Histone methylation in pancreatic cancer and its clinical implications

Table 3 Different enzymes and plant homeodomain finger domain

Type of enzyme	Name of enzyme	PHD domain	Histone substrates	Function
Histone demethylation enzyme	KDM1B/LSD2	PHD	H3K4me2	Unknown[25]
	KDM2A	PHD	H3K36me2/me1	Unknown[150]
	KDM4A-C	Two PHD	Unknown	Unknown[155,197]
	KDM5A	PHD1	Unmethylated H3K4 histone tail	PHD1 finger by H3 N-terminal tail peptides stabilizes binding of the substrate to the catalytic finger and improves the catalytic efficiency of demethylation[198,199]
		PHD2	Unmodified H3K4	Unknown[158]
		PHD3	H3K4me3	PHD3 finger can recruit substrate and it relates to demethylation propagation along nucleosomes via a positive-feedback regulatory mechanism[151,199]
	KDM5B	PHD1	H3K4me0	PHD1 finger recognizes the N-terminus of histone H3, provides an anchoring mechanism for KDM5B and PHD1-H3K4me0 is interaction is important for inhibition of migration[17]
		PHD2	Couldn’t bind to histone	Unknown[17]
		PHD3	H3K4me3/H3K4me0	PHD3 finger detects H3K4me3, anchors at chromatin and spreads the transcriptionally inactive state
	KDM5C	PHD1	H3K4	PHD1 finger stabilizes the substrate peptide and helps to position the H3K4 in the JmjC finger exactly[162]
	PHF8(KDM7subfamily)	PHD1	Suppressive marks on H3K9me2/me3 and H3K27me2/me3 and H4k20me2/me3	PHD1 finger plays a significant role in PHF8 substrate recognition and helps to improve substrate affinity and specificity[164]
Histone methylation enzyme	KMT2A, KMT2B	PHD1	Unknown	PHD1 finger is necessary for a context-dependent regulation of holocomplex formation and implicated in tumor suppression[143]
		PHD2	Unknown	PHD2 finger shows the E3 ubiquitin ligase activity and involve in homo-dimerization[144,200]. Mutation in PHD2 will enhance transactivation ability and help to recruit target gene promoters
		PHD3	H3K4me3/me2	Unclear, one possibility is binding of H3K4me3 by PHD3 is necessary for the transcription-promoting effects of KMT2A/2B, another is to set a broad, methylated chromatin finger[145]
		PHD4	Unknown	PHD4 finger mediates intramolecular interactions between the N-terminal and C-terminal fragments of KMT2A with PHD1, and improves its stability[143]
	KMT2C	Eight PHD fingers	Unknown	These fingers help KMT2C to recruit to its target genes correctly[30,146]
	KMT2D	Seven PHD fingers	Unmodified histone H4 and asymmetrical H4R3me2	These fingers are essential for methyltransferase activity of KMT2D and KMT2D-mediated differentiation[201]
	KMT2E	PHD	H3K4me3	PHD finger binds to H3K4me3 specially and facilitates the recruitment of KMT2E to active transcription chromatin regions[148,149,202]

All current research on the regulation of writers and erasers by plant homeodomain domain. “Unknown” means that the corresponding literature was not mentioned. This table is sorted by types and subfamilies of enzymes. JmjC: Jumonji C; KMT: Histone lysine methyltransferase; PHD: Plant homeodomain.