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Table 1 Genes involved in regulation of epigenetic histone marks and/or chromatin remodeling

From: Epigenome alterations in aortic valve stenosis and its related left ventricular hypertrophy

Gene name; official gene symbol Epigenetic function Expression in stenotic valves and aortic valve cells [reference]
AT-rich interaction domain 1A; SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily F Member 1; ARID1A Chromatin remodeling cofactor ↑ PAVECs* [177]
AT-rich interaction domain 4B; ARID4B HAT cofactor ↑ HAVICs1 [78]
AT-rich interaction domain 5B; ARID5B HDM cofactor (H3K9me2 → H3K9) ↑ AS [99], ↑HAVICs1 [78], ↑ PAVICs# [178], (NOTH1+/−) ECsa [67]
Anti-silencing function 1B histone chaperone; ASF1B Histone (H3/H4) chaperone HAVECsb [63], HAVECsc [77]
ASH2 like histone lysine methyltransferase complex subunit; ASH2L HMT cofactor, component of COMPASS H3K4 methyltransferase complex HAVECsc [77], ↑ PAVICs# [178], ↓ HAVECs by miR-483p and unidirectional shear stress [179]
ATRX, chromatin remodeler; ATRX Chromatin remodeling ↑ HAVICs1 [78]
BTG3 associated nuclear protein; BANP Histone acetylation HAVECsc [77]
BRCA1 associated protein 1; BAP1/ KIAA0272 Deubiquitination (H2AK119ub1 → H2AK119), PcG protein; ↑ PAVECs* [177]
BRCA1 Associated RING Domain 1; BARD1 Histone ubiquitination (H2AX, H2A, H2B, H3, H4 → H2AXub, H2Aub, H2Bub, H3ub, H4ub) ↓ PAVECs* [177]
Bromodomain adjacent to zinc finger domain 1A; BAZ1A/ACF1 Histone chaperone HAVECsc [77]
BCL6 corepressor; BCOR PcG protein ↑ AS [99]
BMI1 proto-oncogene, polycomb ring finger; BMI1 PcG protein HAVECsb [63]
Bromodomain containing 1; BRD1 Histone acetyl-lysine reader ↓ HAVICs1 [78]
Bromodomain containing 9; BRD9 Histone acetyl-lysine reader ↓ HAVICs1 [78]
Brain and reproductive organ-expressed; TNFRSF1A modulator; BRE Histone [H2A(X)] ubiquitination cofactor ↓ HAVICs1 [78], ↓ PAVECs* [177]
Bromodomain and PHD finger containing 1; BRPF1 Histone acetyl-lysine reader, component of the MOZ(KAT6A/MYST3)/MORF(KAT6B/MYST4) HAT complex HAVECsb [63], ↓ PAVICs** [180]
Bromodomain and WD repeat domain containing 1; BRWD1 Histone acetyl-lysine reader; chromatin remodeling ↑ HAVICs1 [78]
Coactivator associated arginine methyltransferase 1; CARM1/PRMT4 Histone-Arginine(R) methyltransferase (H3R17 → H3R17me, H3R17me2a) HAVECsb [63], ↓ HAVICs1 [78]
Chromobox 2; CBX2 Methyl-lysine(K) reader (H3K9me3, H3K27me3), component of PRC1-like complex (NOTH1+/−) ECsa [67]
Chromobox 3; CBX3 Methyl-lysine(K) reader (H3K9me3), epigenetic repressor- interacts with MECP2 and modulates epigenetic gene silencing during myogenic differentiation ↑ AS [99], cardiomyocytes of AS patients with cardiomyopathy [181]
Chromobox 4; CBX4 Methyl-lysine(K) reader (H3K9me3), component of PRC1-like complex ↑ BAVc vs. TAVn [182]
Chromobox 7; CBX7 Methyl-lysine(K) reader (H3K9me3, H3K27me3), component of PRC1-like complex ↓ HAVICs1 [78]
