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Covalent modifications of histones during development and disease pathogenesis #
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Contents #

Histone acetylation #

Histone acetylation is a modification that neutralizes the positive charge of the target lysine, and it occurs at specific lysines on the four core histones (Fig. 1).


It has been proposed that histone acetylation can alter histone-DNA interactions, creating a more open chromatin architecture.

This modification is catalyzed by histone acetyltransferases (HATs) through the transfer of the acetyl moiety from acetyl-coenzyme A to the ε-amine of target lysine residues (Table 1).


Consistently, given the histone acetylation can create a more open chromatin structure, many transcriptional coactivators, such as Gcn5/PCAF, CBP/p300 and SRC-1, have been shown to possess intrinsic HAT activity.

Histone acetylation can be reversed by the enzymatic action of the histone deacetylases (HDACs). The interplay between HAT and HDAC activities thus regulates cellular histone acetylation levels.

Similar to transcriptional coactivators possessing HAT activity, many transcriptional corepressor complexes, such as mSin3a, NCoR/SMRT and NURD/Mi-2, contain subunits with HDAC activity.

The Rpd3 small complex (Rpd3S) could be an exception to this rule, being an HDAC-containing complex that associates with the actively transcribing, elongating form of RNA polymerase II.

Through this association, Rpd3S has been implicated in preventing inappropriate initiation within the protein-coding region of actively transcribed genes. However, its overall function can still be catalogued as a repressor of inappropriate transcriptional initiation.

Histone ubiquitination #

Histone ubiquitination has been reported to occur on histones H2A, H2B and H3. In higher eukaryotes, histone H2A is mostly monoubiquitinated at lysine 119, though polyubiquitination has been reported, but this residue is not modified in the budding yeast Saccharomyces cerevisiae.

Histone H2B, in contrast, is found only in the monoubiquitinated form (human Lys120; yeast Lys123). The ubiquitination site on histone H3 has yet to be characterized.

Histone ubiquitination is catalyzed by the formation of an isopeptide bond between the carboxy-terminal glycine of ubiquitin and the ε-group of a lysine residue on histones. This bond is formed with the sequential catalytic actions of E1-activating and E2-conjugating enzymes and E3-ligases.

Whareas the same E1-activating enzyme is involved in the ubiquitination of all target proteins, different E2-conjugating enzymes are required for the ubiquitination of different substrates. E3-ligases provide protein target specificity.

In budding yeast, Rad6, an E2-conjugating enzyme, in conjunction with Brel, an E3-ligase, are required for histone H2B monoubiquitination, whereas for histone H2A the polycomb group RING finger protein Ring1b acts as the E2-ligase.

As will be discussed later in the review, H2B monoubiquitination is required for proper histone methylation by other enzymes, a process known as Histone crosstalk (Fig 2).


Histone ubiquitination cab be reversed by deubiquitinase. Ubp8 associates with Gcn5-containing complexes (SAGA and SLIK) and its activity is needed for the full expression of SAGA- and SLIK-regulated genes.

Thus, while ubiquitination of H2B is required for specific steps in gene activation, its quick removal may also be important. Recently, an H2A deubiquitinase(2A-DUB) that removes ubiquitin from Lys119 of H2A (H2AK119, in the notation we will use) as part of a coactivation complex with PCAF has been identified.

Histone phosphorylation #

Histones are often phosphorylated at specific sites during cell division (Fig.1). Several distinct kinases are required for the phosphorylation of histones on different residues (Table 1).

Phosphorylation of histone H2A is induced by a DNA damage signalling pathway, and this modification is dependent on phosphatidylinositol-3-OH kinases, such as Mec1 in yeast.

Histone H2B phosphoylation is catalyzed by the sterile-20 kinase in yeast and Mst1 (mammalian sterile-20-like kinase) in mammals.

Phosphorylation at histone H2S10 and H3S28 during mitosis is regulated by the Aurora kinases, which are highly conserved from yeast to human.

Other kinases in the MSK/RSK/Jil-1 family can mediate phosphorylation of histone H3 at Ser10 during gene expression.

Histone H4S1 phosphorylation was recently linked to sporulation in yeast. A sporulation-specific kinase, Sps1 (a member of the sterile-20 family of kinases), is required for this modification.

