Histone demethylation and timely DNA replication

It is well-established that silent regions of the genome replicate late during S phase. In this issue of Molecular Cell, Black et al. (2010) uncover a conserved role for the JMJD2 family of histone demethylases in promoting replication within silent chromatin regions that contain histone H3 lysine 9 methylation and HP1.     

Interspecies structural diversity among chlamydial genes encoding histone H1.

Recently, a eukaryotic histone H1-like protein has been detected in Chlamydia trachomatis serovar L2 [Hackstadt et al., Proc. Natl. Acad. Sci. USA 88 (1991) 3937-3941; Tao et al., J. Bacteriol. 173 (1991) 2818-2822]. We have cloned the corresponding gene from C. trachomatis serovar J and the Chlamydia psittaci strain mn. Sequencing demonstrated absolute gene identity between the two C. trachomatis serovars L2 and J, but divergence in the C. psittaci strain mn. These differences resulted in altered aa residues (in particular no cysteines) and a smaller molecular mass for H1 from C. psittaci strain mn. The amino acid (aa) sequence comparisons with other histone proteins show best alignment to sea urchin H1, notably in the C terminus, for both C. trachomatis and C. psittaci histones. Chlamydial interspecies aa homology, however, is most conserved at the N terminus, suggestive of a bi-functional role for these unique histone proteins.     

HDAC3 at the fulcrum of an epithelial-mesenchymal balance

In this issue of Molecular Cell, Wu et?al. (2011) reveal an essential role for a chromatin modifier, histone deacetylase 3 (HDAC3), in hypoxia-induced epithelial-mesenchymal transition (EMT); HIF-activated HDAC3 integrates with WDR5 to impose chromatin modifications that culminate in EMT.     

O2 sensing: only skin deep?

In this issue, two papers implicate histone H3 lysine 56 acetylation in histone deposition in chromatin. Li et al. (2008) show that acetylation of H3K56 promotes S phase chromatin assembly that is mediated by the histone chaperones CAF-1 and Rtt106. Chen et al. (2008) establish that the acetylation mark promotes chromatin reassembly following DNA double-strand break repair.     

A histone deacetylase regulates addiction

Epigenetic modification of chromatin has been proposed to translate environmental stimuli into persistent "cellular memories." Recent studies suggest that epigenetic pathways regulate long-term behavioral adaptation in the nervous system. In this issue of Neuron, Renthal et al. utilize genetic manipulations of HDAC5 to provide strong evidence for a role for histone acetylation in the behavioral response to cocaine.     

The enigmatic role of Sir2 in aging

In this issue of Cell, Longo and colleagues (Fabrizio et al., 2005) examine the role of Sir2, a histone deacetylase, in chronological aging in yeast by measuring the long-term survival of nondividing cells. In contrast to measurements of aging for mitotic cells, cell survival in the nonmitotic state is decreased by Sir2 activity under conditions that mimic calorie restriction.     

160 A dynamic model for the linker histone

Linker histones play an important role in the packing of chromatin. This family of proteins generally consists of a short, unstructured N-terminal domain, a central globular domain, and a C-terminal domain (CTD). The CTD, which makes up roughly half of the protein, is intrinsically disordered in solution but adopts a specific fold upon interaction with DNA (Fang et al., 2012). While the globular domain structure is well characterized, the structure of the CTD remains unknown. Sequence alignment alone does not reveal any significant homologs for this region of the protein. Construction of a model thus requires additional information. For example, the atomic model for the rat histone H1d CTD, proposed over a decade ago, used novel bioinformatics tools and biochemical data (Bharath et al., 2002). New fluorescence resonance energy transfer (FRET) studies of the folding of the CTD in the presence of linear DNA, single nucleosomes, and oligonucleosomal arrays (Caterino et al., 2011; Fang et al., 2012) have stimulated our interest in constructing a dynamic model of the protein. We have obtained preliminary information about the structure and dynamics of the linker histone CTD through ab initio folding simulations using the Rosetta modeling package (Rohl et al., 2004). By analyzing a large number of conformations sampled through a Monte Carlo procedure, we get a clearer picture of the preferred states of the protein and its dynamics. Our results show that the CTD may frequently adopt a structure with 3–5 helices and helix-turn-helix motifs in specific regions. Some of the best scoring structures show high similarity with the HMG-box-containing proteins previously used as templates by Bharath et al. Further clustering analysis of our results hints of a preferred set of conformations for the CTD of the linker histone. Comparison of these models with distances measured by FRET may help account for the distinct structures of the CTD observed upon binding to different macromolecular partners.     

SETting the clock for histone H4 monomethylation

In this and a previous issue of Molecular Cell, Oda et al. (2010), Abbas et al. (2010), and Centore et al. (2010) determined that the H4K20 histone methyltransferase PR-Set7/Set8 is posttranslationally regulated by the PCNA-dependent CRL4(Cdt2) ubiquitin ligase.     

Silence of the rings

Two recent papers (de Napoles et al., 2004 and Wang et al., 2004) have linked monoubiquitylation of histone H2A to the activities of E3 ubiquitin ligases that reside in Polycomb-group repressor complexes.     

The proteasome: not just degrading anymore

The proteasome is a large multiprotein complex that has a critical role in the degradation of ubiquitylated proteins. A fascinating paper in this issue of Cell (Lee et al., 2005) now reveals that the proteasome recruits the SAGA histone acetyltransferase complex to a target promoter during gene activation. This finding adds to the growing body of evidence indicating that the proteasome has nonproteolytic functions.     

P-Rex1, a guanine exchange factor that is overexpressed in breast cancer, is a convergence node for ErbB and CXCR4 signaling

In this issue of Molecular Cell, Wu et al. (2011) reveal that ubiquitylation of histone 2B lysine 34 stimulates histone methyltransferase activity on nucleosomes, a finding with implications for the general mechanism by which monoubiquitylation may influence subsequent modification activities.     

The ways of PARP

Two papers in this issue of Cell describe two roles of poly(ADP-ribose) polymerase (PARP) in modulating chromatin structure: as a structural component replacing linker histone (Kim et al., 2004) and as a constituent of a corepressor complex poised to dismiss repression upon receipt of an activating signal (Ju et al., 2004).     

The Ezh2 methyltransferase complex: actin up in the cytosol

Ezh2, a polycomb group protein, is known to function in histone methylation, thereby regulating gene expression. However, in a recent study by Su et al., the Ezh2-containing complex has been given an additional role in cellular regulation. Cytosolic Ezh2 methyltransferase complexes were shown to associate with Vav1 and control receptor-induced actin polymerization and proliferation in a methylation-dependent manner. Overall, these findings implicate lysine methylation as a posttranslational modification crucial for receptor-mediated signal transduction events.