Chromobox 8; CBX8 Methyl-lysine(K) reader (H3K9me3, H3K27me3), component of PRC1-like complex ↑ BAVc vs. TAVn, ↑ TAVc vs. TAVn [182]
CECR2, histone acetyl-lysine reader; CECR2 Histone Acetyl-Lysine(K) reader, component of CERF SWI/SNF chromatin remodeling complex ↓ AS [99], ↓ BAVc vs. TAVn, ↓ TAVc vs. TAVn [182], ↑ BAVr vs. BAVc [183]
Chromatin assembly factor 1 subunit A; CHAF1A Histone chaperone and epigenetic regulator, primary component of CAF1 HAVECsb [63]
Chromatin assembly factor 1 subunit B; CHAF1B Histone chaperone and epigenetic regulator, primary component of CAF1 complex HAVECsb [63]
Chromodomain helicase DNA binding protein 1; CHD1 Chromatin remodeling factor ↓ PAVECs* [177]
Chromodomain helicase DNA binding protein 1; CHD1L Chromatin-remodeling following DNA damage, interacts with poly(ADP-ribose) and catalyzes PARP1-stimulated nucleosome sliding ↓ HAVICs1 [78]
Chromodomain helicase DNA binding protein 9; CHD9 Chromatin related mesenchymal modulator, associates with A/T-rich regulatory regions in promoters of genes that participate in the differentiation of progenitors during osteogenesis HAVECsc [77]
CREB binding protein; CREBBP CREB and its paralog p300 (EP300) constitute the KAT3 family of HATs in mammals ↑ HAVICs1 [78]
CXXC finger protein 1; CXXC1 Binds DNA sequences with unmethylated CpG, epigenetic regulator of both cytosine and histone methylation, component of COMPASS/SETD1A/B HMT complex ↓ HAVICs1 [78]
DEK proto-oncogene; DEK Chromatin remodeling, histone chaperone ↓ PAVECs* [177]
Double PHD fingers 3; DPF3 Histone acetylation and methylation reader of BAF chromatin remodeling complex, recruits BRG1 to genomic targets HAVECsb [63], ↑ hypertrophic hearts of AS patients [96]
EMSY, BRCA2 interacting transcriptional repressor; EMSY /C11orf30 Histone methylation cofactor, part of EMSY/KDM5A/SIN3B HMT complex ↓ PAVICs# [178]
Enhancer of polycomb homolog 1; EPC1 PcG protein, component of the NUA4 HAT complex ↑ PAVECs* [177]
Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit; EZH2 /KMT6 PcG protein, Histone methylation (H3K27 → H3K27me1, H3K27me2, H3K27me3) ↓ PAVECs* [177]
EYA transcriptional coactivator and phosphatase 1; EYA1 Dephosphorylation of Tyr(Y)-142 in H2AX (H2AXY142ph) ↓ AS [99], ↑ BAVc vs. TAV; ↑ BAVr vs. TAV [183]
EYA transcriptional coactivator and phosphatase 4; EYA4 Dephosphorylation of Tyr(Y)-142 in H2AX (H2AXY142ph) HAVECsb [63], ↓ BAVc vs. TAVn [182]
Histone deacetylase 1; HDAC1 Class I HDAC member HAVECsc [77], ↓ PAVECs* [177]
Histone deacetylase 3; HDAC3 Class I HDAC member ↓ HAVICs1 [78]
Histone deacetylase 5; HDAC5 Class II HDAC member HAVECsb [63], ↑ PAVECs* [177]
Histone deacetylase 7; HDAC7 Class IIa HDAC member ↓ HAVICs1 [78]
Histone deacetylase 9; HDAC9 Class II HDAC member ↓ HAVICs1 [78]
Histone cell cycle regulator; HIRA Histone chaperone, cooperates with ASF1A to promote replication-independent chromatin assembly, required for early steps of osteoblastic differentiation, interacts with OGT and regulates nucleosome assembly and cellular senescence. HAVECsb [63], ↓ AS [99]
