Table 1.

Histone modifying enzyme that regulate macrophage phenotype in diabetic wound.

Types of histone modifications	Major regulator	Target histone	Function	Expression in diabetic wound	Pharmacologic inhibitors to promote the M2 phenotype	Reference
Histone methylation	MLL1	H3K4me3	Control wound macrophage function by regulating the PGE2 pathway	Upregulation	Nanocarrier containing the COX-2 inhibitor	(51)
	MLL1	H3K4me3	Early deficit and late overexpress in diabetic wound macrophages	Upregulation	MI-2	(34)
	MLL1	H3K4me3	Influence diabetic macrophage’s responsiveness to TLR4 stimulation	Upregulation	TAK-242	(52)
	Setdb2	H3K9me3	Inhibit the production of NF-κB-mediated inflammatory cytokines and XO-mediated UA in macrophages	Downregulation	NA	(10)
Histone demethylation	Jmjd3	H3K27me3	Result in the expression of inflammatory cytokines (IL-12) and lead to persistent wound inflammation	Upregulation	NA	(25)
	Jmjd3	H3K27me3	Shape macrophage toward a proinflammatory state	Upregulation	GSK-J4	(53)
	Jmjd3	H3K27me3	Regulate STING in pathologic wound macrophage	Upregulation	GSK-J1	(11)
Histone acetylation	MOF	H4K16ac	Promote NF-κB-mediated inflammatory gene transcription in diabetic wound macrophages	Upregulation	Etanercept	(54)
Histone deacetylation	HDAC3	N/A	Pharmacological blockade of HDAC3 regulates macrophage activation	Upregulation	BG45	(55)
	HDAC6	N/A	HDAC6 inhibitor inhibits tubulin-mediated IL-1β secretion	Upregulation	TSA	(56)

MLL1, mixed lineage leukemia 1; Setdb2, the histone methyltransferase; Jmjd3, Jumonji domain-containing protein 3; HDAC, histone deacetylase; MOF, the histone acetyltransferase males absent on the first; N/A, function or target not available.