Table 2 Studies on the role of histone modifications in allergic diseases meeting the primary selection criterion

Harb et al. [84]

Analysis of the association between prenatal fish oil exposure (maternal fish oil intake) and CB CD4+ T-cell H3ac and H4ac levels at promoters of PRKCZ and several other important T-cell genes (placebo n = 34; fish oil n = 36)

Significantly higher H3ac levels at the PRKCZ and IFNG, and lower H3/H4ac levels at the IL13 and TBX21 were observed in CB CD4+ T-cells obtained from newborns of mothers supplemented with fish oil during pregnancy compared to newborns of placebo-treated mothers. The infants born from the fish oil-supplemented mothers were at the lower risk of developing allergic diseases [81, 82]

Harb et al. [83]

Comparison of H3ac and H4ac levels at gene promoters of Th1, Th2, Th17, and Treg cells between CB CD4+ T-cells obtained from neonates with either high (n = 12) or low (n = 11) maternal serum folate levels estimated during the last trimester selected form a larger cohort based on conventional extremes of exposure design

Significantly higher GATA3 promoter H3ac and H4ac levels were observed in the high folate group. Significantly higher IL9 promoter H4ac levels in high folate arm (and a tendency towards a similar association for H3ac) were also found. A tendency towards lower IFNG promoter H4ac was observed in high folate group. Statistical analyses included adjustment for CB serum vitamin D levels

Stefanowicz et al. [66]

Comparison of global and gene-specific [TP63 (ΔNp63 isoform), EGFR, and STAT6] histone acetylation and methylation status in alveolar epithelial cells (AECs) obtained from asthmatic (n = 5) and healthy (n = 5) non-transplantable teenage human lung donors

Higher global H3K18ac and H3K9me3 levels were observed in asthmatic subjects. Higher association of H3K18ac (but not H3K9me3) around the transcription start sites of TP63 (ΔNp63 isoform), EGFR, and STAT6 was found in asthmatics. Non-significant increase in protein expression of those three genes was detected in AECs treated with HDACi (TSA)

Cahill et al. [62]

Analysis of the effect H3K27ac at the PTGER2 promoter on EP2-expression in polyp fibroblasts obtained from aspirin-exacerbated respiratory disease (AERD) patients (n = 18), aspirin-tolerant and asthma-free control subjects with chronic rhinosinusitis and polyposis (aspirin-tolerant controls; n = 9), and healthy control subjects undergoing sinus surgery for concha bullosa (n = 8)

Independent of disease state, the levels of H3K27ac at PTGER2 were variable (in contrast to the H3K27ac at PTGER4 that were constant across samples) and correlated significantly with EP2 receptor expression (PTGER2 mRNA levels). After HDACi (TSA) treatment, PTGER2 mRNA levels increased in fibroblasts obtained from subjects with AERD or aspirin-tolerant controls but not in those from healthy controls

Marwick et al. [69]

Analysis of oxidant-associated inflammation (such as observed in severe asthma)-induced H3S10ph at promoters of inflammatory genes on the anti-inflammatory effect of corticosteroids (CS)

The induction of H3S10ph at promoters of the IL6, CCL2, and CXCL8 in alveolar macrophages from severe asthmatic patients was not reduced by CS. Application of a selective p38α MAPK inhibitor, SB239063, and IKK-2 inhibitor, TPCA-1, resulted in reduced induction of H3S10ph; this inhibitory effect was even stronger when SB239063 or TPCA-1 were combined with CS

Borriello et al. [68]

Analysis of the effect of IL-3 and IL-4 on STAT5 and STAT6 (respectively) binding and H3ac at the CCL17 locus, encoding CCL17, a marker of the alternative activation of human monocytes

IL-3 and IL-4 together increased H3ac at CCL17 locus. IL-4 alone but not in combination with IL-3 induced STAT6 binding at the CCL17 locus. No identifiable STAT5 binding at the CCL17 locus was observed