Helicase like transcription factor; SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 3; HLTF Chromatin remodeling cofactor, member of the SWI/SNF family, acts as a ubiquitin ligase for ‘Lys-63’-linked polyubiquitination of chromatin-bound PCNA. Blood dried spots- congenital AS [42]
IKAROS family zinc finger 1; IKZF1 Chromatin remodeling ↑ BAVc vs. TAVn, ↑ TAVc vs. TAVn [182]
Inhibitor of growth family member 3; ING3 Chromatin remodeling, HAT cofactor, component of the NUA4 HAT complex, binds H3K4me3 histone marks ↑ HAVICs1 [78], ↓ AS [88], ↓ PAVECs* [177]
INO80 complex subunit C; INO80C Chromatin remodeling cofactor, component of the INO80 chromatin remodeling complex ↑ HAVICs1 [78]
Janus Kinase 2; JAK2 Phosphorylation of Tyr(Y)-41 of histone H3 (H3T41 → H3Y41ph) ↑ rat AVICs*** [64]
Jade family PHD finger 1; JADE1 /PHF17 Histone acetylation (H3, H4 → H3ac, H4ac), component of HBO1 HAT complex ↓ AS [99]
Jade Family PHD Finger 2; JADE2 Histone acetylation (H3, H4 → H3ac, H4ac), component of HBO1 HAT complex HAVECsc [77]
Arginine demethylase and lysine hydroxylase; JMJD6 Histone arginine demethylase (H3R2me, H4R3me → H3R2, H4R3) and a lysyl-hydroxylase. ↑ PAVICs# [178]
Lysine acetyltransferase 2A; KAT2A /GCN5 HAT HAVECsc [77], ↓ PAVECs* [177]
Lysine acetyltransferase 2B; KAT2B HAT HAVECsb [63], ↑ HAVICs1 [78]
Lysine acetyltransferase 6A; KAT6A /MYST3 HAT (H3, H4 → H3ac, H4ac), component of MOZ/MORF HAT complex ↓ PAVECs* [177]
Lysine acetyltransferase 7; KAT7 /HBOA/MYST2 HAT (H4 → H4ac), component of HBO1 HAT complex ↓ PAVECs* [177]
Lysine acetyltransferase 8; KAT8 /MYST1/MOF HAT (H2A, H3, H4 → H2Aac, H3ac, H4ac), member of the MYST HAT family HAVECsb [63]
Lysine demethylase 1A; KDM1A / KIAA0601 Histone demethylase (H3K4me1, H3K4me2, H3K9me → H3K4, H3K9), component of NuRD complex ↓ PAVECs* [177]
Lysine demethylase 3A; KDM3A/ JMJD1 Histone demethylase (H3K9me1, H3K9me2 → H3K9) HAVECsb [63]
Lysine demethylase 5C; KDM5C /Xe169/ JARID1C Histone demethylase (H3K4me3 → H3K4me2, H3K4me1) ↑ PAVICs** [180], ↓ PAVECs* [177]
Lysine demethylase 6B; KDM6B /JMJD3 Histone demethylases (H3K27me2. H3K27me4 → H3K28), promotes osteogenic differentiation of human MSCs, regulates osteoblast differentiation via transcription factors RUNX2 and SP/OSX ↑ PAVICs# [178]
Lysine demethylase 7A; KDM7A /JHDM1D Histone demethylase (H3K9me2, H3K27me2, H4K20me1 → H3K9, H3K27, H4K20) HAVECsb [63]
Lysine methyltransferase 2A; KMT2A /MLL HMT (H3K4 → H3K4me), catalytic subunit of MLL1/MLL complex ↓ PAVECs* [177], ↓ AS [99]
Lysine methyltransferase 2B; KMT2B /KIAA0304 HMT (H3K4 → H3K4me3) ↓ PAVECs* [177]
Lysine methyltransferase 2E; KMT2E HMT (H3K4 → H3K4me1, H3K4me2) ↓ PAVICs# [178]
L(3)Mbt-Like 3 (Drosophila); L3MBTL3 /KIAA1798 Methyl-lysine(K) reader (H4K20me), putative PcG protein HAVECsc [77], ↑ HAVICs1 [78], ↑ PAVECs vs. PAEC* [177]
Lysyl oxidase like 2; LOXL2 Counteracts HMTs, acts as H3K4me2/3 deaminase, thus giving cells an additional method for removing methylated residues ↑ AS [99], ↑ BAVc vs. TAVn, ↑ TAVc vs. TAVn [182]
