Trends in Genetics
Volume 19, Issue 11, November 2003, Pages 629-639
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Histone lysine methylation: a signature for chromatin function

https://doi.org/10.1016/j.tig.2003.09.007Get rights and content

Abstract

The rapid progress in deciphering the processes of covalent histone modifications has broadened our understanding of transcriptional regulation. Histone lysine methylation, along with DNA methylation, establishes the framework for long-term epigenetic maintenance. Recent studies of the mechanisms of specific histone lysine methylation have revealed a complex process that controls aspects of short- and long-term transcriptional regulation, in addition to the propagation of bulk chromosome structure and stability. In this article, we review the functional properties of histone lysine methylation and the enzymes that catalyze this covalent modification.

Section snippets

Histone lysine methyltransferase-mediated repression (H3-K9, H3-K27, H4-K20)

The first identified and best characterized HKMTs selectively methylate H3-K9 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. There are numerous reports demonstrating the silencing effects correlated with, or resulting from, H3-K9 methylation, including the inactive X chromosomes (Xi) of female mice and humans 15, 18, 19, 20, and developmentally regulated genes [21]. Highly condensed centromeric (heterochromatic) regions of chromosomes correspond with a specific degree of methyl addition to H3-K9.

Histone lysine methyltransferase-mediated activation (H3-K4, H3-K36, H3-K79)

Transcriptionally competent euchromatin is methylated at three positions, H3-K4, H3-K36 and H3-K79. Although H3-K9 methylation corresponds to transcriptionally silent regions, H3-K4 methylation is generally associated with transcriptionally active chromatin. The enzymes that are responsible for catalyzing methylation within active euchromatin are in Table 1. The functional interplay of the covalent modifications within histone tails becomes evident from the consequences of transcriptional

Simultaneous methylation at H3-K4 and H3-K9

It is clear that methyl H3-K4 and H3-K9 correspond to functionally distinct biological ramifications and physical distributions. Biochemical experiments that measured the effect of histone methylation on transcription in vitro have firmly established a functional interplay between these methylation events 54, 72. However, it has been shown that in some chromosomal regions, the distributions of these two methylated residues are indistinguishable. It was reported that both methylated K4 and K9

Histone lysine methylation and disease

The methylation of specific lysines within H3 and H4 has consequences for global and specific gene expression. Mutations in the components of the systems that establish and maintain HKMT-mediated epigenetic regulation induce profound large-scale defects, such as decreased genomic stability, in addition to alterations in specific biological pathways that are manifested in distinct diseases. The Polycomb (PcG) and trithorax group (trxG) of proteins regulate the long-term expression patterns of

Concluding remarks

The rapid progress within the past few years toward elucidating the molecular basis of histone methylation has been instrumental to our understanding of epigenetics. The remarkable specificity and interplay between covalent histone modifications highlights the complexity of the histone code. Although much has been learned, there are still several unanswered questions regarding how histone methylation events translate into tightly controlled gene expression. The maintenance of transcriptional

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