibility of developing new therapies and biomarkers for ALS based on age-related changes in circRNAs and dysregulation of RNA editing.

show abstract

Densely methylated DNA traps Methyl-CpG–binding domain protein 2 but permits free diffusion by Methyl-CpG–binding domain protein 3

Cited by 11 publications

References 58 publications

A paradigm for post‐embryonic Oct4 re‐expression: E7‐induced hydroxymethylation regulates Oct4 expression in cervical cancer

A paradigm for post‐embryonic Oct4 re‐expression: E7‐induced hydroxymethylation regulates Oct4 expression in cervical cancer

Deciphering D4Z4 CpG methylation gradients in fascioscapulohumeral muscular dystrophy using nanopore sequencing

Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets

Contact Info

Product

Resources

About