Science Literature

The past few years has seen a steadily increasing awareness of the phenomenon of antisense transcription, but there has been very little insight into what antisense transcription products actually do. As is well known, DNA provides a template for the transcription of RNA sequences that are then used to make protein products. The distinction between sense and antisense transcription is helpfully made here:

"RNA, which is a single strand of nucleotides, is made by enzymes as an exact base-to-base copy of DNA. Since DNA is double-stranded, only one of these strands, the so-called sense strand, encodes for proteins. In normal DNA transcription, the two strands are split apart, and only the sense strand is copied. The other DNA strand, the "antisense" strand, can also be transcribed into RNA. Antisense transcription is the "reverse" expression of genomic DNA. If the same molecule of DNA is transcribed into antisense RNA, then the transcript has the reverse sequence as the original DNA sequence."

Antisense transcription is not an easy concept to illustrate, but this is how Nature Reviews Genetics did it.

The number of eukaryotic genes that have antisense transcripts seems to be quite high. This finding is stimulating many research projects, three of which have appeared recently in Science. Seila et al. have looked at the factors affecting transcription initiation. The first thing they noted relates to process.

"Transcription of DNA by RNA polymerase II (RNAPII) is an orchestrated process subject to regulation at numerous levels: binding of RNAPII to the promoter, transcription initiation, and elongation. These phases and their transitions require concerted action by many protein complexes and are accompanied by changes in local chromatin structure."

They noted some short (16-30 nucleotide) RNAs near the transcription start site (TSS) of protein-encoding genes. These were given the name TSSa-RNA. They appear to be intimately associated with promoters.

"Based on their direction and position relative to TSSs, we hypothesize that sense and antisense TSSa-RNAs arise from divergent transcription, defined as nonoverlapping transcription initiation events that proceed in opposite directions from the TSS. Divergent transcription is likely a common feature of mammalian TSSs given the presence of TSSa-RNAs in all cell types examined in this study."

There has been considerable uncertainty about whether these short RNAs and the antisense genes have functionality. Not long ago, they would have been lumped in with other "junk" materials and their production would have been regarded as a side-effect within the cell's complex genetic system. This has now changed. Gene regulation is the favoured role for these genetic elements. In a review published a few months ago, Beiter et al. wrote:

"So far, the regulatory potential of gene overlaps has been demonstrated only in a few selected cases of experimentally characterized antisense transcripts. Facing the large-scale antisense transcription observed in eukaryotic genomes, it still remains an open challenge to distinguish transcriptional noise from biological function of gene overlapping patterns."

All three of the new papers in Science develop our understanding of functionality. Seila et al. suggest a possible mechanism giving functionality to the TSSa-RNAs. Core et al. start their abstract with the statement: "RNA polymerases are highly regulated molecular machines." These authors comment on the need for regulation of the elaborate genetic system that can be found in cells: "Transcription of coding and non-coding RNAs by eukaryotic RNA polymerases requires their collaboration with hundreds of transcription factors, to direct and control polymerase recruitment, initiation, elongation and termination." They identify several possible functions for divergent transcription. In addition, He et al. conclude:

"The distribution of antisense transcripts was distinct from that of sense transcripts, was nonrandom across the genome, and differed among cell types. Antisense transcripts thus appear to be a pervasive feature of human cells, suggesting that they are a fundamental component of gene regulation."

Beiter et al. point out that "the mammalian genome contains a large layer of hidden biological information". Antisense transcription has been revealed to be widespread and these new papers are underlining the message that the transcription products have functionality within the "complex interplay between proteins, regulatory RNAs, and chemical and structural alterations of the genome itself". The DNA molecule has an extraordinary depth of information: one strand carries the instructions for the assembly of proteins whereas the other strand of the same DNA gene feeds transcription products into the regulatory system. ID scientists have always been sceptical of the Junk DNA hypothesis and these new findings confirm that the presumption of functionality is highly beneficial for biological science. The keywords are "information" and "systems biology". The systems that we see are exquisitely designed, not cobbled together by an incremental evolutionary process.

Papers discussed:

Divergent Transcription from Active Promoters
Amy C. Seila, J. Mauro Calabrese, Stuart S. Levine, Gene W. Yeo, Peter B. Rahl, Ryan A. Flynn, Richard A. Young, Phillip A. Sharp
Science Express, online 4 December 2008 | DOI: 10.1126/science.1162253

Nascent RNA Sequencing Reveals Widespread Pausing and Divergent Initiation at Human Promoters
Leighton J. Core, Joshua J. Waterfall, John T. Lis
Science Express, online December 4, 2008 | Science DOI: 10.1126/science.1162228

The Antisense Transcriptomes of Human Cells
Yiping He, Bert Vogelstein, Victor E. Velculescu, Nickolas Papadopoulos, and Kenneth W. Kinzler
Science Express, online December 4 2008; 10.1126/science.1163853

Antisense transcription: A critical look in both directions
T Beiter, E Reich, R Williams, P Simon
Cellular and Molecular Life Sciences, 2008 Sep 15; | doi 10.1007/s00018-008-8381-y