Leucine rich repeats and WD repeat domain containing 1; LRWD1 Chromatin remodeling, binds H3K9me3, H3K20me3 and H4K27me3 in a cooperative manner with DNA methylation ↓ HAVICs1 [78]
MYC associated factor X; MAX Histone modification write cofactor involved in histone methylation and acetylation, epigenetic sensor of 5-carboxylcytosine ↓ PAVICs** [180], ↑ PAVECs vs. PAEC$ [177]
Microspherule protein 1; MCRS1 Putative regulatory component of INO80 chromatin remodeling complex with HAT activity (H4K5, H4K8, H4K16 → H4K5ac, H4K8ac, H4K16ac) ↓ HAVICs1 [78], ↓ PAVECs vs. PAEC$ [177]
Megakaryoblastic Leukemia (Translocation); MKL1/ MRTFA Epigenetic orchestrator that connects chromatin and histone modification to: oxidative stress and oxLDL-induced endothelial injury, LPS and endothelin induced proinflammatory gene expression in macrophages and VSMCs, correspondingly; expression of SMC differentiation markers; TGFβ-induced fibrogenesis; cardiac hypertrophy ↑ AS [184]
Nucleosome assembly protein 1 like 2; NAP1L2 Histone modification cofactor; associated with histone H3 and H4 acetylation involved in nucleosome assembly and exchange of H2A-H2B dimmers HAVECsb [63], ↓ AS [88], ↓ BAVc vs. TAVn, ↓ TAVc vs. TAVn [182]
Nuclear autoantigenic sperm protein; NASP Histone chaperone, chromatin remodeling HAVECsb [63], HAVECsc [77]
Nuclear receptor corepressor 2; NCOR2 Histone acetylation eraser HAVECsb [63], ↑ HAVICs1 [78], (NOTH1+/−) ECsa [67]
O-linked N-acetylglucosamine; GlcNAc transferase; OGT O-GlcNAc transferase, PcG protein, modifies members of the TET family HAVECsc [77], ↑ HAVICs1 [78], ↑ PAVECs* [177], LV tissue from AS patients [185], ↓ HAVECs by miRNA-181b and oscillatory shear stress [186]
Poly; ADP-ribose polymerase 1; PARP1 Chromatin remodeling; Histone H1 poly[ADP]-ribosylation, modulates chromatin architecture in a context-dependent manner, controls epigenetic modifications of both histones and DNA, poly(ADP-ribosyl)ation (PARylation)--participates in the establishment and maintenance of a genome methylation pattern ↑ PAVECs vs. PAEC* [177], ↑ TAVc vs. BAVc, leukotriene C4(LTC4) treated VICs [187]
PAX3 and PAX7 binding protein 1; PAXBP1 /C21orf66 Adapter protein linking the transcription factors PAX3 and PAX7 to the histone methylation machinery, involved in myogenesis. ↓ AS [184], ↑ HAVICs1 [78]
PAX interacting protein 1; PAXIP1 HMT cofactor (H3K4 → H3K4me3), subunit of the MLL3/MLL4 HMT complex ↓ PAVECs* [177]
Polycomb group ring finger 2; PCGF2 /MEL18 PcG protein, component of PRC1-like complex ↑ PAVECs* [177]
Polycomb group ring finger 5; PCGF5 PcG protein, component of PRC1-like complex ↑ AS [114]
PHD finger protein 1; PHF1 PcG protein, component of PRC2 complex ↓ HAVICs1 [78], ↑ PAVECs vs. PAECs* [177]
PHD finger protein 2; Jumonji C domain-containing histone demethylase 1E; PHF2 /GRC5 Lysine(K) demethylase (H3K9me2 → H3K9), component of PKA-dependent PHF2-ARID5B HDM complex ↑ PAVECs vs. PAECs*$ [177]
