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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive Oct 11, 2013

 





During the transcription of DNA into RNA, when RNA is shut off, a gene becomes methylated, which is the equivalent of 'turned off' or silenced.

 

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Genes Protect Themselves Against Being 'Turned Off'

Harvard Stem Cell Institute (HSCI) researchers have settled a century-old debate over whether DNA methylation acts to silence gene expression, or if genes are turned off by other means before they are methylated.

As explicated today in the journal Nature, methylation in fact enforces gene silencing, and it is levels of a newly identified form of RNA produced by individual genes that determines whether they are turned off by the addition of a methyl (CH3) group by the enzyme DNA methylase 1 (DNMT1).

The study, led by HSCI Principal Faculty member Daniel Tenen, MD, found that during transcription of DNA to RNA, a gene produces a small amount of what the investigators named “extracoding RNA,” which stays in the nucleus and binds to DNMT1, blocking its ability to methylate, or silence the gene. The discovery of RNA’s new function has therapeutic potential as an on-off switch for gene expression.


“We have demonstrated, at least for one gene in detail, and probably thousands more, that extracoding RNA serves to protect the gene from methylation. When the RNA is shut off, which we did by various means, the gene becomes methylated.”

Daniel Tenen, MD, heads laboratories at Beth Israel Deaconess Medical Center and director, Cancer Science Institute of Singapore, National University of Singapore. Postdoctoral fellow Annalisa Di Ruscio, MD, PhD, and laboratory staff member Alexander Ebralidze, PhD, were major contributors to the work.


The biological irony is that DNMT1 has long been considered a DNA-binding enzyme, so it is surprising that it is able to bind so well to extracoding RNA, Tenen explained.

“If you put extracoding RNA into a cell, you can actually inhibit the ability of DNMT1 to maintain methylation patterns of that gene and induce demethylation in a gene-selective manner,” Tenen said. “The reason this is interesting is the cancers and other disease are treated using demethylation agents, so this gives us the opportunity to try to direct gene-specific demethylation.”

Abstract
DNA methylation was first described almost a century ago; however, the rules governing its establishment and maintenance remain elusive. Here we present data demonstrating that active transcription regulates levels of genomic methylation. We identify a novel RNA arising from the CEBPA gene locus that is critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extend the generality of this finding to numerous gene loci. Collectively, these results delineate the nature of DNMT1–RNA interactions and suggest strategies for gene-selective demethylation of therapeutic targets in human diseases.

This work was supported by the National Institutes of Health, the Italian Foundation for Cancer Research, Fondazione Roma, an American Italian Cancer Foundation Fellowship, the Singapore National Research Foundation, the Singapore Ministry of Education, and the Singapore Ministry of Health.

Research cited: DNMT1-interacting RNAs block gene specific DNA methylation. Nature. October 9, 2013

Original press releas: http://www.hsci.harvard.edu/genes-protect-themselves-against-being-silenced