Cancer Initiation: The paradox of global hypomethylation and local hypermethylation in terms of the sea-saw molecular logic of epigenetics

Tuesday, May 20, 2014

The paradox of global hypomethylation and local hypermethylation in terms of the sea-saw molecular logic of epigenetics


The observation of global DNA hypo-methylation is relatively easy to understand given our simplistic model of loss of a checkpoint in the cell cycle coupled incomplete duplication of methylation patterns during the DNA "maintenance" operations of the synthesis and growth phase phase of the cell cycle. The actual duplication if the cells methylation imprint is mediated by DNA Methyl - Transferase 1, (DNMT1) the catalytic portion of a replication complex. For a review and brief description of the DNA Methyl Transferases, we provide a link to Kim[1]. From Kim we have the following description of DNMT1:

 In proliferating cells, DNMT1 is found to be associated with replication foci (Leonhardt et al., 1992), ensuring methylation of the daughter strand during DNA replication. Knockout of Dnmt1 in the mouse genome resulted in global demethylation and embryonic lethality (Li et al., 1992).    (Kim[1] )
  Here, demethylation refers to complete loss of DNA CpG Island methylation, where as the word hypo-methylation refers to under, or incomplete methylation.
As further evidence that the loss of complete methylation is sufficient to induce loss of control of the cell cycle, Pacaud et. al. [3] disrupted the DNMT1 DNA maintenance complex ( DNMT1/PCNA/UHRF1) induces tumorigenesis.
 But  loss of methylation is only half the story, the other half is that tumor suppressors, such as our now familiar mediators of checkpoints ( pRB ) and apoptosis "guardian" genes, ( p53, BRCA1/2 ) become hyper- methylated, and as a result are suppressed.
 Lets look at an actual example related to Non Hodgkins Lymphoma. In Yim[4] We are introduced to our familiar sea/saw regulation of cancer related genes by micro-RNA's:

MicroRNAs (miRNAs) are short, non-coding RNA sequences of 18–25 nucleotides, which can repress the translational of multiple protein-coding mRNAs by sequence-specific binding to the 3′untranslated region. Depending on the genes targeted, miRNA can be tumor suppressive if an oncogene is repressed, or it can be oncogenic when a tumor suppressive gene is repressed. Recently, aberrant methylation of tumor suppressive miRNAs has been reported in different types of cancers including lymphomas. (Yim[4])
So we see, that if a micro-RNA that should be suppressed by promoter methylation is in fact expressed due to the progression of "global hypomethylation", then it may become expressed. If the molecular target gene ( transcript ) of the micro-RNA  is a "tumor supressor", then that target gene will become promoter hyper-methylated and its expression will be blocked.. Yim[4] also provides a slightly more technical description of the expression of a micro RNA, and the details of how it blocks a target.
These intermediates pre-miRNAs are exported via Ran-GTP-dependent exportin-5 (XPO-5) into the cytoplasm, where these pre-miRNA stem-loops are further processed into mature miRNA duplex (Yi et al., 2003). Eventually a single-stranded mature miRNA is produced, ready to function when it is loaded onto the DICER1-TAR RNA-binding protein-containing RNA-induced silencing complex (RISC; Liu et al., 2004). The biosynthesis and processing of miRNA is summarized in Figure Figure11. (Yim[4])
In general terms, the micro-RNA is processed by Dicer into a short single stranded piece of RNA that is incorporated into a silencing complex ( RISC ), which will mediate the hyper-methylation of the promoter of the target gene. By this process, we complete the pathway from loss of checkpoint, global hypomethylation and hyper-methylation of tumor suppressors, thus describing the "paradox".

 In conclusion, we note that micro- RNAs are relatively new addition to the molecular biology soup. Here we see that they provide an important logical component in describing a mechanism behind the often observed phenomenon of tumor suppressor hyper-methylation, while in fact, the majority of the cells DNA is undergoing hypo-methylation as a result of the loss of checkpoints  and/or DNMT1 integrity.

References 

[1]  Gun-Do Kim, Jingwei Ni, Nicole Kelesoglu, Richard J. Roberts, and Sriharsa Pradhan Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases EMBO J. Aug 1, 2002; 21(15): 4183–4195. [PubMed Central]

[2] Sceusi EL1, Loose DS, Wray CJ.
Clinical implications of DNA methylation in hepatocellular carcinoma. HPB (Oxford). 2011 Jun;13(6):369-76.  [PubMed Central]

[3] Pacaud R, Brocard E, Lalier L, Hervouet E, Vallette FM, Cartron PF.
The DNMT1/PCNA/UHRF1 disruption induces tumorigenesis characterized by similar genetic and epigenetic signatures. Sci Rep. 2014 Mar 18;4:4230.  [PubMed Central]

[4] Yim RL1, Kwong YL, Wong KY, Chim CS.  DNA Methylation of Tumor Suppressive miRNAs in Non-Hodgkin's Lymphomas.   Front Genet. 2012 Nov 8;3:233.[PubMed Central]

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