Histone-modifying enzymes

Histone-modifying enzymes are

The four common histone modifications and their respective writer and eraser enzymes are shown in the table below.[16]^{[17][18][19][20][21][22][23][24][25][26]}

Acetylation

Histone acetylation, or the addition of an acetyl group to histones, is facilitated by histone acetyltransferases (HATs) which target lysine (K) residues on the N-terminal histone tail. Histone deacetylases (HDACs) facilitate the removal of such groups. The positive charge on a histone is always neutralized upon acetylation, creating euchromatin which increases transcription and expression of the target gene.^[16] Lysine residues 9, 14, 18, and 23 of core histone H3 and residues 5, 8, 12, and 16 of H4 are all targeted for acetylation.^[17][18]

Methylation

Histone methylation involves adding methyl groups to histones, primarily on lysine (K) or arginine (R) residues. The addition and removal of methyl groups is carried out by histone methyltransferases (HMTs) and histone demethylases (KDMs) respectively. Histone methylation is responsible for either activation or repression of genes, depending on the target site, and plays an important role in development and learning.^[19]

Phosphorylation

Histone phosphorylation occurs when a phosphoryl group is added to a histone. Protein kinases (PTKs) catalyze the phosphorylation of histones and protein phosphatases (PPs) catalyze the dephosphorylation of histones. Much like histone acetylation, histone phosphorylation neutralizes the positive charge on histones which induces euchromatin and increases gene expression.^{[citation needed]} Histone phosphorylation occurs on serine (S), threonine (T) and tyrosine (Y) amino-acid residues mainly in the N-terminal histone tails.^[27]

Additionally, the phosphorylation of histones has been found to play a role in

Additional infrequent histone modifications and their effects are listed in the table below.[28]^{[29][30][31][32][33][34][35][36][37][38][39][40][41]}

O-GlcNAcylation

The presence of

SUMOylation affects the chromatin status (looseness) of the histone and influences the assembly of transcription factors on genetic promoters, leading to either transcriptional repression or activation depending on the substrate.^[31] SUMOylation also plays a role in the major DNA repair pathways of base excision repair, nucleotide excision repair, non-homologous end joining and homologous recombination repair. Additionally, SUMOylation facilitates error prone translesion synthesis.^[32]

ADP-ribosylation

H3P38 lies near the lysine (K) residue H3K36, and changes in P38 can affect the methylation status of K36. The two possible P38 isomers available, cis and trans, cause differential effects that are opposite of each other. The cis position induces compact histones and decreases the ability of proteins to bind to the DNA, thus preventing methylation of K36 and decreasing gene transcription. Conversely, the trans position of P38 promotes a more open histone conformation, allowing for K36 methylation and leading to an increase gene transcription.^[40]

Role in research

Cancer

Alterations in the functions of histone-modifying enzymes deregulate the control of chromatin-based processes, ultimately leading to

Vitamin B12 deficiency in mice has been shown to alter expression of histone modifying enzymes in the brain, leading to behavioral changes and epigenetic reprogramming.^[46][47] Evidences also show the importance of HDACs in regulation of lipid metabolism and other metabolic pathways playing a role in the pathophysiology of metabolic disorders.^[48]

See also

• DNA
• Histone
• Nucleosome
• Chromatin
• Euchromatin
• Heterochromatin
• Histone acetylation and deacetylation
• Histone methylation
• Protein phosphorylation
• Ubiquitin
• O-GlcNAc
• Sumoylation
• ADP-ribosylation
• Citrullination
• Proline isomerization in epigenetics

References