Dysregulation of Epigenetic Mechanisms of Gene Expression in the Pathologies of Hyperhomocysteinemia
Abstract
:1. Introduction
2. HHcy Affects Gene Expression
3. HHcy and DNA Methylation
3.1. SAM/SAH Homeostasis and DNA Methylation
3.2. HHcy & SAH/SAM Levels
3.3. HHcy and DNA Methyltransferases
3.4. HHcy and DNA Methylation in Disease
3.4.1. Atherosclerosis
3.4.2. Uraemia
3.4.3. Cognition and Alzheimer’s Disease
3.5. HHcy and DNA Methylation in Humans
4. Histone Modifications in HHcy
4.1. Histone Modification
4.2. Histone-Modifying Enzymes in HHcy
4.3. Histone Modifications and HHcy
4.4. Crosstalk between DNA Methylation and Histone Modification
5. HHcy and Noncoding RNA Regulation
5.1. MiRNAs
5.2. LncRNAs
5.3. CircRNAs
6. Summary/Prospects
Supplementary Materials
Funding
Conflicts of Interest
Abbreviations
MDPI | Multidisciplinary Digital Publishing Institute |
DOAJ | Directory of open access journals |
TLA | Three letter acronym |
LD | linear dichroism |
AD | Alzheimer’s disease |
ADMA | Asymmetric dimethylarginine |
AHCY | S-adenosylhomocysteine hydrolase |
APP | Amyloid-beta precursor protein |
BACE | β-secretase |
BBB | Blood-brain barrier |
BHMT | Betaine:Hcy methyltransferase |
BLMH | Bleomycin hydrolase |
BPHL | Biphenyl hydrolase like |
CBS | Cystathionine β-synthase |
CFTR | Cystic fibrosis transmembrane conductance regulator |
CRC | Colorectal cancer |
CSE | Cystathionine γ-lyase |
DNMT | DNA methyltransferase |
ECs | Endothelial cells |
EPCs | Endothelial progenitor cells |
EPRS | Glutamyl-prolyl-tRNA synthetase |
FABP4 | Fatty acid-binding protein 4 |
FATP1 | Long-chain fatty acid transport protein 1 |
HAT | Histone acetyltransferase |
HDAC | Histone deacetylase |
HMT | Histone methyltransferase |
HTL | Homocysteine thiolactone |
HUVECs | Human umbilical vein endothelial cells |
5LO | 5-Lipoxygenase |
MAPK | Mitogen-activated protein kinase |
MARS | Met-tRNA synthetase |
MBP | Methylcytosine-binding proteins |
MFN2 | Mitofusin-2 |
MMP | Matrix metalloproteinase |
MTHFR | 5,10-methylenetetrahydrofolate reductase |
MS | Met synthase |
NASH | Nonalcoholic fatty liver disease |
NTD | Neural tube defect |
PDGF | Platelet-derived growth factor |
PON1 | Paraoxonase 1 |
PPAR | Peroxisome proliferator-activated receptor |
PS1 | Presenilin-1 |
ROS | Reactive oxygen species |
SAH | S-adenosylhomocysteine |
SAM | S-adenosylmethionine |
She | Soluble epoxide hydrolase |
SHMT | Serine hydroxymethyltransferase |
SOD-2 | Superoxide dismutase |
SP1 | Specificity protein-1 |
TIMP | Tissue inhibitors of metaloproteinases |
TERT | Telomerase reverse transcriptase |
TLR4 | Toll-like receptor 4 |
VSMCs | Vascular smooth muscle cells |
TLA | Three letter acronym |
LD | linear dichroism |
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Cell Line/Model Organism | Treatment | Effect on | Reference | ||
---|---|---|---|---|---|
SAM, SAH, SAM/SAH | DNMT | Promoter DNA Methylation/Gene Expression mRNA/Protein | |||
HUVEC | Hcy 1 mM, 5 days | NA | NA | ↓genomic DNA methylation ↑SORBS1/↓/↓ | [47] |
