Dmitry Pruss

A positive role for histone acetylation in transcription factor access to nucleosomal DNA

Acetylation of the N-terminal tails of the core histones directly facilitates the recognition by TFIIIA of the 5S RNA gene within model chromatin templates. This effect is independent of a reduction in the extent of histone-DNA interactions or a change in DNA helical repeat; it is also independent of whether a histone tetramer or octamer inhibits TFIIIA binding. Removal of the N-terminal tails from the core histones also facilitates the association of TFIIIA with nucleosomal templates. We suggest that the histone tails have a major role in restricting transcription factor access to DNA and that their acetylation releases this restriction by directing dissociation of the tails from DNA and/or inducing a change in DNA configuration on the histone core to allow transcription factor binding. Acetylation of core histones might be expected to exert a major influence on the accessibility of chromatin to regulatory molecules.

How does DNA methylation repress transcription

DNA methylation has an essential regulatory function in mammalian development, serving to repress nontranscribed genes stably in differentiated adult somatic cells. Recent data implicate transcriptional repressors specific for methylated DNA and chromatin assembly in this global control of gene activity. The assembly of specialized nucleosomal structures on methylated DNA helps to explain the capacity of methylated DNA segments to silence transcription more effectively than conventional chromatin. Specialized nucleosomes also provide a potential molecular mechanism for the stable propagation of DNA methylation-dependent transcriptional silencing through cell division.

Histone acetylation: chromatin in action

Histone acetylation acts as a landmark and determinant for chromatin function. Active roles in the transcription and assembly of chromatin have been discovered for histone acetyltransferases and deacetylases. This review highlights these roles and discusses their significance for the maintenance of cell differentiation.

TARGETING CHROMATIN DISRUPTION : TRANSCRIPTION REGULATORS THAT ACETYLATE HISTONES

The discovery that a transcriptional regulator GCN5p is a histone acetyltransferase (Brownell et al. 1996xBrownell, J.E., Zhou, J., Ranalli, T., Kobayashi, R., Edmondson, D.G., Roth, S.Y., and Allis, C.D. Cell. 1996; 84Abstract | Full Text | Full Text PDF | PubMed | Scopus (1023)See all ReferencesBrownell et al. 1996) provides a new set of possible mechanisms by which transcription might be regulated. These mechanisms lead to a model for the targeted disruption of chromatin structure that requires the selective recruitment of GCN5p to a particular regulatory element. It is of course possible that GCN5p acetylates transcription components other than histones, or that the acetyltransferase activity has no influence on transcription, however, these possibilities seem unlikely in view of the known properties of the Tetrahymena p55 protein and the strong correlation between histone acetylation and transcription.Several observations indicate that there may be other targeted transcriptional regulators in addition to GCN5p with the capacity to modify histones. GCN5p is not an essential gene for viability in yeast (Georgakopoulos and Thireos 1992xGeorgakopoulos, T. and Thireos, G. EMBO J. 1992; 11: 4145–4152PubMedSee all ReferencesGeorgakopoulos and Thireos 1992) and the Tetrahymena histone acetyltransferase appears to selectively modify histone H3 (Brownell et al. 1996xBrownell, J.E., Zhou, J., Ranalli, T., Kobayashi, R., Edmondson, D.G., Roth, S.Y., and Allis, C.D. Cell. 1996; 84Abstract | Full Text | Full Text PDF | PubMed | Scopus (1023)See all ReferencesBrownell et al. 1996). Several distinct patterns of histone acetylation have been defined for individual core histones. Thus, other transcriptional regulators might acetylate different core histones with distinct specificities for different lysine residues in the N-terminal tails. Such capacity for covalent modification through acetylation emerges as a novel function for the transcriptional machinery.The question why mutation of the N-terminal tail domains of individual histones has specific consequences for the expression of particular genes (Grunstein et al. 1992xSee all ReferencesGrunstein et al. 1992) is answered by the specificity and targeting of acetylation patterns as a component of the transcription process. The interaction of the histone acetyltransferase with regulators that themselves interact with DNA binding proteins explains the targeting phenomenon. The potential specificity of histone acetylation patterns directed by a particular acetyltransferase, or the specific requirements for acetylation at an individual promoter can account for why mutations in the N-terminal tails of the histones influence transcription of a restricted set of genes. What emerges from these observations is the opportunity for chromatin structure to be precisely modulated through highly regulated reversible mechanisms. Such modifications might be a prerequisite for transcriptional activation.The recognition that transcription factors might function through enzymatic activities that modulate chromatin structure is important for our understanding of both transcriptional regulation per se and the role of chromatin structure in the nucleus. Gene regulation in eukaryotes involves substantial communication between architectural proteins such as histones and the transcriptional machinery itself.

An Asymmetric Model for the Nucleosome: A Binding Site for Linker Histones Inside the DNA Gyres

Histone-DNA contacts within a nucleosome influence the function of trans-acting factors and the molecular machines required to activate the transcription process. The internal architecture of a positioned nucleosome has now been probed with the use of photoactivatable cross-linking reagents to determine the placement of histones along the DNA molecule. A model for the nucleosome is proposed in which the winged-helix domain of the linker histone is asymmetrically located inside the gyres of DNA that also wrap around the core histones. This domain extends the path of the protein superhelix to one side of the core particle.

Deviant nucleosomes: the functional specialization of chromatin

Regulatory proteins exist with strong sequence and structural similarities to the histone proteins. Molecular genetic and cell biological analyses suggest that these proteins are localized at particular sites within the chromosome. Their assembly into nucleosomal structures confers specialized functions to individual chromosomal domains.

Activators and repressors: making use of chromatin to regulate transcription.

Metazoans and yeast use enzymes that modulate histone acetylation and nucleosomal integrity in order to regulate transcription. Repressor complexes deacetylate histones and stabilize nucleosomes. Activator complexes acetylate histones and disrupt nucleosomes. Variation in chromatin structure makes a major contribution to gene regulation. Here we discuss the enzymatic complexes and molecular machines that make use of chromatin to control transcription.

Chromatin: Hanging on to histones

Transcriptional control at a number of promoters has been found to involve the highly selective recognition of individual core histones by regulatory proteins, showing how the eukaryotic transcriptional machinery is adapted to function in a chromosomal environment.