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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