CELl cycle Feature
CELl cycle Feature
Cell Cycle 10:15, 2407-2409; August 1, 2011; © 2011 Landes Bioscience
When every minute counts
The enzymatic complexity associated with the activation of hormone-dependent genes Miguel Beato and Guillermo P. Vicent* Centre for Genomic Regulation; Pompev Fabra University; Barcelona, Spain
Human cells control gene expression by means of transcription factors that recognized instructions encoded in the DNA sequence of our genome. However, access to these instructions is not easy because the DNA is tightly packed in chromatin in order to fit within the small volume of a cell nucleus. The basic unit of chromatin is the nucleosome, composed of around 147 base pairs of the DNA double helix wrapped into two left-handed superhelical turns around a protein cylinder made of two copies of each of the core histones H3, H4, H2A and H2B, and sealed externally by a copy of the linker histone H1. Linker histones contact the DNA that enters and exits the nucleosome and are involved in stabilizing and compacting a 30 nm fiber of nucleosomes. In doing so, histone H1 limits the access of transcription factors to DNA regulatory information. Although much is known about transcription-induced changes to core histones, how linker histones are affected is less understood. Steroid hormones act by binding and activating specific receptors, which are hormone-dependent transcription factors, but they also activate various kinase-signaling pathways, which target the protein components of chromatin. Within one minute of adding synthetic progesterone analogs to breast cancer cells, the progesterone receptor (PR) recruits to the target genes an ATP-dependent chromatin remodeling complex, NURF, a histone methyltransferase complex, ASCOM, which trimethylates histone H3 at lysine 4, and a Cyclin A/CDK2 complex, that phosphorylates histone H1 and facilitates its displacement. At the same time a
histone demethylase, KDM5B/JARID1B/ PLU1 is displaced from the promoter1 (Fig. 1). This first cycle of chromatin remodeling is a prerequisite for a second cycle starting 5 min after hormone addition, in which a different ATP-dependent chromatin remodeling complex, BAF and a histone acetyltransferase, PCAF, cooperate to promote the displacement of core histones H2A and H2B, that facilitates access to the promoter of additional receptor complexes and other transcription factors necessary for gene induction2 (Fig. 1). It is only after completion of these initial chromatin-remodelling steps that complexes containing mediator and RNA-polymerase with associated basal transcription factors are recruited to the promoter and further steps in transcription initiation, elongation, RNA splicing, etc., can take place. At both phases in activation of the promoter, a histone tail modification stabilizes the binding of an ATP-dependent chromatin remodeling complex to the target promoters. These findings highlight the notion of transcription initiation as a process involving consecutive cycles of enzymatic chromatin remodelling, where each enzyme complex is necessary at a given time point and catalyzes a particular remodelling step. Thus, substantial enzymatic complexity is required for the “eviction” of linker H1 to set up a remodeled chromatin template for regulated gene expression. As eviction of histone H1 is a requisite for hormonal stimulation of breast cancer cell proliferation, component of the chromatin remodeling machineries, such as NURF and ASCOM, could be new targets for the pharmacological
management of hormone-dependent cancers. One question that arises is whether after one minute of hormone induction H1 is evicted alone or in a complex with other repressive components of chromatin, such as HP1γ that has been shown to be associated with hormone target genes.3 Prior to hormone treatment, there is an HP1γdependent repression of the MMTV promoter, which is released by phosphorylation of H3 triggered via the Erk and Msk kinases targeted to the promoter via association with activated PR. This mechanism is reminiscent of that observed during mitosis, which is mediated by the Aurora B-dependent phosphorylation of H3S10 and leads to a general displacement of HP1 proteins from heterochromatin.4 The linker histone H1.4 can interact