Signaling to Chromatin through Histone Modifications

Abstract

and Molecular DNA around a histone octamer core particle containing one H3-H4 tetramer and two H2A-H2B dimers. The valid-Genetics Box 800733 ity of this model has been confirmed by determining the crystal structures of the histone octamer, and of the Charlottesville, Virginia 22908 † Institut de Ge ´ne ´tique et de Biologie Mole ´culaire nucleosome particle (Arents et al., 1991; Richmond et al., 1993; Luger et al., 1997). As revealed by these and et Cellulaire CNRS-INSERM-ULP, B. P. 163 other studies, the C-terminal histone-fold domains of core histones have similar conformations that are critical 67404 Illkirch, Strasbourg France for the assembly of nucleosomes by mediating histonehistone and histone-DNA interactions (reviewed in Wolffe, 1998). In contrast, the N-terminal tails of core histones are less structured and are not essential for Signal Transduction and Chromatin maintaining the integrity of nucleosomes since removal The ability to detect extracellular stimuli and execute the of these tails by trypsin treatment does not diminish appropriate response is crucial to all cellular functions. nucleosome stability (Whitlock and Simpson, 1977; Au-Upon receiving external signals, be it growth factor stimsio et al., 1989). Instead, histone tails are thought to ulation or exposure to stress, distinct pathways are actimake secondary and more flexible contacts with DNA vated that culminate in the induction or repression of and adjacent nucleosomes (Luger et al., 1997) that allow defined sets of genes. The transduction of signals from for dynamic changes in the accessibility of the underlycell surface to the nucleus often involves phosphorylaing genome. tion cascades that not only allow for rapid transmission, How do these N-terminal histone tails participate in but also serve to amplify the signal by activating multiple the modulation of chromatin architecture? One possible factors and genes. The finely tuned combination of these way is that they constitute targets for ATP-dependent signal-induced nuclear effects thus leads to integrated chromatin remodeling factors such as Swi/Snf and cellular responses such as proliferation, differentiation, NURF (Georgel et al., 1997; Lee et al., 1999; Krebs et and apoptosis. al., 2000). Readers interested in the function of these A central goal in the signaling field is the identification remodeling complexes are directed to other reviews of physiologically relevant targets of transduction pathmore focused on that topic (Kingston and Narlikar, 1999; ways. To that end, much attention has been focused Peterson and Workman, 2000). Another way is that these on the signal-induced activation of transcription factors tails are subjected to a diverse array of posttranslational and components of the transcription machinery. Howmodifications, such as acetylation and phosphorylation ever, chromatin, the physiological packaging structure (Figure 1), which may modulate the contacts between of histones and genomic DNA, has largely been nehistones and DNA. Because these modifications are regl...

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

“…Phosphorylation of ubiquitinated H2AX may be a factor in the structural change in chromatin seen following induction of apoptotic cell death (Enomoto et al 2004). The aminoterminal tails of core histones also undergo various post-translational modifications, including acetylation, phosphorylation and methylation (Cheung et al 2000). These modifications occur in response to cell signaling stimuli and have a direct effect on gene expression.…”

Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis

“…Covalent acetylation of specific lysine residues on histone tails by histone acetyltransferases (HATs) promotes chromatin relaxation and transcription, whereas deacetylation by histone deacetylases (HDACs) in a reverse reaction results in chromatin condensation and silencing of gene transcription [10][11][12] . Some chromatin remodeling proteins that share a highly conserved SET domain, originally described in the proteins su(var)-39, enhancer of zeste and trithorax, can methylate unacetylated lysine residues on histone tails, resulting in more permanent silencing of transcription [13][14] or, in some cases, activation of transcription 15 .…”

Chromatin Remodeling, Measured by a Novel Real-Time Polymerase Chain Reaction Assay, Across the Proximal Promoter Region of the IL-2 Gene

“…Recent studies have identified several ATP-dependent multiprotein complexes whose primary function is to alter chromatin structure so that its DNA sequence becomes transparent to the transcriptional apparatus (9 -11). The modification of histone proteins by acetylation or phosphorylation is also thought to alter the packaging of nucleosomes (12)(13)(14).…”