Table 3 Studies on the role of histone modifications in allergic diseases meeting the secondary selection criteria

Zhong et al. [102]

Significantly decreased expression of Th2-related cytokines (IL-4, IL-5) in human CD4+ T-cells and PBMCs was observed after transfection with chemically synthesized PIWI interacting RNA (piRNA), piR30840. Accordingly, antisense inhibition of the endogenous piR30840 resulted in CD4+ T-cells with upregulated IL-4 expression. As no differences in histone methylation levels at the IL4 promoter region between piR30840-transfected and -untransfected CD4+ T-cells were detected, the functioning of piR30840 was not attributed to this type of histone modification but rather to pre-mRNA decay through nuclear exosomes

Zheng et al. [103]

After treatment with TSA, a significant increase of the (lower) transcription of STAT3-dependent genes (IL17A and IL22) in IL-23-stimulated PBMCs from chronic mucocutaneous candidiasis (CMC) patients (n = 16) (back) to control (n = 37) levels was observed. Conversely, TSA significantly decreased the enhanced transcription of STAT1-dependent genes (CXCL10 and IRF1) in IFN-α-stimulated gain-of-function STAT1-mutation Epstein-Barr virus (EBV)-transformed B cell line back to control levels

Vicente et al. [104]

Noticeable regulatory activity characterized by H3K4me1/2 peak identified four putative regulatory elements (PREs) in the 8q21 core region of genetic association (with allergies) in lymphoblastoid cells. Significant correlation between the allergy-associated SNP rs7009110 located on the 8q21 and PAG1 expression

Naranbhai et al. [105]

Significant enrichment of peak cis-eQTL was detected in DNA-hypomethylated regions, and in regions marked by H3K4me3 (associated with promoter activity), H3K27ac and H3K4me1 (associated with active or poised enhancers), and H3K36me3 (associated with gene activation) in neutrophils. Correspondingly, a depletion of peak cis-eQTL was observed in DNA-hypermethylated regions and in regions marked by H3K27me3 and H3K9me3 (repressive histone modifications). A SNP rs2240335, an eQTL in PADI4 (a locus associated with rheumatoid arthritis), was shown to be located within regions marked by H3K27ac and H3K4me1

Lin et al. [106]

Increased H4ac levels at the VCAM1 promoter region correlating with higher VCAM1 expression (protein/mRNA) and promoter activity in human tracheal smooth muscle cells were observed upon pretreatment with ET-1, mediated via Elk-1/p300 interaction, in an ET receptor/Src/RTK/PI3K/AKT/p42/p44 MAPK-dependent manner

Castellucci et al. [70]

Ablation of the IL-10-mediated deacetylation of H4ac at the CXCL8 promoter in LPS-stimulated monocytes was observed after CI-994, a class I HDACi, treatment. Concordantly, IL-10-mediated inhibition of CXCL8 transcription in LPS-stimulated PBMCs obtained from COPD patients (n = 6), due to reduced HDAC2 expression, was dampened compared to acute respiratory failure patients (n = 4) and healthy controls (n = 6)

Hsieh et al. [71]

Noticeable suppression of the LPS-induced MDC/CCL22 expression in THP-1 cells (human monocyte cell line) and human primary monocytes was observed after treatment with sesamin, a class of phytoestrogen isolated from sesame seed Sesamum indicum, due to dampened recruitment of a HAT, CREBBP, and a subsequent decrease in H3ac and H4ac levels at the CCL22 promoter

Sharma et al. [107]

Significant enrichment of active histone marks H3K4me1 and H3K27ac at the regions near to two asthma-associated SNPs in the FADS2 (rs968567) and the NAGA (rs1801311) loci was observed in three different cell lines: Jurkat (human T lymphocyte cell line), Beas-2B (human bronchial epithelial cell line) and A549 (human lung epithelial cell line). Consistently, both SNPs showed significant enrichment of formaldehyde-assisted isolation of regulatory elements (FAIRE) signals in all three cell lines

Escobar et al. [108]

Markedly increased Jumonji, AT Rich Interactive Domain 2 (Jarid2), a DNA-binding protein that recruits the polycomb repressive complex 2 (PRC2) to chromatin, and H3K27me3 islands were detected throughout the genome (among other regions, within 10 kb of the Il22, Il10, and Il9 loci) in miR-155-deficient compared to wild-type mouse Th17 cells

Huber et al. [74]

Significantly elevated levels of the repressive H3K27me3 mark at the conserved noncoding sequence (CNS-1) located 5 kb upstream of exon 1A of the GATA3 gene in primary naïve human CD4+ T-cells after treatment with IFN-α (both, with or without IL-4 co-stimulation) were observed, resulting in a consequential inhibition of GATA3 binding to exon 1A (i.e. down-regulation of a positive-feedback loop of GATA3/GATA3 autoactivation and thus reduced gene expression)

Gschwandtner et al. [109]

When compared to both neonatal and adult human keratinocytes (KCs), fetal human KCs produced more AMPs, and had lower global H3K27me3 levels and higher expression of a histone demethylase JMJD3. JMJD3 knockdown with siRNA led to an increase in H3K27me3 levels and lower AMP production

Coward et al. [58]

Markedly increased H3K9me3 and H3K27me3 levels at the COX2 promoter were detected in primary human fibroblasts from IPF lung (stimulated or not with the COX2 inducer, IL-2β) when compared to fibroblasts from non-fibrotic lung, which were related to the recruitment of HMTs, G9a and EZH2. Substantially decreased H3K9me3 and H3K27me3, and increased H3ac and H4ac levels at the COX2 promoter resulting in COX2 mRNA and protein re-expression were observed in fibroblasts from IPF lung after treatment with G9a or EZH2 inhibitors (more significant effect with IL-2β stimulation)

