How Cells Control The Direction In Which The Genome Is Read
June 25, 2013

Biologists Identify Mechanism That Determines Which Direction Cells Read Genes

redOrbit Staff & Wire Reports - Your Universe Online

Researchers have identified a mechanism that allows cells to read their own DNA in the correct direction, preventing them from replicating the intergenic DNA, or so-called “junk DNA,” that makes up significant parts of our genome.

Although just 15 percent of the human genome consists of protein-coding genes, research in recent years has revealed a surprising amount of the junk DNA does indeed get copied into RNA – the molecule that carries DNA’s messages to the rest of the cell.

Scientists have been working to determine precisely what this RNA might be doing, if anything.

In 2008, MIT researchers, led by Institute Professor Phillip Sharp, discovered much of this RNA is generated through a process known as divergent expression, through which cells read their DNA in both directions moving away from a given starting point.

In the current study, Sharp and colleagues determined how cells initiate, but then halt, the copying of RNA in the upstream, or non-protein-coding direction, while allowing it to continue in the direction in which genes are correctly read. These findings help explain the existence of many recently discovered types of short strands of RNA whose function is unknown.

“This is part of an RNA revolution where we’re seeing different RNAs and new RNAs that we hadn’t suspected were present in cells, and trying to understand what role they have in the health of the cell or the viability of the cell,” Sharp told MIT News.

“It gives us a whole new appreciation of the balance of the fundamental processes that allow cells to function.”

DNA, which resides within the cell nucleus, controls cellular activity by coding for the production of RNAs and proteins. To accomplish this, the genetic information encoded by DNA must first be copied, or transcribed, into messenger RNA (mRNA).

When the DNA double helix unwinds to reveal its genetic messages, RNA transcription can proceed in either direction. To initiate this copying, an enzyme known as RNA polymerase attaches to the DNA at a place known as the promoter. The RNA polymerase then moves along the strand, building the mRNA chain as it goes.

When the RNA polymerase reaches a stop signal at the end of a gene, it halts transcription and adds to the mRNA a sequence of bases known as a poly-A tail, which consists of a long string of the genetic base adenine. This process, known as polyadenylation, helps to prepare the mRNA molecule to be exported from the cell’s nucleus.

The researchers sequenced the mRNA transcripts of mouse embryonic stem cells, and found polyadenylation also plays a critical role in halting the transcription of upstream, noncoding DNA sequences. These regions have a high density of signal sequences for polyadenylation, which prompts enzymes to chop up the RNA before it gets too long.

The researchers found that stretches of DNA that code for genes have a low density of these signal sequences.

They also found another factor that influences whether transcription is allowed to continue. It has been recently shown that when a cellular factor known as U1 snRNP binds to RNA, polyadenylation is suppressed. The researchers found genes have a higher concentration of binding sites for U1 snRNP than noncoding sequences, allowing gene transcription to continue uninterrupted.

The function of all of this upstream noncoding RNA is still the subject of considerable research.

“That transcriptional process could produce an RNA that has some function, or it could be a product of the nature of the biochemical reaction. This will be debated for a long time,” Sharp said.

His lab is now investigating the relationship between this transcription process and the observation of large numbers of so-called long noncoding RNAs (lncRNAs). Sharp said he plans to investigate the mechanisms that control the synthesis of such RNAs and try to determine their functions.

“Once you see some data like this, it raises many more questions to be investigated, which I’m hoping will lead us to deeper insights into how our cells carry out their normal functions and how they change in malignancy,” he said.

The research was published online June 23 in the journal Nature.