Table 2. The role of histone modifications in wound healing.
HDAC= Histone Deacetylase; HAC = Histone Acetyltransferase; HMT=Histone methyltransferase; HDM = Histone demethylase N/A= function or target not available.
| Enzyme | Target modification | Effect on wound healing | Dysregulation in pathologic conditions | Ref. |
|---|---|---|---|---|
| Macrophages | ||||
| Class I HDACs (HDAC1, 2, 3, 8) | H4K16 | M1 macrophage polarization; inhibition improves healing | Induced HDAC3 in DM and HDAC1 in DFU; suppression of HDAC2/ HDAC8 in DFU | 127–130 |
| HDAC6 | cytoplasmic proteins | Pro-inflammatory | Elevated in diabetic mice; inhibition improves healing | 133,134 |
| MOF (HAC) | H4K16ac | Pro-inflammatory | Elevated in diabetic mouse models; inhibition improves healing | 135 |
| Setdb2 (HMT) | H3K9me3 | Anti-inflammatory | Decreased in patients with type 2 DM | 136 |
| MLL1 (HMT) | H3K4me3 | Pro-inflammatory; inhibits healing | Elevated in monocytes of patients with type 2 DM | 137–139 |
| Ash1l (HMT) | H3K4me3, H3K36me3 | Anti-inflammatory | Human genetic polymorphisms associated with SLE/RA and RA | 140,141,226,227 |
| Jmjd3 (HDM) | H3K27, H3K4 | Pro-inflammatory, promotes M2 polarization | Increased in DIO mice and type 2 DM; inhibition improves healing | 142–145 |
| Neutrophils | ||||
| Peptidylarginine deiminase 4 (PAD-4) | H3 citrullination | NET formation; inhibition improves healing | Elevated PAD4 in patients with DM increased NETosis in DFU | 114,115,117 |
| unknown | H4 acetylation | NET formation (low levels), and neutrophil apoptosis (high levels) | 119–122 | |
| Keratinocytes | ||||
| HDAC2 | H4K16 | Inhibits wound healing | Downregulated in DFU | 128,130,168,228 |
| Sirtuins aka Class III HDACs | H3K9 | Improves proliferation&healing | N/A | 168 |
| PCAF (HAC) | Rb-acH3K14ac/K9ac/K8ac | Promotes keratinocyte differentiation & improves healing | Increased in patients with Type 1 or 2 DM | 163–166 |
| Ash1l (HMT) | H3K4me3, H3K36me3 | Induces keratinocyte terminal differentiation | Aged Ash1l knockout mice show epidermal hyperplasia; deficiency impairs wound healing | 172 |
| Jmjd3 (HDM) | H3K27, H3K4 | Promotes keratinocyte migration and differentiation | Increased in DIO mice and patients with type 2 DM | 142,143,169–171 |
| Brg1 | SWI2/SNF2 remodeling complex | Induces keratinocyte terminal differentiation & improves healing | N/A | 148,175 |
| Mi-2β or Chd4 | nucleosome remodeling complex | Inhibits keratinocyte differentiation and proliferation | Deficiency impairs barrier repair | 174 |
| Fibroblasts | ||||
| HDAC1 | Fli1 & COL1A2 | Regulation of collagen production | Upregulated in DFU | 130,160 |
| HDAC 4, 6, and 8 | N/A | Promote myofibroblast differentiation; HDAC6 delays diabetic murine wound healing | HDAC4 - upregulated in DFU HDAC8 - downregulated in DFU HDAC6 - upregulated in diabetic mouse |
130,134,158 |