HUVEC | Hcy 10, 30 μM, 72 h Hcy 100, 300 μM, 72 h | NA NA | NA NA | ↓DDAH2/↑/NA ↑DDAH2/↓/NA | [48] |
HUVEC | Hcy 1 mM, 48 h | NA | ↑DNMT1 protein | ↑DDAH2/↓/NA | [49] |
HUVEC | Hcy 100, 200, 500 μM, 72 h | NA | ↓DNMT1 mRNA, protein | ↓LOX-1/↑/↑ | [50] |
HUVEC | Hcy 50, 100, 200 μM, 24 h | NA | ↓DNMT1 mRNA, protein ↓DNMT activity | ↓PDGF-A, -C, -D/↑/NA | [51] |
HUVEC | Hcy 200 μM, 8 h | NA | ↑DNMT3B ↓DNMT activity | ↓p66shc/↑/↑ | [52] |
HUVEC | D,L-Hcy 50 μM, Ado 40 μM, 10 μM Ado-deaminase inhibitor, 48 h | NA | ↓DNMT1 activity =DNMT3 activity | ↓Cyclin A/↓/NA | [53] |
HUVEC | Hcy 25, 50, 100, 200 μM, 24, 48, 72 h | NA | NA | ↓sEH/↑/↑ mRNA | [54] |
HUVEC | Hcy 25, 50, 100, 200 μM, 72 h | NA | NA | ↓hTERT/↓/↓ | [55] |
Human foam cells | Hcy 50, 100, 200, 500 μM, 48 h | NA | ↓DNMT1 mRNA, protein | NA/↓miR-148a/152/NA | [56] |
Human foam cells | Hcy 100 μM, 72 h | NA | NA | ↓FABP4/↑/↑ | [57] |
Human monocytes | Hcy 50, 100, 200, 500 μM, 48 h | ↓SAM, ↑SAH ↓SAM/SAH | ↑DNMT activity | ↑PPARγ/↓/↓ | [58] |
T/G HA-VSM | Hcy 50, 100, 200 and 500 μM, 72 h | NA | ↑DNMT1 mRNA, protein | ↑PTEN/↓/↓ | [59] |
VSMC | D,L-Hcy 50, 100, 200, 500 μM, 72 h | NA | ↑DNMT3B protein | ↑p53/↓/↓ | [60] |
VSMC | Hcy 50, 100, 200, 500 μM, 72 h | NA | ↑DNMT3A mRNA, protein | ↑/↓miR-143/NA | [61] |
VSMCs | Hcy 50, 100, 200 and 500 μM, 72 h | NA | ↑DNMT1 mRNA, protein | ↑MFN2/↓/↓ | [62] |
HL-1 cardiomyocytes | Hcy 5, 100 μM, 72 h | NA | ↑DNMT1 mRNA, protein | NA | [63] |
Human hepatocytes (HL-7702) | Transfection with Ad-CFTR L-Hcy 100 μM, 24 h | NA | NA | ↑CRFT/↓/↓ | [64] |
Human primary retinal endothelial cells (HRECs) | Hcy 20, 50, 100 μM | NA | ↑DNMT activity | NA | [65] |
Human retinal pigments epithelial cells (ARPE-19) | Hcy 20, 50, 100 μM | NA | ↑DNMT activity | NA | [65] |
Mouse Cbs−/−, Cbs+/− retinas | None | NA | ↑DNMT activity | NA | [65] |
Mouse endothelial progenitor cells differentiated from primary bone marrow mononuclear cells isolated from femur and tibia of female C57BL/6J mice | High-Met, low-folate, low-vitamin B6 & B12 diet 8 weeks | NA | ↑DNMT1 mRNA, protein =DNMT3A mRNA, protein ↑DNMT activity | ↑global DNA methylation ↑Cbs/↓/↓ | [66] |
Mouse brain endothelial cells (bEnd.3) | Hcy 100 μM, 24 h | NA | ↑ DNMT1 mRNA, protein ↑DNMT3A mRNA, protein ↓ DNMT3B mRNA, protein | NA | [67] |
Mouse brain endothelial cell line (bEnd.3) | Hcy 50, 100, 200 μM, 24 h | NA | ↑DNMT3A protein ↓DNMT3B protein | NA | [68] |
Mouse myoblast C2C12 cells | Hcy 500 μM, 3 days | NA | ↑DNMT3A protein ↑DNMT3B protein | NA | [69] |
Mouse neuro 2A cells, neuroblastoma cell line stably expressing human APP carrying the K670N, M671L Swedish mutation (N2A-APPswe) | DL-Hcy 50 μM, adenosine 40 μM, erythro-9-(2-hydroxy-3-nonyl)-adenine hydrochloride 10 μM, 24 h | ↓SAM ↑SAH | ↓DNMT1 protein ↓DNMT3A protein ↓DNMT3B protein | ↓5LO/↑/↑ | [70] |
Model Animal, Tissue | Treatment | Plasma/Tissue tHcy, μM | Effect on | Reference | ||
---|---|---|---|---|---|---|
