Localized Readiness

Science Signaling  06 Apr 2010:
Vol. 3, Issue 116, pp. ec107
DOI: 10.1126/scisignal.3116ec107

Cells are able to store “memory” of an earlier response to a signal. Gialitakis et al. studied such a mechanism in HeLa cells (an epithelial cell line derived from a human cancer). These cells respond to interferon-γ (IFN-γ) by increasing transcription of genes encoding major histocompatibility complex (MHC) class II proteins. Cells that had been exposed to IFN-γ and then had the stimulus removed for 96 hours were more sensitive to a second treatment with IFN-γ than were unprimed cells. The cells previously exposed to IFN-γ showed faster and greater accumulation of mRNA encoded by MHCII genes. The increased transcriptional responsiveness was associated with a persistent loss of histone H3, indicative of loss of nucleosomes, which may provide a more open conformation of the chromatin, and persistent dimethylation of histone H3. IFN-γ also caused increased production of the promyelocytic leukemia (PML) protein, which localizes in nuclear structures known as PML bodies that have been suggested to be sites of localized transcriptional activation. The MHCII locus was shown by immunostaining and fluorescence in situ hybridization to be more closely associated with PML bodies in cells responding to IFN-γ or in cells that had been primed by such a response. The mixed lineage leukemia (MLL) methyltransferase complex also showed altered localization to the vicinity of PML bodies in primed cells or cells responding acutely to IFN-γ. Depletion of PML with siRNA decreased the IFN-γ–induced increase in dimethylation at the MHCII promoter and prevented the sustained priming effect. Transcriptional activation of the MHCII gene in response to IFN-γ was diminished in cells depleted of PML, as was the priming effect on a later response to IFN-γ. The results provide additional evidence for the importance of subnuclear localization not only for transcriptional regulation but also for the long-term memory effects that can be maintained over multiple generations in replicating cells. The authors propose that such mechanisms could allow cells to maintain certain genes in a state poised for increased responsiveness to a subsequent signal for activation.

M. Gialitakis, P. Arampatzi, T. Makatounakis, J. Papamatheakis, Gamma interferon-dependent transcriptional memory via relocalization of a gene locus to PML nuclear bodies. Mol. Cell. Biol. 30, 2046–2056 (2010). [Abstract] [Full Text]