Transcriptional status is closely related to nuclear positioning. Silenced genes, for example, are often associated with heterochromatin at the nuclear periphery, whereas active genes occupy different nuclear domains. The new results show that even close linkage to genes that are not transcribed does not prevent an activated gene from leaving heterochromatin.
The authors imaged three adjacent genes, CFTR (mutations in which cause cystic fibrosis), and its closest neighbors, GASZ and CORTBP2, in various cell types. When none of the genes were expressed, all three were closely associated with the nuclear envelope and peripheral heterochromatin. In cells that transcribed only one or two of the genes, only the active ones were found in the nuclear interior, separated from heterochromatin.
Repositioning might be controlled by histone modifications, which can be stably inherited through mitosis. Chemically induced histone acetylation pushed CFTR from the periphery into the interior. CFTR transcription was not activated, at least in the short term, but positioning may be important for maintaining transcriptional status. If so, gene therapy strategies for cystic fibrosis may need to overcome this additional layer of complexity. ▪