PHD finger protein 19; PHF19 PcG protein, chromatin remodeling, HAT cofactor, binds H3K36me3 and recruits the PRC2 complex ↓ HAVICs1 [78]
Protein Kinase N1; PKN1 Histone phosphorylation at threonine(T)11 (H3T11 → H3T11ph) ↓ HAVICs1 [78]
PR/SET domain 1; PRDM1 HMT cofactor (H3K9 → H3K9me), lack intrinsic HMT activity, but instead recruits G9A/EHMT2/H3K9 HMT HAVECsb [63], (NOTH1+/−) ECsa [67], HAVECsc [77], ↑ HAVICs1 [78]
PR/SET domain 4; PRDM4 Histone arginine methylation (H4R3 → H4R3me2s) ↓ PAVECs* [177]
PR/SET domain 6; PRDM6 /PRISM HMT cofactor (H3R2, H4K20 H3R2me1, H3R2me2, H4K20me1), acts as a transcriptional repressor of VSMCs gene expression, lack intrinsic HMT activity, but instead recruits G9A/EHMT2/H3K9 HMT ↓ PAVICs** [180]
PR/SET domain 8; PRDM8 HMT preferentially acting on H3K9 HAVECsb [63]
Protein arginine methyltransferase 1; PRMT1 Arginine(R) methyltransferase (H4R3 → H4R3me1, H4R3me2a), participate in reading of repressive DNA methylation marks HAVECsc [77], ↓ HAVICs1 [78]
Protein arginine methyltransferase 5; PRMT5 Arginine(R) methyltransferase (H3R8, H4R3 → H3R8me, H4R3me) ↓ HAVICs1 [78]
RB binding protein 4, chromatin remodeling factor; RBBP4 Histone chaperone, part of the Mi-2/NuRD chromatin remodeling complex ↑ HAVICs1 [78], ↓ PAVECs* [177]
RB binding protein 5, histone lysine methyltransferase complex subunit; RBBP5 HMT cofactor (H3K4 → H3K4me1, H3K4me2, H3K4me3), part of the COMPASS and MLL1/MLL complex ↑ HAVICs1 [78]
RB transcriptional corepressor like 1; RBL1 Recruits and targets histone methyltransferases KMT5B and KMT5C, leading to epigenetic transcriptional repression, controls histone H4 Lys-20 trimethylation. ↓ PAVECs* [177]
RB transcriptional corepressor like 2; RBL2 Chromatin remodeling, repression of DNMTs (e.g. DNMT3A, DNMT3B) and control of global DNA methylation, ↓ HAVICs1 [78], ↓ AS [114]
RuvB like AAA ATPase 1; RUVBL1 Chromatin remodeling, Histone phosphorylation, component of the NuA4 and INO80 complex ↓ HAVICs1 [78], ↓ PAVECs* [177]
SAM domain, SH3 domain and nuclear localization signals 1; SAMSN1 Implicated in the epigenetic control of gene expression, regulates the activity of HDAC1 ↑ AS [99], ↑ AS [114], ↑ TAVc vs. TAVn [182]
SATB homeobox 1; SATB1 Chromatin remodeling cofactor HAVECsb [63]
SET domain bifurcated 1; SETDB1 HAT (H3K9 → H3K9me3 ↑ PAVICs# [178]
SET domain and mariner transposase fusion gene; SETMAR HAT (H3K4, H3K36 → H3K4me, H3K36me) ↑ HAVICs1 [78]
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 1; SMARCAL1 Chromatin remodeling ↑ PAVICs# [178], ↓ PAVECs vs. PAEC$ [177]
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2; SMARCA2 Chromatin remodeling, histone modification reader (targets H3) ↑ HAVICs1 [78]
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1; SMARCB1 core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, histone modification reader (targets H3K56) ↓ HAVICs1 [78], ↓ PAVECs* [177]
SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 1; SMARCC1 Chromatin remodeling cofactor HAVECsc [77]
SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 2; SMARCC2 Chromatin remodeling cofactor ↑ PAVECs* [177]
SMYD family member 5; SMYD5 HMT (H4K20 → H4K20me3), part of NCoR complex ↓ HAVICs1 [78]
Suppressor of variegation 3–9 homolog 2; SUV39H2 /KMT1B HAT (H3K9me1 → H3K9me3) HAVECsb [63]
Transcriptional adaptor 3; TADA3 HAT cofactor, component of the PCAF complex ↓ HAVICs1 [78]
TATA-box binding protein associated factor 5 like; TAF5L HAT cofactor, component of the PCAF complex ↓ HAVICs1 [78]
Tripartite motif containing 24; TRIM24 Human chromatin reader, lysine acetylated histone binding ↑ HAVICs1 [78]
Tripartite motif containing 28; TRIM28 Histone modification reader (targets H3) ↓ HAVICs1 [78]
Ubinuclein 1; UBN1 HMT cofactor HAVECsc [77]
Ubiquitin protein ligase E3 component n-recognin 2; UBR2 /KIAA0349 Modification Histone ubiquitination (targets H2A) ↓ PAVECs* [177]
Wolf-Hirschhorn syndrome candidate 1; WHSC1 /NSD2 HMT (H3K27 → H3K27me) HAVECsb [63], (NOTH1+/−) ECsa [67]
Wolf-Hirschhorn syndrome candidate 1-like 1; WHSC1L1 /NSD3 member of the NSD methyltransferase family (targets H3K4, H3K27) ↑ HAVICs1 [78]
  1. Legend: AS- aortic valve stenosis; ASF1A- anti-silencing function 1a histone chaperone; BAVc- calcified stenotic bicuspid aortic valve; BAVr- bicuspid aortic valve with redundant leaflets and/or minimal calcification; BRG1- SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; DNMTs- DNA methyltransferase; HAT-histone acetyltransferase; HAVECs- human aortic valve endothelial cells; HAVICs- human aortic valve interstitial cells; HDM- histone demethylase; HMT- histone methyltransferase; (NOTH1+/−) ECs- hiPSC (human induced pluripotent stem cell)-derived endothelial cells generated from two patients with nonsense mutations in NOTCH1; MECP2- methyl CpG binding protein 2; CAF1-; oxLDL- oxidized low-density lipoprotein; LPS- lipopolysaccharide; PAECs- porcine aortic endothelial cells; PAVECs- porcine aortic valve endothelial cells; PAX3- paired box 3; PAX7- paired box 7; PcG- polycomb group protein; PCNA- proliferating cell nuclear antigen; RAVICs- rat aortic valve interstitial cells; RUNX2 – runt related transcription factor 2; SP7/OSX- osterix; SMC -smooth muscle cell; TAVc- calcified stenotic tricuspid aortic valve; TAVn -noncalcified tricuspid aortic valve, without stenosis; TGFβ- transforming growth factor beta; VSMCs- vascular smooth muscle cells
  2. 1Genes altered > 1.2-fold with a p < 0.05 in the HOTAIR siRNA microarray data; aNOTCH1 haploinsufficiency, shear or static flow significant; baffected by flow and decreased NOTCH1; cshear-sensitive transcripts; *shear stress conditions modeling laminar flow; **male vs. female; *** inhibition of NOTCH1 signaling; # 2 years old vs. Juvenile Rapacz familial hypercholesterolemic (RFH) swine. NOTE: Official gene symbols are presented in bold and italicized, aliases are presented in italics