9. Histone Methylation

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9.1. Chromatin 

 

Enclosing genomic DNA via linkage to histone proteins is making the chromatin structure (Van Holde K., 1998 as cited in Cheung P and Lau P., 2005) (Cheung P and Lau P., 2005).

 

As one hundred forty six base pairs (146 bp) of DNA envelope around an octameric histone core, consisting of two copies of histones H2A, H2B, H3 and H4, then the nucleosome, which is the nascent replicating unit of chromatin, is formed (Komberg R D and Lorch Y., 1999) (Cheung P and Lau P., 2005) (Altaf M et al., 2007 as cited in Mushtaq A et al., 2021) (Farooq Z et al., 2016) (Mushtaq A et al., 2021).

 

The chromatin organisation helps hinder nuclear elements’ access to the main DNA. However, chromatin conformation can be changed as a result of posttranslational modifications of histone protein, which in turn controls gene expression (Felsenfeld G and Groundine M., 2003 as cited in Cheung P and Lau P., 2005) (Cheung P and Lau P., 2005). 

 

Diversity of histone/nucleosome structures is caused by a range of posttranslational modifications such as acetylation, phosphorylation, methylation, ubiquitylation and sumoylation (Cheung P and Lau P., 2005). Some of these modifications like, methylation, are more secure and influence the preservation of the expression status of loci in the genome (Cheung P and Lau P., 2005). Other modifications such as acetylation and phosphorylation are adjustable and flexible and are linked to gene expression (Cheung P and Lau P., 2005). 

 

It is also essential to emphasize that the positions on the histones, where these modifications take place, are varied and explicit (Cheung P and Lau P., 2005). 

 

Also, histones can participate in signalling by associating upstream pathways to the downstream ones and facilitating the transmission of these signals in the nucleus, which leads to activation or repression of downstream genes (Cheung P et al., 2000) (Cheung P and Lau P., 2005).

 

Chromatin References Book

 

1. Van Holde K 1998 Chromatin. New York: Springer Verlag

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Chromatin Reference 

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1.        Altaf, M., Saksouk, N. & Côté, J. Histone modifications in response to DNA damage. Mutat. Res. Mol. Mech. Mutagen. 618, 81–90 (2007).

2.        Cheung, P., Allis, C. D. & Sassone-Corsi, P. Signaling to Chromatin through Histone Modifications. Cell 103, 263–271 (2000).

3.        Cheung, P. & Lau, P. Epigenetic Regulation by Histone Methylation and Histone Variants. Mol. Endocrinol. 19, 563–573 (2005).

4.        Farooq, Z., Banday, S., Pandita, T. K. & Altaf, M. The many faces of histone H3K79 methylation. Mutat. Res. Mutat. Res. 768, 46–52 (2016).

5.        Felsenfeld, G. & Groudine, M. Controlling the double helix. Nature 421, 448–453 (2003).

6.        Kornberg, R. D. & Lorch, Y. Twenty-Five Years of the Nucleosome, Fundamental Particle of the Eukaryote Chromosome. Cell 98, 285–294 (1999).

7.        Mushtaq, A. et al. Role of Histone Methylation in Maintenance of Genome Integrity. Genes (Basel). 12, 1000 (2021).

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9.2. Histone Methylation and Su(var)

 

Histones, especially H3 and H4, are methylated at several lysines (Lys), mainly 

(Lys4, Lys9, Lys27, Lys36, Lys79 (on H3) and Lys20 (on H4) and arginine (Arg) residues (Lee D Y et al., 2004 as cited in Cheung P and Lau P., 2005) (Cheung P and Lau P., 2005).  

 

Lysine is also known to be prone to mono-, di-, or trimethylation and that makes them to be associated with more functional variety for every location of Lys methylation (Cheung P and Lau P., 2005).

 

The fact that one of the Su (var) genes encrypts a histone methyltransferase (HMT) was the key discovery as far as H3 Lys-methylation activity is concerned (Cheung P and Lau P., 2005).

 

The Suv39H1 in humans, which is a homologue and the equivalent to Drosophila Su(var) 3-9 gene and in the fission yeast S. pombe, is Clr4, has an enzymatic ability to particullarly methylate H3 at Lys9 (Rea S et al., 2000 as cited in Cheung P and Lau P., 2005) (Cheung P and Lau P., 2005).  

 

Histone H3 at Lys9, (a residue that can be either methylated or acetylated), becomes specifically methylated by Clr4. This event occurs due to histone deacetylase (HDAC) complex facilitating deacetylation process at the aforementioned residue and consequently initiate configuration of heterochromatin in S. pombe (Cheung P and Lau P., 2005).  

 

Also, the methylation of histone H3 on Lys9 results in the formation of a motif, which is particullarly distinguished and linked to by the chromodomain HP1 (Cheung P and Lau P., 2005). 

 

A deficit in localization of a homolog of HP1, i.e., SW6, is the outcome of interruption in the Clr4 gene (Cheung P and Lau P., 2005).  This, in turn, demonstrates that formation of heterochromatin in vivo, is dependent on the deployment of HP1, which is facilitated through methylation of H3 (Nakayama J et al., 2001 as cited in Cheung P and Lau P., 2005) (Cheung P and Lau P., 2005).  