Drosophila melanogaster and mice undergoing spermatogenesis can also phosphorylate H4S1, indicating a conserved role for histone modification during chromatin compaction associated with germ cell development.

Histone methylation #

Histone acetylation in transcription and genome stability #

Histone ubiquitination and transcriptional regulation #

Like histone acetylation, histone ubiquitination is important in the regulation of gene expression. In fact, several early studies showed an abundance of ubiquitinated histones at transcriptionally active gene loci.

For example, HSP70 gene contains transcriptionally poised RNA polymerase II, and up to 50% of nucleosomes are ubiquitinated on histone H2A. However, nucleosomes associated with untranscribed satellite DNA contain only one ubiquitinated H2A per 25 nucleosomes.

Histones H2A and H2B associated with transcriptionally active sequences in Tetrahymena thermophila macronuclei, chicken erythrocytes and bovine thymus are found to be highly ubiquitinated when compared to transcriptionally silenced regions. In addition, inhibiting transcription abolished ubiquitinated H2B.

Although the above studies indicate a positive correlation between transcription and histone ubiquitination, the relationship is actually much more complex. For instance, histones present at the active immunoglobulin κ-chain genes are unubiquitinated, whereas the transcriptionally inactive T. thermophila micronuclei and mouse spermatid sex body carry ubiquitinated histones.

Thus, links between transcriptional status and histone ubiquitination are context dependent, based on gene location or possibly the presence of other histone covalent modifications.

The identification of Rad6 as an E2-conjugating enzyme for H2B monoubiquitination has helped elucidate the regulatory role of histone ubiquitination in transcription (Fig. 2).

In budding yeast, the deletion of RAD6 results in defective telomeric and HML silencing through the regulation of histone methylation of Lys4 and Lys79.

This fission yeast Rad6 homolog is also required for mating-type silencing. Thus, although the silencing function of Rad6 seems to be conserved, it is considered an indirect effect mediated by cross-talk to methylation sites.

Rad6-mediated H2B monoubiquitination is crucial in the regulation of the transcription of a specific subset of RNA polymerase II-transcribed genes. For example, H2BK123 monoubiquitination is required to active the transcription of SAGA-regulated genes such as GAL1, SUG2 and PHO5.

The machinary and factors reponsible for H2BK123 monoubiquitination are highly conserved from yeast to human.

Histone phosphorylation and Cell cycle regulation #

Post-translational phosphorylation occurs on all four histones. However, its biological ramifications are context dependent. For example, histone H4S1 phosphorylation has an evolutionarily conserved role in chromatin compaction during the later stages of gametogenesis.

However, phosphorylation of histone H2B (on Ser14 in human, Ser10 in yeast) correlates with meiotic chromosome condensation and disappears during meiotic divisions.

Apoptic chromatin condensation has been linked to histone H2B phosphorylation in human and yeast cells. Histone H2A phosphorylation is also correlated with mitotic chromosome condensation.

Upon exposure to DNA-damaging agents, Ser129 and Ser139 of the yeast histone H2A and of the mammalian histone H2A variant histone H2A. X are phosphorylated.

This type of a modification is required for efficient nonhomologous end-joining repair of DNA, thus suggesting that histone H2A phosphorylation mediates structural changes in chromatin that faciliatate DNA repair.

Histone pohsphorylation can also have a role in transcription. Histone H3S10 phosphorylation is associated with gene activation in mammalian cells and with transcription induced by the heat-shock response in D. melanogaster.

Furthermore, histone H3 phosphorylation has been shown to establish the transcriptional competence of early response genes such as FOS and JUN. More specifically, this modification occurs rapidly upon activation of the RAS-MAP Kinase pathway(MAPK/ERK pathway) by growth factors and phorbol esters in serum-starved cells.

A small fraction of highly acetylated histone H3 is also phosphorylated, indicating that the latter modification may contribute to gene activation by stimulating HAT activity on the same histone tail.

Indeed, both phosphorylation and acetylation of histone H3 at the Fos and Jun loci occur upon transcriptional activation.

Histone methylation and transcriptional regulation #

Histone demethylases and their roles in development #

Histone modification changes in development #

Histone modifications in imprinting and X-inactivation #

Genomic imprinting is an epigenetic mechanism that restricts gene expression to one parental allele, resulting in differential contributions from the maternal and parental genomes during development. Histone modificaion appear to be key regulators of genomic imprinting.

