Table 1 Key examples of epigenetics-modifying enzymes that are considered targets for drug development and their major biological functions
From: Epigenetics-targeted drugs: current paradigms and future challenges
Epigenetic modification | Type | Epigenetics-modifying enzyme | Biological processes | Reference(s) |
|---|---|---|---|---|
DNA methylation | Writer | DNMT1 | Maintains DNA methylation after replication | |
DNMT2 | Binds to DNA with very weak methyltransferase activity; involved in RNA methylation | |||
DNMT3A | Promotes the genome-wide de novo DNA methylation | |||
DNMT3B | Promotes the genome-wide de novo DNA methylation | |||
DNMT3L | Increases the methyltransferase activity of DNMT3A or DNMT3B | |||
Eraser | TET1 | Active DNA demethylation and binds to DNA via the CXXC zinc finger domain | ||
TET2 | Active DNA demethylation and binds to DNA via the interaction with DNA binding proteins | |||
TET3 | Active DNA demethylation and binds to DNA via the CXXC zinc finger domain | |||
Reader | MeCP1 | Preferentially binds to methylated DNA and represses transcription | ||
MeCP2 | Binds to a single methyl-CpG pair, not influenced by sequences flanking the methyl-CpGs | |||
MBD1 | Recruits chromatin-modifying enzymes to both methylated and unmethylated CpG islands; largely silence transcription | |||
MBD2 | A transcriptional repressor or activator depending on the cellular context | |||
MBD3 | Interacts with NuRD complex to cause transcriptional repression | |||
MBD4 | Exerts DNA glycosylase activity and functions in DNA repair | |||
UHRF1 | Negatively regulates transcription via the binds to 5hmC and 5mC on DNA, as well as H3K9me3, and H3R2me0; recruits DNMT1 to methylate DNA | |||
UHRF2 | Allosterically activated by 5hmC and participates in DNA demethylation during neuronal commitment | |||
Histone acetylation | Writer | HAT1 (KAT1) | Acetylates H4K12/K5 predominantly; has less activity for H2A | |
GCN5 (KAT2A) | Acetylates H3 and H4 and its primary sites are H3K14 | |||
PCAF (KAT2B) | Acetylates H3 and H4 predominantly and its primary sites are H3K14; has less activity for H2A and HAB | |||
CBP/P300 (KAT3A/KAT3B) | Acetylates H2A, H2B, H3, H4 and its primary sites are H3K14/K18/K27 | |||
Eraser | HDAC1 | Removes acetylated modifications from H1, H2A, H2B type 1/2 and H3 | ||
HDAC2 | Removes acetylated modifications from H1, H2A, H2B type 1/2 and H3 | |||
HDAC3 | Removes acetylated modifications from H2BK12/K15/K16 | |||
HDAC4 | A very weak deacetylase activity on histone | |||
HDAC9 | A very weak deacetylase activity on histone | |||
SIRT1 | Removes acetylated modifications from H1K2, H3K9, and H4K16 | |||
SIRT2 | Removes acetylated modifications from histones during G2/M transition and mitosis | |||
SIRT6 | Removes acetylated modifications from H3K9 and H3K56 | |||
SIRT7 | Removes acetylated modifications from H3K18 | |||
Reader | BRD2 | Recognizes H4K12ac preferentially | ||
BRD4 | Recognizes H3K27ac preferentially | |||
ENL | Recognizes H3K9/K18/27ac preferentially | |||
AF9 | Recognizes H3K9ac preferentially and H3K27/K18ac to a lesser extent | |||
YEATS2 | Recognizes H3K9ac preferentially; functions as a selective histone crotonylation reader | |||
GAS41 | Recognizes H3K18/K27ac preferentially; binds to H3K14 | |||
Histone methylation | Writer | EZH2 | Catalyzes mono-, di-, and tri-methylation of H3K27 and H3K9, as well as non-histones substrates | |
DOT1L | Catalyzes mono-, di-, and tri-methylation of H3K79 | |||
SETDB1 | Catalyzes trimethylation of H3K9 | |||
GLP/G9a | Catalyzes mono- or di-methylation of H3K9 and non-histone substrates | |||
SMYD2 | Catalyzes both trimethylation of H3K36 and non-histone substrates | |||
NSD | Catalyzes the dimethylation of H3K36 | |||
PRMT1 | The member of type I PRMTs; the dominant enzyme catalyzing asymmetric dimethylarginine production in proteins and mainly functions as a transcriptional activator | |||
PRMT5 | The member of type II PRMTs; functions as a transcriptional suppressor or coactivator depending on the cellular context | |||
Eraser | LSD1(KDM1A) | Removes methylation modifications at H3K4 and H3K9; acts as a coactivator or a corepressor depending on the cellular context | ||
KDM2 | Removes methylation modifications at H3K4; H3K9, and H3K36; stimulates and inhibits gene transcription | |||
KDM7 | Removes mono- and di-methylated modifications on H3K9 and H3K27 | |||
KDM3 | Removes mono- and di-methylated modifications from lysine H3K9 | |||
KDM4 | Removes methylated modifications from H3K9 and H3K36 | |||
KDM5 | Removes di- and tri-methylated modifications ftom H3K4 | |||
KDM6A | An X-linked protein removing methylated modifications from H3K27 | |||
KDM6B | Removes trimethylated modifications from H3K27 | |||
Reader | MBT | Recognizes lysine residues on H3 and H4, and helps form monomethylated, dimethylated, or trimethylated modifications | ||
Chromodomain | Recognizes dimethylated lysine residues of H3K9 and H3K27 | |||
Tudor | Recognizes methylated lysine and arginine residues on histones H3 and H4 | |||
PWWP | Recognizes H3K36me2/3; binds to dsDNA in a non-specific manner | |||
PHD | Recognizes H3K4me2/3/0, H3K14ac or H3K27me0 to a lesser extent | |||
WDR | Recognizes lysine and arginine methylation of H3 | |||
RNA methylation | writer | METTL3 | Catalyzes m6A methylation | |
METTL14 | Binds to METTL3 and enhances the catalytic activity of METTL3 | |||
Eraser | FTO | RNA m6A demethylation; regulates RNA splicing | ||
ALKBH5 | RNA m6A demethylation; regulates RNA metabolism and export | |||
ALKBH3 | Removes the methyl group at the m6A from tRNA; functions an m1A demethylase | |||
Reader | YTHDF1 | Responsible for mRNA translation | ||
YTHDF2 | Responsible for mRNA degradation | |||
IGF2BP | Regulates mRNA translation | |||
Chromatin remodeling | Mover | SMARCA2 | DNA-stimulated ATPase in the SWI/SNF complex | |
SMARCA4 | DNA-stimulated ATPase in the SWI/SNF complex; binds to acetylated peptides on H3 and H4 | |||
Reader | Polybromo-1 | Recognizes H3K14ac preferentially | ||
BRD7 | Recognizes acetylated modifications on histones and non-histones substrates | |||
BRD9 | Recognizes butyryllysine, and crotonyllysine histone peptide modifications |