 

Furthermore, in double-null (dn) mouse embryo, the fatality and chromosomal wavering are caused by an interruption in Suv39h1 and Suv 39h2 (as two Su (var) 3-9 homologs) (Peters A H F M et al., 2001) (Cheung P and Lau P., 2005). 

 

Also a particular loss of Lys9 trimethylated form of H3 at pericentric heterochromatin in double null (dn) mouse embryos fibroblast was discovered, as antibodies specific to mono-, di-, and trimethylation state of Lys9-methylated H3 were used (Peters A H et al., 2003) (Cheung P and Lau P., 2005). 

 

Histone Methylation and SET Domain

 

SET is called after three established proteins that share the domain: Su(VAR)3-9, enhancer of zeste [E(Z)], and trithorax (TRX) and it is a highly conserved domain, which is found in a considerable number of proteins from yeast to human (Jenuwein T et al., 1998 as cited in Cheung P and Lau P., 2005) (Cheung P and Lau P., 2005).  

 

It is known that the SET domain of the proteins facilitates HMT functionality after structural-functional analysis performed on Suv39H1 and Clr4 (Cheung P and Lau P., 2005).  

 

Histone Methylation and Su(var) References

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1.        Cheung, P. & Lau, P. Epigenetic Regulation by Histone Methylation and Histone Variants. Mol. Endocrinol. 19, 563–573 (2005).

2.        Jenuwein, T., Laible, G., Dorn, R. & Reuter, G. SET domain proteins modulate chromatin domains in eu- and heterochromatin. Cell. Mol. Life Sci. 54, 80–93 (1998).

3.        Lee, D. Y., Teyssier, C., Strahl, B. D. & Stallcup, M. R. Role of Protein Methylation in Regulation of Transcription. Endocr. Rev. 26, 147–170 (2005).

4.        Nakayama, J., Rice, J. C., Strahl, B. D., Allis, C. D. & Grewal, S. I. S. Role of Histone H3 Lysine 9 Methylation in Epigenetic Control of Heterochromatin Assembly. Science (80-. ). 292, 110–113 (2001).

5.        Peters, A. H. F. M. et al. Partitioning and Plasticity of Repressive Histone Methylation States in Mammalian Chromatin. Mol. Cell 12, 1577–1589 (2003).

6.        Peters, A. H. F. M. et al. Loss of the Suv39h Histone Methyltransferases Impairs Mammalian Heterochromatin and Genome Stability. Cell 107, 323–337 (2001).

7.        Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).

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9.3. Histone Methylation a Perpetual Mark or Not?

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Many studies confirmed that there are resemblances between the half-life of histones and methyl-lysine occupied in them, which results in irretrievability of histone methylation (Byvoet P et al., 1972 as cited in Bannister A J et al., 2002) (Duerre J A and lee C T., 1974 as cited in Bannister A J et al., 2002) (Bannister A J et al., 2002). Therefore, one can conclude that any functioning procedure is unable to eliminate the methyl group from histone (Bannister A J et al., 2002). Consequently, the methyl group will stay on the promoter until it is switched to the unaltered form due to innate turnover of histone or DNA replication (Bannister A J et al., 2002).

 

This “permanent methyl mark” is attuned with some types of transcriptional silencing, similar to the ones discovered at centromeric heterochromatin and at DNA-methylated promoter (Kouzarides T., 2002) (Bannister A J et al., 2002).

 

It is also logical to conclude that having a stable methyl group as a fraction of an epigenetic mark paves the way for the silenced state after replication, and is known to be hereditary (Zhang Y and Reinberg D., 2001) (Bannister A J et al., 2002).

 

However, in regulated gene expression the turnaround of histone methylation is essential when one considers the functional role of methylation (Bannister A J et al., 2002). In one instance, methylation of K9 H3 in the G1 phase of the cell cycle causes the suppression of the cyclin E promotor functionality (Nielsen S J et al., 2001 as cited in Bannister A J et al., 2002) (Bannister A J et al., 2002). Thus, cyclin E is uttered as the essential turnaround of K9 methylation takes place. Also, cyclin E promoter in known to be induced in G1/S phase transition, which is significant for aforementioned activities taking place (Bannister A J et al., 2002).

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Histone Methylation a Perpetual Mark or Not?  Reference

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1.        Bannister, A. J., Schneider, R. & Kouzarides, T. Histone Methylation. Cell 109, 801–806 (2002).

2.        Byvoet, P., Shepherd, G. R., Hardin, J. M. & Noland, B. J. The distribution and turnover of labeled methyl groups in histone fractions of cultured mammalian cells. Arch. Biochem. Biophys. 148, 558–567 (1972).

3.        Duerre, J. A. & Lee, C. T. IN VIVO METHYLATION AND TURNOVER OF RAT BRAIN HISTONES. J. Neurochem. 23, 541–547 (1974).

4.        Kouzarides, T. Histone methylation in transcriptional control. Curr. Opin. Genet. Dev. 12, 198–209 (2002).

5.        Nielsen, S. J. et al. Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561–565 (2001).

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