The tissue-specific genes VpreB1 and λ5 share the same locus and are both strongly activated in pre–B cells but repressed in ES cells. The group now finds that repression in ES cells requires proteasome activity. Proteasome inhibition in ES cells led to increased transcription and the recruitment of a number of general transcription factors to the locus.
This transcriptional up-regulation, however, occurred all over the locus rather than at the genes' normal transcription start sites. The novel transcription start sites were mainly located around a known intergenic regulatory region. The many transcription factor binding sequences in such a region would be likely to attract and assemble nonspecific transcription factor complexes in the open chromatin environment of ES cells. Thus it appears that the proteasome's job is to ensure that these complexes don't inappropriately activate transcription.
Proteasome levels are similar in all cell types, yet in pre–B cells the transcription complex necessary for VpreB1 and λ5 activation must be proteasome resistant. “There's some evidence that certain kinds of protein motifs get recognized by proteasomes,” says Dillon. He suggests that these motifs might be available in ES cells but then get masked when the proteins form complexes that include tissue-specific transcription factors.
Although the exact mechanism is unknown, proteasome inhibition also up-regulated other tissue-specific loci in ES cells, suggesting that proteasome policing might be a general mechanism for keeping inappropriate transcription in check.