SAM SAH SAM/SAH | DNMT | Promoter DNA Methylation/Gene Expression mRNA/Protein | ||||
Male ApoE−/− mice, Aorta | High-Met diet 20 weeks | Plasma tHcy 2.67 ± 0.79 (control diet) vs. 13.79 ± 0.54 (ApoE-/-) and 6.40 ± 0.28 (ApoE+/+) (high-Met diet) | ↑SAM ↑SAH ↑SAM/SAH | ↓DNMT1 mRNA, protein =DNMT3A mRNA, protein =DNMT3B mRNA, protein | ↓FABP4/↑/↑ | [57] |
Male ApoE−/− mice | High-Met diet 15 weeks | NA | NA | ↑DNMT3B protein | NA/↓miR-125b/NA | [60] |
Male Tg-127T Cbs−/− mice 3-month-old Brain cortices | None | Plasma tHcy 296 vs. 5.5 (controls) [71] | NA | ↓DNMT1 protein ↓DNMT3A protein ↓DNMT3B protein | ↓5LO /↑/↑ | [70] |
Male Cbs-deficient mice, 8–12-week-old, Heart | High-Met diet | NA | NA | ↑DNMT1 protein ↑DNMT activity | ↑Genomic DNA methylation | [63] |
Male C57BL/6J mice, 8-week-old, Aortic intima | High-Met diet 4 or 8 weeks | Plasma tHcy 27.6 ± 4.5 or 61.5 ± 31.4 vs. 5.2 ± 1.3 in the control group after 4 or 8 weeks, respectively | NA | NA | ↓PDGF-A, -C and -D/↑/↑ | [51] |
Male C57BL/6J mice, 6–8-week-old Blood | High-Met diet 8 weeks | Plasma tHcy 61.5 ± 31.4 vs. 5.2 ± 1.3 in the control group after 4 or 8 weeks, respectively [51] | NA | NA | ↓mTERT/↓/NA | [72] |
Male C57BL/6J mice, 6–8-week-old, Aorta | High-Met diet 4 or 8 weeks | Plasma tHcy 61.5 ± 31.4 vs. 5.2 ± 1.3 in the control group after 4 or 8 weeks, respectively [51] | NA | NA | ↓mTERT/↓/↓ | [55] |
Male Sprague-Dawley rats, 4-week-old Blood | High-Met diet 8 weeks | Serum tHcy level 66.8±11.7 | NA | NA | ↓rTERT/↓/NA | [73] |
Male Cbs-deficient mice 8–12-week-old Brain | High-Met diet | NA | NA | ↑DNMT1 mRNA, protein ↑DNMT3A mRNA, protein ↑DNMT activity | ↑Genomic DNA methylation | [74] |
Male and female 3xTg-AD mice, Brain cortices | Folate, vitamin B6, B12-deficient diet 7 months | NA | ↓SAM ↑SAH | ↓DNMT1 protein ↓DNMT3A protein ↓DNMT3B protein | ↓5LO/↑/↑ | [70] |
Cbs+/− mice, 8–10-week-old, Liver | None | 3.46 times higher than in Cbs+/+ mice | NA | ↑DNMT1 mRNA, protein =DNMT3A mRNA, protein =DNMT3B mRNA, protein | ↑CRFT/↓/↓ | [64] |
Male C57BL/6J mice, Stelic animal model, Liver | Streptozotocin injection at 2nd day High-fat diet 6, 12, 20 weeks | =liver Hcy ↑plasma Hcy | ↑liver SAM ↑liver SAH ↓liver SAM/SAH ↑plasma SAH | ↑DNMT1 mRNA, protein ↑DNMT3A mRNA, protein ↑DNMT3B mRNA, protein | ↑Ahcy/↓/? | [75] |
Male C57BL/6J mice, CFD model, Liver | Low-Met, w/o choline and folic acid (CFD) diet 12 weeks | ↑liver Hcy ↑plasma Hcy | ↓liver SAM =liver SAH | NA | NA Ahcy/↓/? | [76] |
Male Fisher 344 rats, 4-week-old Liver, preneoplastic liver, and liver tumor | Low-Met, w/o choline and folic acid diet, 36, 54 weeks | NA | NA | NA | ↓LINE-1 | [77] |
Male F344 rats 4-week-old Liver | Low-Met, w/o choline and folic acid diet, 9, 18, 24, and 36 weeks, followed by 18 weeks of feeding a methyl-adequate diet with sufficient content of Met, choline, and folic acid | NA | ↓ SAM ↓ SAM/SAH | NA | ↓global DNA methylation (reversible after 9 weeks and irreversible after 18-36 weeks of the methyl-deficient diet) | [78] |
