In the last issue, we briefly reviewed what we know about histones. Histones are constituent of nucleosomes and control gene expression by regulating chromatin state. Post-translational modifications of histones are thought to exert gene expression regulation by influencing chromatin density or recruiting other protein complexes, with common modifications including methylation, acetylation, phosphorylation, ubiquitination, and many more. Xiao Heng will introduce these common histone modifications one by one, and today let's start with methylation.
, histone methylation sites
Histone methylation mostly occurs on the basic amino acids of H3 and H4, i.e., lysine, arginine, and histidine. Lysine residues can be monomethylated (me1), dimethylated (me2), or trimethylated (me3); Arginine can be monomethylated (me1), symmetric dimethylated (me2s), or asymmetric dimethylated (me2a); It has also been reported that histidine is predominantly monomethylated, but further verification is still needed [1]. The most widely studied histone methylation sites are lysines of H3 and H4, including H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20; In addition, arginine methylation sites include H3R2, H3R8, H3R17, H3R26, and H4R3.
, histone methylation distribution
Methylation modifications at different sites of histones can produce different biological effects. H3K4 and H3K36 methylation occurs in transcriptionally active genomic regions and is involved in transcriptional activation [2, 3]. H3K9Me3 2 and H3K27Me3 are commonly found on transposons and inactive genes, which inhibit transcription by recruiting protein complexes that bind to nucleosomes and alter chromatin structure. The h3k9me3 modification is enriched in heterochromatin, and h3k9me2 is commonly involved in gene silencing in euchromatin.
, regulation of histone methylation
Similar to DNA methylation and RNA methylation, histone methylation modifications are reversible and are normally in a state of dynamic equilibrium. Histones can be methylated by "writing" enzymes (histone methyltransferases [HMTS)], removed by "erasing" enzymes (histone demethylases, HDMS), and recognized by "readers" (histone methylation recognition proteins) to regulate chromatin structure and thus gene expression.
Histone methyltransferases (HMTs
Histone methylation occurs in the Lys and ARG side chains, catalyzed by lysine methyltransferases (KMTS) and arginine methyltransferases (PRMTs), respectively.
kmtsTo date, two protease families have been identified to catalyze the transfer of methyl groups from S-adenosylmethionine to histone lysine residues, namely SET domain-containing proteins and Dot1L proteins. In humans, there are 55 proteins containing SETdomains, half of which have KMT activity, and SETD3 is a histidine methyltransferase, and some enzyme activity is unknown. The SET domain is an important component of histone methyltransferases, which is responsible for the enzymatic catalytic activity of methyltransferases, and the main KMTS are SET1, SET2, MLL, SUV39, EZH and other families. Another SET-free DOT1L protein is mainly responsible for catalyzing H3K79 methylation, and there are fewer types of such proteins.
prmtsMammalian cells contain three types of methylated arginine residues, namely monomethylated arginine (MMA, RME1), symmetric dimethylated arginine (ADAM, RME2A), and asymmetric dimethylated arginine (SDMA, RME2S), with MMA being an intermediate between SDMA and ADMA, of which ADAM is the most common form. Histone arginine methylation is mainly catalyzed by nine members of the PRMTS family, which are divided into type enzymes (PRMT and 8), type enzymes (PRMT5 and 9) and type enzymes (PRMT7) according to their catalytic activity. Type enzymes and type enzymes catalyze SDMA and ADMA, respectively, and MMA is generated by type enzymes.
Histone demethylase (HDM
Lysine demethylase (KDM
A large family of proteases involved in the demethylation of methylated lysine has been identified, which is further divided into KDM1 containing a FAD-dependent amine oxidase domain and dioxygenase (KDM2-8) containing a Fe-dependent JMJC domain. KDM1 can remove mono- and dimethylation markers, but not the trimethylated form, and its amine oxidase domain hydrogenates lysine-amine groups to form unstable imine groups, which are subsequently spontaneously hydrolyzed to formaldehyde. The KDM2-8 subfamily removes the three methylated forms of lysine, and the demethylation activity of the JMJC domain requires fe-ketoglutarate (2-OG) and oxygen to convert the methyl group to hydroxymethyl, which is then released as formaldehyde.
Arginine demethylase
Arginine demethylase is still understudied. The identified arginine demethylase is arginine deiminase 4 (PADI4). PADI4 removes methylation by converting arginine to citrulline, a process that is not actually considered demethylation, but is demethylated due to the loss of methyl groups during the arginine-to-citrulline conversion. In addition, PADI4 does not specifically target methylated arginine, it acts on both methylated and unmethylated arginine.
Histone methylation recognizes proteins
Recognition of histone methylation sites is achieved by proteins with methyl-binding domains, and domains for lysine methylation and arginine methylation may differ. Domains that recognize histone lysine methylation include PHD, chromo, WD40, tudor, double tandem tudor, MBT, ankyrin repeats, ZF-CW, and PWWP, and the protein families containing these domains recognize different lysine methylation forms.
Research on arginine methylation recognition proteins is limited, and more experimental validation is still needed. It has been found that the ADD domain of DNA methyltransferase DNMT3A can recognize H4R3Me2 but not H4R3Me2A, thus linking histone arginine methylation and DNA methylation. In addition, TDRD3 is a transcriptional coactivator, and its TUDOR domain recognizes H3R17Me2A and H4R3Me2A, which enriches and activates or promotes gene transcription at the transcription start site.
This issue mainly briefly introduces the types of histone methylation and related modification enzymes and recognition proteins, and we will continue to introduce different types of methylation forms in the next issue. Hanheng Biotech has been focusing on virus packaging for more than ten years, if you have any needs, please feel free to contact and consult
References
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