DNA-RNA-Protein Gang together in Silence

Heritable modifications can occur other than at the nucleotide sequence, a phenomenon called ‘epigenetics’ that plays a significant role in regulating gene expression. For a little over 30 years DNA methylation has been shown to be positively correlated with transcriptional gene silencing. In the January 03 issue of Trends in Plant Science (vol. 8:53-55), Trevor Stokes at the Department of Plant Molecular Biology, New York University, discusses the recent progress shedding light in gene silencing through the interplay of DNA, RNA, and protein components.

The author begins his review emphasizing the role of another type of methylation, namely, histone methylation, considered in many cases important for epigenetic gene regulation. However, how both types of methylation (DNA- and histone methylation) interconnect is yet to be worked out. Recently, Anne-Valérie Gendrel and her associates (INRA, France) along with Lianna Johnson and associates (UCLA, USA) reported that two systems of methylation, DNA and histone, are interdependent in heterochromatic portions of the genome and that reductions in DNA methylation correlate with a switch to an inactive methylated form of histones.

Two methylation systems are linked:
Histone tails undergo post-translational modification and such changes result in the alteration of chromatin structure modulating gene expression. The author points out that there is a minimum of two types of Methylated H3 histone. In one type: methylation occurs on lysine 4 designated H3mK4 (H = histone; m = methylation; k = lysine), while in the other, it is formed on lysine 9, designated H3mK9. H3mK4 and H3mK9 are distinguished by another feature: H3mK4 is associated with active chromatin, whereas H3mK9 has methylated lysine 9, indicating that it is associated with inactive chromatin. Using chromatin immunoprecipitation (ChIP), the two teams came up with similar results, namely, loss of DNA methylation led to changes in the patterns of histone methylation in heterochromatic regions of the genome. They noticed that these changes reflected transcriptional activation (= derepression) as demonstrated in ddm1 (decrease in DNA methylation1) mutants of Arabidopsis. Plants and filamentous fungi have similar enzymes that methylate DNA. In these organisms, DNA methylation is associated with gene silencing and transposon control.

With the help of ddm1 mutants, loss of DNA methylation causes a shift in histone methylation, thereby activating transcriptional factors in heterochromatic regions. Through methylation switching of lysine (from 9 to 4) in histone 3, inactive chromatin changes to actively transcribed genomic regions. The putative genes in that region as well as transposable elements become transcriptionally active after the switchover.

Histone and DNA methylation cross talk: The results from both groups indicate that histone- and DNA methylation work in close association, affecting transcription factors that modulate gene expression as exemplified by Arabidopsis in which loss of H3 K9 methylation led to reductions in a specific subset of DNA methylation targets. The effect of loss of histone methylation in Neurospora crassa (pink bread mold) is more drastic. There is a total loss of genomic DNA methylation in this genetic model microorganism, following loss of histone methylation. The results indicate that H3mK9 is the key player in determining which portions of DNA within the genome need to be methylated in certain cases. It will be important to uncover whether histone methylation occurs under the influence of DNA methylation or both work as a team, guided by an underlying factor such as DDM1. Johnson and associates hold a different viewpoint. According to them the loss of H3mK9 is due to transcriptional activation that leads to its substitution by H3mK4.

Role of small RNA species in directing methylation for gene silencing: Thomas Volpe and associates have shown that silenced genomic regions in fission yeast, Schizosac- charomyces pombe are targeted by either small interfering RNAs (siRNAs) or RNA interference (RNAi), accompanied by post-transcriptional gene silencing (PTGS). It was demonstrated that a silenced centromeric marker gene in S. pombemutants was activated. It is believed that these RNAs signal H3K9 methylation and guide histone modifications to the appropriate hetero- chromatic region. However, unlike higher plants, fission yeast lacks DNA methylation and as such the same model cannot explain the two systems.

At the end of the article the author points out of the similarity of the conservation region of the two methylation systems that plants and fungal systems share, indicating that it is a general cross-kingdom phenomenon.


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