A similar effect of P16 hydroxymethylation and true-methylation on the prediction of malignant transformation of oral epithelial dysplasia: observation from a prospective study

Liu, Hongwei; Liu, Zhaojun; Liu, Xue Wei; Xu, Shumao; Wang, Lei; Yang, Liu; Zhou, Jing; Gu, Lin; Gao, Yan; Liu, Xiao Yong; Shi, Huidong; Sun, Zheng; Deng, Dajun

doi:10.1186/s12885-018-4787-6

Cited by 7 publications

(7 citation statements)

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“…The global 5hmC levels are decreased in cancer genomes [29,30], probably through downregulation or mutation of the TET1/2/3 genes in cancer development [33][34][35]. However, certain proportion of 5hmCs remain in some cancer or precancer tissues [23]. Recently, we found that all P16 mRNA clones in the HCT116 cells were transcribed only from the mutant P16U alleles, and none from the methylated: hydroxymethylated (M: H) P16 alleles [21], and that both true P16M and P16H could similarly increase the risk for malignant transformation of oral epithelial dysplasia in a prospective study [23].…”

Section: Discussionmentioning

confidence: 99%

“…Our recent study demonstrates the presence of dense 5hmCs in the P16 exon-1 CGI in HCT116 cells, and no mRNA transcripts from the hydroxymethylated P16 (P16H) alleles were detected in the cells [21,22]. P16H was detected in 9.3% of human oral epithelial dysplasia (OED) tissues, and the malignant transformation risk was similar between P16Mpositive OED patients with and without P16H [23]. It is a fundamental question in epigenetic research to clarify whether hydroxymethylation of TSS-CGIs affects transcriptional activation of genes including P16.…”

Section: Introductionmentioning

confidence: 99%

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DNA hydroxymethylation increases the susceptibility of reactivation of methylated P16 alleles in cancer cells

Gan

Qin

et al. 2019

Epigenetics

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It is well established that 5-methylcytosine (5mC) in genomic DNA of mammalian cells can be oxidized into 5-hydroxymethylcytosine (5hmC) and other derivates by DNA dioxygenase TETs. While conversion of 5mC to 5hmC plays an important role in active DNA demethylation through further oxidation steps, a certain proportion of 5hmCs remain in the genome. Although 5hmCs contribute to the flexibility of chromatin and protect bivalent promoters from hypermethylation, the direct effect of 5hmCs on gene transcription is unknown. In this present study, we have engineered a zinc-finger protein-based P16-specific DNA dioxygenase (P16-TET) to induce P16 hydroxymethylation and demethylation in cancer cells. Our results demonstrate, for the first time, that although the hydroxymethylated P16 alleles retain transcriptionally inactive, hydroxymethylation could increase the susceptibility of reactivation of methylated P16 alleles.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNA hydroxymethylation increases the susceptibility of reactivation of methylated P16 alleles in cancer cells

Gan

Qin

et al. 2019

Epigenetics

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“…Recently, we found that all P16 mRNA clones in the HCT116 cells were transcribed only from the unmethylated P16 alleles, and none from the methylated: hydroxymethylated (M:H) P16 alleles [21], and that both true P16M and P16H could similarly increase the risk for malignant transformation of oral epithelial dysplasia in a prospective study [23]. The findings of the present study show that the P16-TET-induced hydroxymethylation of P16 alleles in both H1299 and AGS cells retain transcriptional silence, which provides a possible mechanism to explain the above observations.…”

Section: Discussionmentioning

confidence: 99%

“…Our recent study demonstrated that there were dense 5hmCs in the P16 exon-1 CGI in HCT116 cells, and no mRNA transcripts from the hydroxymethylated P16 (P16H) alleles were detected in the cells [21,22]. P16H was detected in 9.3% of human oral epithelial dysplasia (OED) tissues [23]. However, the malignant transformation risk was similar between P16M-positive OED patients with and without P16H.…”

