lncRNA Regulates Tumor Suppressor Two Ways

A little redundancy can be a good thing. A team of researchers led by Dr. Kevin Morris at the Scripps Institute, in La Jolla, recently showed that a little redundancy in the regulation of PTEN, a tumor suppressor gene, can be pretty useful…but also really complicated.

PTENpg1, a PTEN pseudogene, regulates PTEN via both sense and antisense RNAs, and there’s a histone modification in the mix, too.

PTEN gets silenced in lots of cancers. The team from Sweden, the U.S., and Australia already knew that PTENpg1 encodes a sense long-noncoding RNA (lncRNA). This lncRNA acts as a sponge to tie up miRNAs that target PTEN mRNA. The upshot? PTEN mRNA sticks around and gets translated.

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But studies on other pseudogenes show that antisense RNAs (asRNAs) from a pseudogene also can regulate gene expression. So, the team took a closer look to see if PTEN regulation also involved asRNAs.

Here’s some of what they found:

  • Yup, the PTEN pseudogene encodes three dominant asRNA isoforms.
  • The PTENpg1 asRNA α and unspliced isoforms suppress PTEN mRNA expression. How? They hang out at the PTEN promoter and get DNA methyltransferase 3A and Enhancer of Zeste to methylate histone H3 to form H3K27me3.
  • The asRNA β isoform, however, has a totally different function. It seems to act as a sponge itself, binding and stabilizing the PTENpg1 lncRNA.

Dr. Kevin Morris chimed in, “Importantly, the observations presented here tell us that some long non-coding RNAs (thought to be junk), in this case emanating from a pseudogene, are mechanistically relevant and act, in the case of PTEN, as a master regulator of both transcription and translation. It shows that long-non-coding RNAs, even though not conserved, have a great potential to evolve into important regulatory units and have been overlooked as a major mechanistic player in human cells.”

There’s a lot going on in this paper, so head on over and read more at Nature Structural & Molecular Biology, February 2013.