Advancing Epigenetics Towards Systems Biology

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March 2010

Stefan Janusz reports on how genes are poised for transcription

A publication by researchers at the MRC Clinical Sciences Centre (Genome Function Group) has shown that genes supposedly hidden from transcriptional machinery can still be poised and ready to be expressed.

The study focused on the urokinase-type plasminogen activator (uPA) in human HepG2 cells. Here it fits the 'standard model' of gene activation: sitting silently on the nuclear territory of chromosome 10 until treatment with an inducing compound switches on its expression. When activated, the majority of uPA genes relocate outside of their chromosome territory.

The observation that gene movement outside chromosome territories is associated with expression has led some researchers to propose that genes which do not move will remain silent, because they have less access to RNA polymerase factories. However in this study, Carmelo Ferrai and Sheila Xie show that the genes are already interacting with transcription factories, even before activation and while still located inside the chromosome territories.

The team led by Dr Ana Pombo in collaboration with Dr Massimo Crippa investigated whether relocation of the uPA gene during activation was accompanied by changes in chromatin structure that might facilitate transcription. Surprisingly, they found that even before the gene was chemically induced, the regulatory regions of uPA were already open: histone modifications associated with gene activity were present and the regions were bound by the RNA polymerase transcription complex.

Two critical phosphorylation targets control RNA polymerase II activity during transcription: serine-2 and serine-5. When only serine-5 is phosphorylated, the polymerase is poised – inactive but ready. When serine-2 and serine-5 are both phosphorylated, the gene is expressed. Before induction, most of the uPA genes within the chromosome 10 territory were only phosphorylated on serine-5, and therefore characterised as poised. Once chemically activated, the gene bound the fully active polymerase and moved out of its territory. Surprisingly, the interior of the territory was also accessible to the double phosphorylated polymerase, in contrast with current models that assume that the transcriptional machinery has limited access to the interior of chromosome territories.

The authors also found that after activation, the frequency with which uPA alleles are transcribed was the same whether the gene was inside or outside of the territory, again in contrast to the standard model. However, before activation genes inside the territory were largely silent – those few on the outside were transcribed at a rate equal to that of the induced gene. This study provides novel insights into the mechanisms of repression of poised genes prior to activation.

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