Male F344 rats 4-week-old Brain | Low-Met, w/o choline and folic acid diet, 18, 36 weeks | ↑Hcy After 36 weeks ~0.15 vs. 0.1 nmol/mg protein | =SAM =SAH =SAM/SAH | ↓DNMT1 protein ↑DNMT3A protein ↑DNMT3B protein | ↑DNA methylation within unmethylated GC-rich DNA domains =methylation within methylated GC-rich DNA regions | [79] |
Male Sprague-Dawley rats, 8 weeks old | High-Met diet Low-Met diet 4 weeks | ↑plasma tHcy | ↓SAM ↑SAH ↓SAM/SAH | ↑DNMT3A mRNA, protein ↑DNMT3B mRNA, protein | ↓genome methylation in B1 repetitive elements | [80] |
Male Cbs+/− and Cbs+/+ mice 8–10-week-old, Brain | 5′-aza (0.5 mg/kg body weight) intraperitoneally for 6 weeks, +/− Met, +/− folic acid (FA) | ↑Hcy | NA | ↓DNMT3B protein | ↑5-mC in brain DNA from CBS+/−, + Met mice; tended to decrease in FA-supplemented mice | [68] |
Male ApoE−/− C57BL6J mice, 6-week-old, Aorta | High-Met, low folate/B12 diet 20 weeks | ↑Serum Hcy | NA | ↓DNMT1 mRNA, protein | NA | [56] |
Male C57BL/6J sEH+/+ and sEH−/− mice, 8-week-old, Aortic intima | High-Met diet 4, 8 weeks | ↑Plasma tHcy | NA | NA | ↓sHE/↑/NA | [54] |
Gene Name | Access. No. | Protein Name | Fold Change at HTL 10 μM 1000 μM | |
---|---|---|---|---|
SETD2 | 29072 | Histone-lysine N-methyltransferase SETD2 | 17.9 | 6.1 |
SETD7 | 80854 | Lysine methyltransferase 7 | 1.1 | 3.9 |
EZH2 | 2146 | Histone-lysine N-methyltransferase EZH2 | 2.3 | 5.4 |
EHMT1 | 79813 | Euchromatic histone-lysine N-methyltransferase 1 | 2.0 | 3.7 |
H2AFY | 9555 | H2A histone family, member Y | 1.7 | 2.5 |
EHMT2 | 10919 | Euchromatic histone-lysine N-methyltransferase 2 | 1.7 | 2.5 |
EPC1 | 80314 | Enhancer of polycomb homolog 1 (Histone acetylase) | 1.8 | 2.0 |
EP300 | 2033 | E1A-binding protein (Histone acetylase) | 2.1 | 2.8 |
HIST1H2BK | 85236 | Histone cluster 1, H2bk | 2.3 | 2.5 |
JARID2 | 3720 | Jumonji, AT-rich interactive domin 2 | 3.6 | 2.7 |
MBD3 | 53615 | Methyl-CpG binding domain protein 3 | 1.5 | 2.5 |
SUV420H2 | 84787 | Histone-lysine N-methyltransferase | −1.9 | −3.3 |
DOT1L | 84444 | Histone-Lys N-methyltransf, H3K79 specific | −2.5 | −2.3 |
SMYD3 | 3009 | Histone-lysine N-methyltransferase | −2.8 | −11.3 |
JMJD2B | 23030 | Lysine-specific demethylase 4B | −1.9 | −3.0 |
BRD8 | 10902 | Bromodomain-containing protein 8 | −2.8 | −4.8 |
CBX2 | 12416 | Chromobox prot homol 2 (H2AK119 ubiq.) | −6.0 | −7.1 |
HIST1H2AJ | 8330 | Histone cluster 1, H2ak | −2.7 | −4.1 |
HIST1H1B | 3009 | Histone cluster 1, H1b | −7.7 | −9.4 |
Organism/Cell Line | Treatment | Effect | References |
---|---|---|---|
Acetylation | |||
HUVEC | Hcy or HTL 1, 10, 100, 1000 μM | ↓H3K9ac | [19,150] |
HUVEC | Hcy 50 μM 24 h | ↑H3K9ac ↑H3K14ac | [52] |
HL-1 cardiomyocytes | Hcy 100 μM, 72 h | ↑H3K9ac | [63] |
Human colorectal cancer cell line HCT116 | Met restriction 24 h | ↓H3K9ac | [149] |
Male C57BL/6J mice Stelic animal model Liver | Streptozotocin injection at 2nd day High-fat diet from 4th week of age 6, 12, 20 weeks | ↓H4K16ac | [75] |