Harb et al. [72]

Comparison of H3ac and H4ac levels at Th1, Th2 and Treg-cell-related genes in isolated CD4+ T-cells obtained from children with allergic asthma (n = 14) and form healthy control children (n = 18)

Higher H3ac and H4ac levels at the IL13 locus observed in children with allergic asthma when compared to healthy controls. This difference correlated with higher IL-13 protein levels in supernatants of anti-CD3/CD28-stimulated PBMCs of allergic asthmatic children compared with healthy controls. The levels of H3ac at the FOXP3 locus were higher in allergic asthmatics than in healthy controls

Clifford et al. [54]

Comparison of ASMCs H3ac and H4ac, H3K9me2/3, H3K4me2/3, and DNA methylation levels at the CXCL8 promoter between asthmatic (n = 7) and non-asthmatic subjects (n = 6)

No differences in H4ac, H3K9me2/3 and H3K4me2/3 or in DNA methylation levels were detected between asthmatic and non-asthmatic subjects. However, significantly higher H3ac levels, specifically H3K18ac, and higher binding of bromodomain-containing HATs, p300 and PCAF, were observed in asthmatics. BET inhibitors reduced CXCL8 secretion

Perry et al. [55]

Analysis of the effect of BET bromodomains on the TGF-β-induced proliferation and cytokine release in ASMCs [from healthy (n = 9), non-severe asthmatic (n = 9), and severe asthmatic (n = 9) subjects]

An inhibition of FCS + TGF-β-induced cell proliferation as well as IL-6 and CXCL8 expression (IL6 and CXCL8 mRNA levels, and IL-6 and CXCL8 protein release) after treatment with BET bromodomain mimics JQ1/SGCBD01 and I-BET762 was observed. A higher concentration of both mimics was needed depending on the asthma severity

Comer et al. [56]

Comparison of H3ac and H4ac levels at the COX2 locus in ASMCs obtained from asthmatic (n = 7) and non-asthmatic subjects (n = 5) before and after treatment with cytomix (IL-1β, TNF-α, and IFN-γ)

No differences in histone acetylation between the asthmatic and non-asthmatic ASMCs were detected. Moreover, no differences in histone acetylation were observed after the cytomix treatment in both groups. Higher COX-2 protein levels were found in asthmatics, most likely due to posttranslational regulation (miR-155)

Seumois et al. [73]

Comparison of global H3K4me2-marked cis-regulatory regions in naïve, Th1, and Th2 CD4 + T-cells obtained from asthmatic (n = 12) and non-asthmatic subjects (n = 12)

Differential enrichment of H3K4me2 was observed in 200 enhancer regions in the three cell types when comparing asthmatic vs. non-asthmatic subjects. 163 of 200 asthma-associated enhancers were Th2-specific and 84 of them contained binding sites for transcription factors involved in T-cell differentiation (e.g. GATA3, TBX21 and RUNX3)

Zhang et al. [67]

Analysis of the anti-inflammatory and steroid-enhancing effects of vitamin D in monocytes obtained from patients with steroid-resistant (SR; n = 11) and with steroid-sensitive (SS; n = 8) asthma

Significant increase in H4ac levels at the glucocorticoid response element upstream of the DUSP1 locus (encoding for MKP-1) occurred after treatment of the monocytes obtained from both SS and SR patients with dexamethasone. Preincubation with calcitriol resulted in a significant enhancement in the dexamethasone-mediated H4ac. Higher H4ac was observed in SS patients than in SR patients

Kobayashi et al. [85]

Analysis of the effect of passive smoking on HDAC2 expression and activity and on corticosteroid sensitivity in alveolar macrophages (AMs) obtained from children with severe asthma exposed (n = 9) or not exposed (n = 10) to passive smoking

