Hypomethylation of the DNMT3L promoter in ocular surface squamous neoplasia

Ophthalmic Pathology Services, Kallam Anji Reddy Campus, L. V. Prasad Eye Institute, Hyderabad, India.
Archives of pathology & laboratory medicine (Impact Factor: 2.84). 08/2010; 134(8):1193-6. DOI: 10.1043/2009-0417-OA.1
Source: PubMed


Cancer is known to have epigenetic inputs, with events like genomewide hypomethylation and gene-specific hypermethylation of DNA. The DNA methyltransferase enzymes act as effectors of this reprogramming. A previous study revealed that hypomethylation at the DNA methyltransferase 3-like (DNMT3L) promoter could be a potential biomarker in cervical tumors. Because the pathobiology of ocular surface squamous neoplasia (OSSN) is similar to that of cervical tumors, we wanted to determine whether similar changes occur in the methylation pattern at the DNMT3L promoter in OSSN.
To evaluate the methylation status of the DNMT3L promoter in OSSN compared with healthy conjunctiva.
We evaluated DNA methylation at the DNMT3L promoter in the tumor tissues of 6 patients with histologically proven OSSN and in healthy conjunctiva tissue from 7 individuals for controls using the sodium bisulfite-assisted conversion of genomic DNA. Extracted genomic DNA was treated with sodium bisulfite and amplified with specific primers for the DNMT3L promoter region. The specific polymerase chain reaction products were cloned and sequenced.
The mean age of these patients was 50.2 years (range, 35-65 years). Histologically, 4 OSSN cases were invasive; 2 were intraepithelial. Healthy conjunctival tissues exhibited a methylated promoter region, whereas a variable loss of methylation was observed in all 6 OSSN cases.
We have, for the first time to our knowledge, identified loss of methylation at the DNMT3L promoter in OSSN cases, but its physiologic significance is yet to be understood. Further studies are warranted to substantiate our results.

Download full-text


Available from: Guru Prasad Manderwad, Jan 28, 2015
  • Source
    • "It has been suggested that regions that show interaction with both PRC1 and PRC2 complexes have epigenetic regulatory properties and are part of large CpG islands [41]–[43]. DNMT3L DMC, which is part of a CpG island, is methylated in most somatic tissues [15]–[17] and we show here it interacts with PRC1, PRC2 and PhoRC polycomb repressive complexes. This would indicate that DNMT3L DMC possess essential attributes of a regulatory element. "
    [Show abstract] [Hide abstract]
    ABSTRACT: DNMT3L, a member of DNA methyltransferases family, is present only in mammals. As it provides specificity to the action of de novo methyltransferases, DNMT3A and DNMT3B and interacts with histone H3, DNMT3L has been invoked as the molecule that can read the histone code and translate it into DNA methylation. It plays an important role in the initiation of genomic imprints during gametogenesis and in nuclear reprogramming. With important functions attributed to it, it is imperative that the DNMT3L expression is tightly controlled. Previously, we had identified a CpG island within the human DNMT3L promoter and first exon that showed loss of DNA methylation in cancer samples. Here we show that this Differentially Methylated CpG island within DNMT3L (DNMT3L DMC) acts to repress transcription, is a Polycomb/Trithorax Response Element (PRE) and interacts with both PRC1 and PRC2 Polycomb repressive complexes. In addition, it adopts inactive chromatin conformation and is associated with other inactive chromatin-specific proteins like SUV39H1 and HP1. The presence of DNMT3L DMC also influences the adjacent promoter to adopt repressive histone post-translational modifications. Due to its association with multiple layers of repressive epigenetic modifications, we believe that PRE within the DNMT3L DMC is responsible for the tight regulation of DNMT3L expression and the aberrant epigenetic modifications of this region leading to DNMT3L overexpression could be the reason of nuclear programming during carcinogenesis.
    Full-text · Article · Apr 2014 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: DNA methyltransferase 3-like (DNMT3L) is one of the key players in de novo DNA methylation of imprinting control elements and retrotransposons, which occurs after genome-wide epigenetic erasure during germ cell development. In this review, we summarise the biochemical properties of DNMT3L and discuss the possible mechanisms behind DNMT3L-mediated imprinting establishment and retrotransposon silencing in germ cells. We also discuss possible connections between DNMT3L and non-coding RNA-mediated epigenetic remodelling, the roles of DNMT3L in germ cell development and the implications in stem cell and cancer research.
    Full-text · Article · Jun 2012 · Biology of the Cell
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cancer has been considered a genetic disease with a wide array of well-characterized gene mutations and chromosomal abnormalities. Of late, aberrant epigenetic modifications have been elucidated in cancer, and together with genetic alterations, they have been helpful in understanding the complex traits observed in neoplasia. "Cancer Epigenetics" therefore has contributed substantially towards understanding the complexity and diversity of various cancers. However, the positioning of epigenetic events during cancer progression is still not clear, though there are some reports implicating aberrant epigenetic modifications in very early stages of cancer. Amongst the most studied aberrant epigenetic modifications are the DNA methylation differences at the promoter regions of genes affecting their expression. Hypomethylation mediated increased expression of oncogenes and hypermethylation mediated silencing of tumor suppressor genes are well known examples. This chapter also explores the correlation of DNA methylation and demethylation enzymes with cancer.
    No preview · Article · Jan 2013 · Sub-cellular biochemistry
Show more