Female Cbs+/− mice (129P2-Cbstm1Unc/J) 16-weeks old Femur bone | Met-rich, low folate vitamin B6, B12 diet 8 weeks | ↑H3K27ac | [148] |
Male Wistar rats 4–6-months old Brain cortex | Hcy 1.2 μmol/g of body weight injected subcutaneously once a day 21 days | ↑H3K9ac ↑H4K12ac | [151] |
Methylation | |||
Male C57BL/6J mice Stelic model Liver | Streptozotocin injection at 2nd day High-fat diet from 4th week of age 6, 12, 20 weeks | ↑H3K27me3 in NASH-derived hepatocellular carcinoma | [75] |
Female Wistar rats Brain Heart Liver | Met-rich, deficient in B vitamins (folic acid, B6 and B12) 8 weeks | ↓H3R8me2a (brain) = H3R8me2a (heart, liver) = H3R17me2a (brain, heart, liver) = H4R3me2a (brain, heart, liver) | [152] |
Male Fisher 344 rats, 4-weeks old, Liver, Preneoplastic liver, Liver tumor | Low-Met and lacking in choline and folic acid diet 36, 54 weeks | ↓H4K20me3 ↑H3K9me3 (preneoplatic nodules and liver tumors) | [77] |
Cbs+/− mice 8–10-weeks old, Liver | None | ↑H3K27me3 = H3K27me1 = H3K27me2 | [64] |
Tg-I278T Cbs−/− mice, Brain, Liver, Heart, Kidney | None | ↓H4R3me2a (liver) = H4R3me2a (brain) | [28] |
Human colon cancer cells HCT116 | Met restriction 24 h | ↓H3K4me3 ↓H3K9me3 ↓H3K27me3 | [149] |
Human colon cancer cells SW620, SW480, HCT8, HT29, NCI-H5087 | Met restriction 24 h | ↓H3K4me3 | [149] |
C57BL/6J mice 8-week-old, Liver | Low-Met diet 12 weeks | ↓H3K4me3 | [149] |
Male C57BL/6J mice 7-week-old | Low-Met diet 12 weeks | ↓H3K4me3 | [153] |
Human colon cancer cells HCT116 | Met restriction 24 h | ↓H3K4me3 | [153] |
Human hepatocytes (HL-7702) | Transfection with Ad-CFTR L-Hcy 100 μM, 24 h | ↑H3K27me3 | [64] |
N-homocysteinylation | |||
HUVEC | HTL or Hcy 1, 10, 100, 1000 μM; 24 h | ↑N-Hcy-H1, -H2A, -H2B, -H3, -H4 | [19,150] |
Human embryos | NA | 39 N-Hcy-sites: 8 in H2a, 16 in H2b, 8 in H3, 7 in H4 | [36] |
Chicken embryos | 0.5 μL of 0.5 mM HTL injected into the neural groove | ↑N-Hcy-histone | [36] |
Mouse neural stem cells (NE4C) | DL-Hcy or L-HTL 0.1, 0.5, 1 mM 8 h | ↑N-Hcy-histone | [36] |
HEK293 cells | DL-Hcy or L-HTL 0.1, 0.5, 1 mM 8 h | ↑N-Hcy-histone | [36] |
HEK293 cells | MARS knockdown | ↓ N-Hcy-histone | [36] |
HEK293T, HCT116, HeLa cells | HTL 0.01, 0.1, 1 mM 24h | ↑ H3K23Hcy ↑ H3K79Hcy | [154] [155] |
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Perła-Kaján, J.; Jakubowski, H. Dysregulation of Epigenetic Mechanisms of Gene Expression in the Pathologies of Hyperhomocysteinemia. Int. J. Mol. Sci. 2019, 20, 3140. https://doi.org/10.3390/ijms20133140
Perła-Kaján J, Jakubowski H. Dysregulation of Epigenetic Mechanisms of Gene Expression in the Pathologies of Hyperhomocysteinemia. International Journal of Molecular Sciences. 2019; 20(13):3140. https://doi.org/10.3390/ijms20133140
Chicago/Turabian StylePerła-Kaján, Joanna, and Hieronim Jakubowski. 2019. "Dysregulation of Epigenetic Mechanisms of Gene Expression in the Pathologies of Hyperhomocysteinemia" International Journal of Molecular Sciences 20, no. 13: 3140. https://doi.org/10.3390/ijms20133140