Where long noncoding RNAs meet DNA methylation

DNA methylation is a fundamental epigenetic mechanism governing regulation of gene expression during mammalian development. A recent study published in Nature shows a novel long noncoding RNA (lncRNA) arising from the CEBPA gene locus (termed ecCEBPA) that is critical for regulation of DNA methylation at this site through the association of ecCEBPA with DNA methyltransferase 1, DNMT1.

lncRNA

DNA methylation was the first discovered epigenetic mechanism1,2. It is a chemical modification of genomic DNA by the addition of a methyl group (-CH3) to the cytosine or adenine DNA nucleotides. Typical DNA methylation occurs in a CpG dinucleotide context, where predominantly CpG sites are methylated in the genome. Most of the CpG clusters, known as CpG islands, occur near transcriptional start sites (TSSs) where they are predominantly un-methylated3. The establishment and maintenance of methylation patterns resulting in modulation of gene expression is one of the key steps in epigenetic regulation during normal developmental programs. In mammalian cells, DNA (Cytosine-5-)-Methyltransferase 1 (DNMT1) is the most abundant DNA methyltransferase to transfer a methyl group to DNA. It is highly expressed during the S phase, localizing to replication foci and interacting with the proliferating cell nuclear antigen (PCNA) to maintain DNA methylation marks during replication. This protein is known to add a methyl group to the un-methylated cytosines in methyl-CpG:CpG DNA from methylated parent and un-methylated daughter strands to generate fully methylated methyl-CpG: methyl-CpG pairs4.

Long noncoding RNAs (lncRNAs) have been defined as transcripts of > 200 nucleotides without protein coding capacity. Depending on their locus of expression, they can be categorized as intragenic or intergenic5. While recent genome-wide studies indicated that over 74% of human genome was transcribed, only 2% of these transcripts correspond to protein-coding genes6. While lncRNAs have been shown to have a broad range of biological functions both in the cytoplasm and the nucleus, a large number of nuclear lncRNAs were shown to originate from distal regulator elements (enhancers) to positively regulate gene expression7,8,9. Interestingly, while lncRNAs display tissue-specific expression patterns10, they have a low evolutionary conservation rate between species11. (read more…)

  • Lai F, Shiekhattar R. (2014) Where long noncoding RNAs meet DNA methylation. Cell Res [Epub ahead of print]. [article]

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