with HP1 and their association is mediated by the methylation of H1.4 at K26. The Chromo domain of HP1 mediates binding to methylated K26, which is prevented by CDK2-dependent phosphorylation of H1.4.5,6 Thus the interaction between H1 and HP1 depends on the posttranslational modifications present on the linker histone. Here again, two convergent layers of regulation involving histone phosphorylation are critical during activation of hormone-regulated genes. On one side, H1 phosphorylation mediates its eviction from target chromatin and precludes binding to HP1. On the other side, H3S10 phosphorylation mediates the displacement of HP1γ from target chromatin. Furthermore, PKA mediated phosphorylation of HP1γ at S83 in euchromatin is associated with impaired silencing activity.6 Thus, in order to respond to external
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*Correspondence to: Guillermo P. Vicent; Email:
[email protected] Submitted: 04/27/11; Accepted: 04/28/11 DOI: 10.4161/cc.10.15.16200 Comment on: Vicent GP, et al. Genes Dev 2011; 25:845–62. www.landesbioscience.com
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Figure 1. For figure legend see page 2409. 2408
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Figure 1 (See opposite page). A model depicting the initial steps of MMTV promoter activation. In the uninduced state, the MMTV promoter is silent and is associated with repressive complexes that include HP1γ and KDM5B. After 1 min of hormone, the activated complexes of pPR, pErk and pMsk1, with either the NURF complex or the methyltransferase ASCOM complex, are recruited to the MMTV promoter. The combined action of the ASCOM complex and the displaced KDM5B increases histone H3 in K4 trimethylation, stabilizing NURF at the promoter. NURF remodeling facilitates access of the Cdk2-CyclinA kinase, which phosphorylates histone H1 and promotes its displacement, leading to unfolding of the chromatin fiber. In a second cycle, PR-BAF complexes are recruited along with PCAF that generate H3K14ac and anchor the BAF complex, enabling ATP-dependent H2A/ H2B displacement. At both phases in activation of the promoter, a histone tail modification stabilizes the binding of an ATP-dependent chromatinremodeling complex to the target promoters.
stimuli eukaryotic cells dispose of very rapid phosphorylation-mediated mechanisms to displace repressive components from genes marked for activation. How all these different kinase-pathways activated by hormones are inter-connected is still unknown. Histone H1 in mammals consists of a family of closely related, single-gene encoded proteins, including five somatic subtypes (from H1.1 to H1.5) and a terminally differentiated expressed isoform (H1.0). Although they have been assumed to be highly redundant, inducible knockdown of individual somatic H1 subtypes in
breast cancer cells enhance and inhibit different subset of genes and generate specific phenotypes, suggesting non-redundant effects on gene expression.7 Whether these are related to their differences as substrates for various kinases or other modifying enzymes remains to be established. Other open questions are, how the remodeled chromatin state returns to the ground state, how activation cycles are orchestrated,8 and whether there is an epigenetic “memory” after the initial round of activation. Given the complexity of the initial steps, we should be up for many more new players in these processes.
References 1. 2. 3. 4. 5. 6. 7. 8.
Vicent GP, et al. Genes Dev 2011; 25:845-62; PMID: 21447625; DOI: 10.1101/gad.621811. Vicent GP, et al. PLoS Genet 2009; 5:1000567; PMID: 19609353; DOI: 10.1371/journal.pgen.1000567. Vicent GP, et al. Mol Cell 2006; 24:367-81; PMID: 17081988; DOI: 10.1016/j.molcel.2006.10.011. Fischle W, et al. Nature 2005; 438:1116-22; PMID: 16222246; DOI: 10.1038/nature04219. Daujat S, et al. J Biol Chem 2005; 280:38090-5; PMID: 16127177; DOI: 10.1074/jbc.C500229200. Lomberk G, et al. Nat Cell Biol 2006; 8:407-15; PMID: 16531993; DOI: 10.1038/ncb1383. Sancho M, et al. PLoS Genet 2008; 4:1000227; PMID: 18927631; DOI: 10.1371/journal.pgen.1000227. Métivier R, et al. Cell 2003; 115:751-63; PMID: 14675539; DOI: 10.1016/S0092-8674(03)00934-6.
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