Sense and antisense in the human genome

I hope you all had a wonderful holiday. Short post today, as I'm sure we're all still digesting all the yummy holiday food and sweets, and maybe some of you are still celebrating. One of my recurrent topics on the blog has been antisense genes. Until recently, I had no idea such things existed, let alone in humans. It turns out, they are quite abundant in humans.

Antisense genes are overlapping genes that are transcribed on opposite DNA strands. I've discussed how antisense genes regulate conjugation in bacteria, and how antisense RNA transcripts can be used in gene therapy. Today I'd like to discuss a paper that examined five different human cell types and found evidence for antisense transcripts in thousands of genes.

As you know, a gene is a piece of DNA, and a gene transcript is the RNA trasncribed from that gene. DNA is made of two strands coiled together, which are conventionally referred to as the plus strand and the minus strand. The general thought has been that sense transcripts produce functional proteins, whereas antisense transcripts have regulatory functions. For example, they can "silence" a gene since the antisense RNA will attach to the sense RNA and a double-stranded RNA can no longer produce a protein.

In [1], He et al. developed a technique that allows to change the RNA transcript in a way that, once turned back into DNA, it will only match either the plus or the minus DNA strand. This way one can establish from which strand it had been transcribed. The researchers analyzed five cell types: PBMC, peripheral blood mononuclear cells isolated from a healthy volunteer; Jurkat, a T cell leukemia line; HCT116, a colorectal cancer cell line; MiaPaCa2, a pancreatic cancer line; MRC5, a fibroblast cell line derived from normal lung. They called "S genes" the ones that contained only sense tags or had a sense/antisense tag ratio of 5 or more; "AS genes" contained only antisense tags or had a sense/antisense tag ratio of 0.2 or less; and finally, "SAS genes" contained both sense and antisense tags and had a sense/antisense ratio between 0.2 and 5.

I found this figure in particular to be quite interesting:

From the figure, it's clear that sense genes tend to accumulate in the exons (the coding bits of a gene), whereas the antisense genes accumulate more in the promoters, regions upstream of a gene that regulate and promote transcription, and, though to a less extent, in the terminator regions. The authors of the paper used these data to argue that, while

"promiscuous expression would lead to a uniform distribution of antisense tags across the genome, the observed distribution was nonrandom, localized to genes and within particular regions of genes, much like sense transcripts."

In other words, antisense genes are non-randomly distributed and may in fact contribute to antisense-mediated regulatory mechanism that, according to the data presented in [1] affects from 2900 to 6400 human genes. More on this in the next post! Happy Holidays, everyone!

[1] He, Y., Vogelstein, B., Velculescu, V., Papadopoulos, N., & Kinzler, K. (2008). The Antisense Transcriptomes of Human Cells Science, 322 (5909), 1855-1857 DOI: 10.1126/science.1163853