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Histones and Chromatin

In eukaryotes, chromatin is organised as either euchromatin or heterochromatin. The lightly packed euchromatin is transcriptional active, whereas the more tightly packed heterochromatin is primarily not transcribed.
The dynamic nature of chromatin plays a crucial role in central genetic processes such as transcription, replication, recombination and DNA-repair and their regulation.

In heterochromatin, DNA is highly condensed in nucleosomes by histone proteins (H2A, H2B, H3, and H4). The posttranslational modification of histones (acetylation, methylation, ubiquitylation, phosphorylation and ADP ribosylation) is part of the epigenetic regulation.

Chromatin-marking systems

  • Histone acetylation correlates with transcriptional activity, whereas histone hypoacetylation is a conserved hallmark of heterochromatin. Many scientists believe that lysine acetylation acts as a beacon to recruit other activating chromatin modifying enzymes (and basal transcription machinery as well).

  • Another conserved histone modification is lysine methylation. Like hypoacetylation, H3K9 methylation generally correlates with heterochromatin in higher eukaryotes. Histone methylation is an irreversible modification. DNA methylation and histone methylation, two different epigenetic marks, seem to be linked.

  • Histone ubiquitination has been reported to regulate replication and meiosis in vertebrates. Accumulating evidence indicates that ubiquitin plays an important role in regulating transcription either through proteasome-dependent destruction of transcription factors or proteasome-independent mechanisms.

  • In DNA excision repair of mammalian cells, the processing of ADP-ribose by the poly ADP-ribosylation system of chromatin is stimulated several thousand-fold. The auto modification cycle catalyses a temporary dissociation from and re-association of histones with DNA ("histone shuttle"). In addition, histone shuttling driven by the poly ADP-ribosylation system seems to be involved in nucleosomal unfolding of chromatin in DNA excision repair.

  • Phosphorylation of histones appears to regulate processes such as transcription, DNA repair, apoptosis and chromosome condensation

  • Sumoylation is a post-translational modification system, biochemically analogous to, but functionally distinct from, ubiquitinylation. Sumoylation involves the covalent attachment of a SUMO (small ubiquitin-related modifier) to substrate proteins. This modification system has crucial roles in many different biological processes, including protein localisation and stability, transcriptional activities, nucleocytoplasmic signalling and transport and genome replication, as well as the regulation of gene expression.

  • Biotinylation of histones is a reversible process and depends on the exogenous biotin supply, but exact mechanisms of histone debiotinylases remain uncertain. It is proposed that biotin deficiency may result in abnormal chromatin structures.

The awareness that posttranslational histone modifications can influence each other by either enhancing or inhibiting gave rise to the hypothesis that they compose so-called a combinatorial code, regulating and determining some phenotypic traits by, inter alia, by the recruitment of chromatin-associated proteins.

For further information visit:
Grant PA. A tale of histone modification. Genome Biology 2001, 2:reviews0003-reviews0003.6
Zhang Y. Transcriptional regulation by histone ubiquitination and deubiquitination. Genes & Dev. 2003. 17: 2733-2740
Structure of nucleosome by Zheng Lab (video)