Table 1.
Epigenetic Control of Inflammation and Fibroblast Activation
| Phase of Fibrosis Development | Epigenetic Modification | Evidence | Ref. # |
|---|---|---|---|
| Inflammation | |||
| Histone acetylation | VPA treatment leads to a reduction in IL-1β and TNF-α expression in the left ventricle. | (46) | |
| SAHA reduces IL-1α, IL2, and TNF-α expression in DOCA-salt hypertensive rats. | (47) | ||
| VPA treatment suppresses the M1 phenotype of cultured macrophages. | (65) | ||
| Class I HDAC inhibitors promote the M2 anti-inflammatory phenotype of macrophages. | 66, 67, 68 | ||
| Class IIa HDACs are positive regulators of the M1 proinflammatory phenotype. | 69, 70, 71 | ||
| BET reader | BET inhibition potently suppresses a network of cardiac NF-κB responsive genes that control the innate immune response. | 53, 54, 55 | |
| BET reader proteins play fundamental roles in regulating macrophage inflammatory phenotypes. | 74, 75, 76 | ||
| Histone methylation | KMT1 represses proinflammatory genes associated with the M1 phenotype by promoting the formation of H3K9me3 marks on regulatory elements. | (60) | |
| KMT3 negatively regulates the proinflammatory M1 phenotype by increasing repressive H3K36 dimethylation at promoter regions of proinflammatory genes. | (61) | ||
| KDM6 promotes the M1 macrophage phenotype by removing repressive H3K27 trimethylation marks at regulatory sites for proinflammatory genes. | (62) | ||
| DNA methylation | In the setting of obesity and diabetes, DNMT1 promotes the M1 macrophage phenotype by hypermethylating of the pro-M2 transcription factor, PPARγ1. | 63, 64 | |
| Fibroblast proliferation/activation | |||
| Histone acetylation | MGCD0103 potently suppresses cardiac fibroblast proliferation and mitigates fibrotic remodeling in response to cardiac injury. | 98, 99, 100, 101 | |
| Inhibition of the p300 HAT blocks the proliferative response of cardiac fibroblasts and suppresses Ang II–mediated cardiac fibrosis. | (103) | ||
| TSA blocks α-SMA expression in lung fibroblasts in association with reduced activation of AKT. | (107) | ||
| The balance of HAT and HDAC expression influences TGF-β–induced transcription of SM22α. | (108) | ||
| BET reader | BET inhibitors block conversion of liver, pancreas and skin fibroblasts into α-SMA+ myofibroblasts. | 109, 110, 111 | |
| In response to stress signaling, BRD4 accumulates on SEs for genes encoding secreted profibrotic factors such as TGF-β2. | (112) | ||
| Knockdown of JMJD1A increases expression of α-SMA. | (113) | ||
| KMT2H directly binds regulatory elements of profibrotic genes, including those encoding α-SMA. | (114) | ||
| DNA methylation | Knockdown of DNMT3B or treatment with the DNMT inhibitor blocks α-SMA expression. | (115) | |
| Cardiac fibrosis correlates with enhanced DNA methylation of promoter sequences regulating the gene encoding RASAL1, a RAS-GTPase–activating protein. | (116) |
BET = bromodomain and extraterminal protein; DNMT = DNA methyltransferase; HDAC = histone deacetylase; SAHA = suberoylanilide hydroxamic acid; SE = superenhancer; TSA = trichostatin A; VPA = valproic acid.