Sanders et al. [59]

Markedly increased H3K9ac and decreased H3K9me3 at the pro-apoptotic BAK1 gene accompanied with increased expression (mRNA) and substantially decreased H3K9ac and increased H3K9me3 levels at the anti-apoptotic BCL2L1 gene accompanied by a decrease in gene expression (mRNA) were observed in primary human IPF fibroblasts after treatment with a HDACi, SAHA

Han et al. [110]

Significantly reduced H3K27me3 levels at the ALOX15 promoter were detected in A549 cells after treatment with IL-4, coinciding with higher ALOX15 mRNA levels. More potent induction of ALOX15 was observed in human monocytes. Significant increase in H3K27me3 levels after depletion of a lysine demethylase UTX (with siRNA) was observed, resulting in reduced IL-4-induced ALOX15 expression. Inhibition of the IL-4-mediated ALOX15 expression in UTX-depleted human monocytes with no changes in the H3K27me3 levels when compared to control monocytes was found

Lakshmi et al. [111]

Markedly reduced expression of PPARy correlated with downregulated HDAC2 expression in lung and human bronchial epithelial cells (HBE) obtained from COPD patients compared with healthy controls. Noticeable suppressed GR-α expression in H292 cells (human lung epithelial cell line) after CSE treatment due to dampened expression of PPARy and HDAC2 was also observed. The suppressive effect of CSE on GR-α and HDAC expression was attenuated with PPARy agonists

Zhang et al. [60]

Downregulation of COL3A1 expression in primary human IPF myofibroblasts with concomitant increases of H3ac, H4ac, H3K9ac, and H3K27me3 levels at COL3A1 promoter was observed after SAHA treatment

Wiegman et al. [112]

Significantly increased HAT activity levels and decreased HDAC2 activity levels (due to protein modification: nuclear phosphorylation and cytoplasmic carbonylation) were observed in lung extracts obtained from mice after ozone exposure compared to air-exposed animals

Che et al. [113]

Inhibition of the sphingosine-1-phosphate (S1P)-induced IL-6 secretion by primary human ASMCs via MKP-1-mediated repression of MAPK-driven activation of mitogen and stress-activated protein kinase 1 (MSK1) and phosphorylation at H3S10 (H3S10ph; global; putatively at IL6 promoter as well) was observed after the treatment of the cells with dexamethasone

Liu et al. [61]

Significantly higher H3K9ac levels at the TERT promoter region were detected in primary human lung fibroblasts from patients with IPF (n = 70) compared with healthy control subjects (n = 117). After treatment of the cells with a HDACi (TSA), significantly elevated TERT mRNA and TERT protein levels (time and dose-dependent increase) were detected in both human lung fibroblasts from patients with IPF and mouse lung fibroblasts from a murine model of bleomycin-induced pulmonary fibrosis

Gerasimova et al. [75]

Noticeable enrichment of asthma-associated non-coding SNPs and H3K4me1 peaks (enhancers) in the Th2 cytokine locus of CD4+ T-cells (when compared with other cell/tissue types) was observed

Li et al. [76]

Significantly decreased LAT expression consistent with decreased H3ac and H4ac levels and increased H3K9me2 levels at the LAT (Lat) upstream region in lung T-cells obtained from ovalbumin-induced allergic airway inflammation rat model when compared with control animals were found. H3ac and H4ac as well as LAT expression noticeably increased after treatment of the cells with TSA

Luo et al. [77]

Increased global H3ac and H3K4me levels were observed in PBMCs of HSP patients with kidney damage (n = 16) compared to HSP patients without kidney damage (n = 8) and healthy controls (n = 22). Higher CD4 + T-cell H3ac and H3K4me3 levels were detected at IL4 regulatory regions of HSP patients when compared to control subjects. Higher expression (mRNA) of several HATs (CREBBP, PCAF, and p300) and HMTs (SETD1A, SETDB1, SUV39H1, and SUV39H2) and lower expression of a few HDACs (HDAC1, HDAC2, HDAC3, and SIRT1) were found in PBMCs of both HSP groups compared to healthy controls

Kallsen et al. [114]

Markedly increased H3ac and H3K4me3 levels at the DEFB1 promoter in A549 cells coinciding with enhanced DEFB1 expression after treatment with class I HDACi (MS-275) were found

Han et al. [78]

Noticeable DNA hypomethylation at 26 unique regions (10–70 kb) was found in naïve CD4+ T-cells obtained from psoriasis patients (n = 12) compared to atopic dermatitis patients (n = 15) and healthy controls (n = 10). These regions coincided incidentally with various strong epigenomic signals, including histone modifications (H3K4me1, H3K27ac, and H3K4me3), and transcription factor binding sites

Robertson et al. [115]

Significantly increased HDAC activity (only at the protein level) was observed in ARNT-depleted N-TERT keratinocytes (15–20% increase) and in ARNT-depleted immortalized human HaCaT keratinocytes (~ 50% increase). After treating ARNT-depleted N-TERT keratinocytes with TSA, the negative effect of ARNT-deficiency on transcription of amphiregulin gene (AREG), an important ligand of EGFR, was abolished

Vazquez et al. [116]

A novel inducible hypersensitive region was identified in human and mouse lymphocytes that is located in intron I of CD69. H3K4me2, H3ac, H3K14ac, and/or H3K4ac levels within this region were found to be dynamically regulated during thymocyte development and/or to be constitutively high in mature T lymphocytes

Zijlstra et al. [117]

Reduced glucocorticoid sensitivity and dampened HDAC activity were observed in 16HBE cells (human bronchial epithelial cell line) after treatment with IL-17A. Overexpression of HDAC2 reversed IL-17A-induced glucocorticoid insensitivity