One example of this process is imprinted X-chromosome inactivation - that is, specific paternal X chromosome inactivation in the preimplantation embryo and placenta.

Inactivation of one female X chromosome also ensures that males and females can express equal levels of X-linked gene products, a process termed Dosage compensation.

In contrast to that in the preimplantation embryo and placental tissues, the choice of X chromosome inactivation in the postimplanation embryo is random.

Recent studies have highlighted the roles of histone modifications and an untranslated RNA, namely Xist, in both imprinted and random X chromosome inactivation.

The inactivation of the paternal X chromosome is initiated by Xist RNA, which is expressed only from the paternal X chromosome at the two-cell stage upon zygotic gene activation. Xist then coats the paternal X chromosome in the majority of the blastomeres from the four-cell stage onwards.

Soon after, both H3K9 acetylation and H3K4 methylation start to decline, and consequently, hypermethylation of H3K9 and H3K27 begins after recruitment of the Ezh2 components of the Polycomb repressor complex to the parternal X chromosome.

The overexpression of Xist in undifferentiated embryonic stem cells is associated with H4K20 monomethylation. However, the relevance of H4K20 monomethylation to X-chromosome inactivation required further investigation.

While the parternal X chromosome is undergoing inactivation, the maternal X chromosome actively resists inactivation, probably because of maternal Xist repression, which may be mediated by another untranslated RNA (Tsix) that is complementary to Xist.

Interestingly, H3K9 is methylated in the female pronucleus of mice, but not in the male pronucleus. This type of differential methylation persists until the late two-cell stage. Therefore, maternal imprinting on the maternal X chromosome and maternal Xist repression could involve H3K9 methylation, associated with heterochromatin formation.

Histone modifications and human diseases #

Altered expression patterns of developmentally regulated genes can lead to many human diseases, including cancer. A growing body of evidence indicates that histone covalent modifications are central in altering gene expression.

The global loss of H4K16 acetylation and H4K20 trimethylation has been linked to Breast cancer and liver cancer. Deregulation of histone acetylation occurs by translocations that generate fusion proteins such as CBP-MOZ and CBP-MORF. Furthermore, these fusion proteins cause leukemia and uterine myomas.

Histone H3 acetylation is also crucial in the development of cancer. Loss of histone H3 acetylation at tumor suppressor genes is observed in a variety of cancers, and many HAT genes are altered in various types of cancers, with a number of gastrointestinal tumors linked to mutations in the p300 HAT gene.

Like histone acetylation, histone H3 methylation is linked to the development of a variety of cancers and other human diseases. More specifically, loss of H3K4 methylation and enrichment of H3K9 methylation are associated with various types of cancers.

Nearly 80% of infant leukemias of different subtypes are caused by chromosomal translocations fo the MLL gene, which is essential for H3K4 methylation. However, a direct role of H3K4 methylation in this process is at present unclear.

Transgenic mice that lack the Suv39 family of H3K9 methyltransferases develop B-cell lymphomas and other types of cancers.

Notably, the cancer cells derived from Suv39h1 and Suv39h2 double knockout mice resemble those in human slowly progessing non-Hodgkin's lymphomas. Furthermore, human Suv39h1 and Suv39h2 histone methyltransferases are implicated in causing cancer by virture of their interactions with the Rb protein, which is important in controlling the cell cycle through regulation of the gene encoding cyclin E.

Members of the mammalian nuclear receptor-binding, SET domain containing family (NSD1, NSD2, and NSD3) are closely related to yeast Set2, which catalyzes H3K36 methylation, and mammalian NSD1 possesses similar activity.

Haploinsufficiency of the NSD1 gene leads to the neurological disorder Sotos syndrome. In addition, translocations of the NSD1 gene lead to the development of certain leukemias.

Like NSD1, specific mutations in NSD2 cause the development of Wolf-Hirschhorn syndrome, which is characterized by developmental defects and mental retardation.

In normal individuals, NSD2 is expressed in rapidly growing embryonic tissues and thus is crucial in development. Therefore, the deregulation of Lys36 methylation and the resulting effect on transcription may be key events in cellular transformation.

Concluding remarks #

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