Significantly lower HDAC2 protein expression and HDAC2 activity in passive smoking-exposed group. Higher levels of phosphorylation of Akt1 in AMs of the passive smoking-exposed group correlated negatively with HDAC2 activity. Significant inhibition (40%) of the TNF-α-induced CXCL8 production in AMs from subjects not exposed to passive smoking after treatment with dexamethasone was observed. In contrast, no significant inhibition was detected in AMs from passive smoking-exposed subjects

Cho et al. [63]

Analysis of the effect of HDACi (TSA) on myofibroblast differentiation and extracellular matrix (ECM) accumulation in nasal polyposis (18 patients)

Suppression of the TGF-β1-induced myofibroblast differentiation and ECM production after treatment with TSA was observed (α-SMA, fibronectin, and collagen type I expression at both RNA transcript and protein levels were diminished). This was due to decreased expression of both HDAC2 and HDAC4 and increased histone four acetylation

Clifford et al. [57]

Comparison of H3ac and H4ac, H3K4me3, H3K9me3, and DNA methylation levels at the VEGFA promoter in ASMCs obtained from asthmatic (n = 7) and non-asthmatic (n = 6) subjects

No differences in the DNA methylation or H3ac or H4ac at the VEGFA locus were identified between asthmatic and non-asthmatic subjects. Nevertheless, slightly but consistently higher H3K4me3 (a mark associated with transcription activation) levels and much lower H3K9me3 (a mark associated with transcription repression) levels were detected in ASMCs obtained from asthmatic subjects. The low H3K9me3 was an aftermath of abortive recruitment of G9a in asthmatic ASMCs. After treatment with BIX-01294, a histone methyltransferase (HMT) G9a inhibitor, VEGF expression increased in cells obtained from non-asthmatics to near asthmatic levels

Cho et al. [64]

Analysis of the effect of HDACi (TSA) on myofibroblast differentiation and ECM accumulation in nasal polyposis (7 patients with chronic rhinosinusitis with nasal polyps vs. normal inferior turbinate tissues)

Increased expression (mRNA/protein) of HDAC2, α-SMA and TGF-β1 was observed in nasal polyp tissues. In addition to its suppressive effect on the TGF-β1-induced myofibroblast differentiation and ECM production (α-SMA and collagen type I expression was diminished after TSA treatment), TSA also reversed TGF-β1-induced morphological changes in nasal polyp-derived fibroblasts (NPDFs). Inhibition of the HDAC2 expression and increased H3ac and H4ac were also a TSA application aftermath. Inhibiting HDAC2 with siRNA had a similar effect to TSA. This TSA suppressive effect was produced by inhibiting the TGF-β1-induced phosphorylation and translocation of Smad2/3 (to nucleus). Moreover, TSA blocked NPDFs proliferation with no cytotoxic effects

Kuo et al. [101]

Analysis of the effect of iloprost, a prostaglandin I2 (PGI₂) analog, on the expression of TNF-α in human myeloid dendritic cells (mDCs) obtained from 6 healthy subjects via histone modifications

Downregulation of the poly I:C-induced H3K4me3 in the TNF promoter region was observed after treatment with iloprost. This suppressive effect was produced by inhibiting the poly I:C-induced translocation of H3K4-specific methyltransferase MLL (mixed lineage leukemia) and WDR5 (WD repeat domain 5) proteins from the cytoplasm to the nucleus

Yang et al. [65]

Analysis of the effect of TGF-β on the ADAM33 mRNA expression and ADAM33 protein in bronchial fibroblasts obtained from asthmatic (n = 7) and healthy (n = 6) subjects during their differentiation into myofibroblasts via histone modifications

Although no difference in transcript levels of ADAM33 between asthmatic and healthy control cells was detected, a suppression of ADAM33 mRNA expression after treatment with TGF-β was observed. This was caused by chromatin condensation at the ADAM33 promoter via histone modification (deacetylation of H3ac, demethylation of H3K4, and hypermethylation of H3K9) and not by DNA methylation. Stimulation of ADAM33 ectodomain shedding was also caused by TGF-β