Section: Introductionmentioning

confidence: 99%

Hydroxymethylated-P16 Allele Is Transcription-Inactive

Gan

Han

et al. 2018

Preprint

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6 # Equal contribution 7 * Corresponding authors 8 Author contributions 9 YG and PL: elucidated the biological function of P16 hydroxymethylation; SQ: discovered 10 P16 hydroxymethylation and its association with gastric carcinogenesis; XH: demonstrated 11 the strand-bias distribution of 5hmCs in the P16 alleles; CC, Z-mL, and BZ: constructed the 12 P16-specific oxygenase; LG performed the animal experiments; BZ performed 13 immunostaining and cell sorting assays and codesigned the study; ZL and JZ: carried out 14 other experiments; DD: designed the study, analyzed the data, and wrote the manuscript. 15 All authors read and approved the final manuscript. 16 Running title: DNA hydroxymethylation does not reactivate gene transcription 17 18 2 ABSTRACT 19 Background: 5-Methylcytosine can be oxidized into 5-hydroxymethylcytosine (5hmC) in 20 the genome. Methylated-P16 (P16M) can be oxidized into completely 21 hydroxymethylated-P16 (P16H) in human cancer and precancer cells. The aim of this study 22 is to investigate the biological function of P16H. 23 Methods: True P16M and P16H were analyzed using bisulfite/TAB-based assays. A 24 ZFP-based P16-specific dioxygenase (P16-TET) was constructed and used to induce 25 P16H. Cell proliferation and migration were determined with a series of biological analyses.26 Results: (A) The 5hmCs were enriched in the antisense-strand of the P16 exon-1 in 27 HCT116 and AGS cells containing methylated-P16 alleles (P16M). (B) P16-TET induced 28 both P16H and P16 demethylation in H1299 and AGS cells and reactivated P16 expression.29Notably, P16H was only detectable in the sorted P16-TET H1299 and AGS cells that did not 30 show P16 expression. (C) P16-TET significantly inhibited the xenograft growth derived from 31 H1299 cells in NOD-SCID mice, but did not inhibit the growth of P16-deleted A549 control 32 cells. P16-siRNA knockdown could rescue P16-TET-inhibited cell migration. 33 Conclusion: Hydroxymethylated P16 alleles are transcriptionally inactive.34 35 36 3 AUTHOR SUMMARY 37 It is well known that 5-methylcytosine (5mC) in genomic DNA of mammalian cells can be 38 oxidized into 5-hydroxymethylcytosine (5hmC) and other derivates by DNA dioxygenase 39 TETs. While conversion of 5mC to 5hmC plays an important role in active DNA 40 demethylation through further oxidations, a certain proportion of 5hmCs remain in the 41 genome. Although it is supposed that occurrence of 5hmCs may contribute to the flexibility 42 of chromatin and the protection of the bivalent promoters from hypermethylation, the direct 43 effect of 5hmCs on gene transcription is unknown. In the present study, we engineered a 44 zinc-finger protein-based P16-specific DNA dioxygenase and used it to induce P16 45 hydroxymethylation and demethylation in cancer cells. Our results demonstrate, for the first 46 time, that the hydroxymethylated P16 alleles retain transcriptionally inactive. This is 47 54It is well known that ten-eleven translocation methylcytosine dioxygenases (TET-1/2/3) 55 oxidize 5-methylcytosine (5mC) to 5-hydrox...

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“…This phenomenon results in fluorescence that can be detected proportionally with the amount of PCR product. For determining absolute methylation rate, two different primer sets, one for methylated and another for unmethylated DNA, are required (Liu et al, 2018).…”

Section: Dna Methylation Analysismentioning

confidence: 99%

Role of genetics and epigenetics in male infertility

2020

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Male infertility is a heterogeneous and common condition that might be a result of genetic or epigenetic variations or both. The frequency of genetic aberrations in azoospermic or severely oligozoospermic men is at least 15%, and the major genetic causes are karyotype abnormalities, microdeletions on Y chromosome, and mutations of cystic fibrosis transmembrane conductance regulator (CFTR) (Hamada, Esteves, & Agarwal, 2013; Hotaling & Carrell, 2014). Beyond these widely accepted genetic causes, a number of both autosomal and particularly X-chromosomal genes are associated with male infertility (Ropke & Tuttelmann, 2017). Furthermore, epigenetic control of gene expression plays a crucial role in both sperm function and fertilising ability (Gunes, Arslan, Hekim, & Asci, 2016a). Epigenetic regulation might be changed by external and internal factors or both, including environmental factors, nutrition and stress (Gunes, 2018b). This review summarises the latest evidence concerning the role of genetics and epigenetics on male infertility. 1.1 | Overview of human genome and genetics The haploid human genome consists of about 3 billion letters (3.3 billion nucleotides) distributed in 24 chromosomes. However, only 1.5% of the human genome encodes a protein (Gregory & Gilbert, 2005; Maher, 2012). The human genome project (HGP) has shown that genomes of nonrelated people exhibit a single base variation in every 1,200-1,500 DNA bases. These variations are

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A similar effect of P16 hydroxymethylation and true-methylation on the prediction of malignant transformation of oral epithelial dysplasia: observation from a prospective study

Cited by 7 publications

References 34 publications

DNA hydroxymethylation increases the susceptibility of reactivation of methylated P16 alleles in cancer cells

DNA hydroxymethylation increases the susceptibility of reactivation of methylated P16 alleles in cancer cells

Hydroxymethylated-P16 Allele Is Transcription-Inactive

Role of genetics and epigenetics in male infertility

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