Promoter H3K4me3 and Gene Expression Involved in Systemic Metabolism Are Altered in Fetal Calf Liver of Nutrient-Restricted Dams
Abstract
1. Introduction
2. Results
2.1. Phenotypic Effect of MUN on Fetuses
2.2. Distribution of MUN-Induced H3K4me3 and H3K27me3 Mark Changes
2.3. Genes and Metabolisms/Pathways Relevant to H3K4me3 and H3K27me3 Alteration
2.4. Difference in Epigenetic Modification and Altered Gene Expression Between Histone Methylation and DNA Methylation
2.5. Relationship Between H3K4me3 and Gene Expression in MUN Fetal Liver
3. Discussion
3.1. Potential Roles of H3K4me3 and H3K27me3 in Gene Expression of MUN Fetal Calf Liver
3.2. Genes with Hyper/Hypo H3K4me3 in Hepatic Metabolisms and Function
4. Materials and Methods
4.1. Animals and Feeding
4.2. Sample Collection
4.3. ChIP-Seq Analysis
4.3.1. Chromatin Preparation and Immunoprecipitation
4.3.2. Next-Generation Sequencing Analysis
4.4. Microarray Analysis
4.5. Gene Ontology and Pathway Analyses
4.6. Gene Expression Analysis with Quantitative PCR
4.7. Comparison of Transcriptional Regulatory Potential Between Histone Methylation and DNA Methylation
4.8. Statistical Analyses
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Symbol | Gene name |
---|---|
ABTB1 | Ankyrin Repeat And BTB Domain Containing 1 |
ADH4 | Alcohol Dehydrogenase 4 |
ALPL | Alkaline Phosphatase, Biomineralization Associated |
ANGPTL4 | Angiopoietin Like 4 |
APOA5 | Apolipoprotein A5 |
ATF4 | Activating Transcription Factor 4 |
CARD9 | Caspase Recruitment Domain Family Member 9 |
CDIP1 | Cell Death Inducing P53 Target 1 |
CLK2 | CDC Like Kinase 2 |
COL6A1 | Collagen Type VI Alpha 1 Chain |
DDIT3 | DNA Damage Inducible Transcript 3 |
DPF1 | Double PHD Fingers 1 |
EIF2A | Eukaryotic Translation Initiation Factor 2A |
EIF2AK3 | EIF2A Kinase 3/4 |
EPHA5 | EPH Receptor A5 |
ETV3 | ETS Variant Transcription Factor 3 |
F2 | Coagulation Factor II, Thrombin |
FADS1 | Fatty Acid Desaturase 1/2 |
GDF15 | Growth Differentiation Factor 15 |
GFI1 | Growth Factor Independent 1 Transcriptional Repressor |
GKAP1 | G Kinase Anchoring Protein 1 |
GR | Glucocorticoid Receptor |
GNAS | G Protein Subunit Alpha S |
G6PC | Glucose 6 Phosphatase |
GRB10 | Growth Factor Receptor-Binding Protein 10 |
HAPLN3 | Hyaluronan And Proteoglycan Link Protein 3 |
HOXA11 | Homeobox A11 |
IGF2 | Insulin-Like Growth Factor 2 |
KBTBD6 | Kelch Repeat And BTB Domain Containing 6 |
LDLRAP1 | Low-Density Lipoprotein Receptor Adaptor Protein 1 |
LSP1 | Lymphocyte-Specific Protein 1 |
MBOAT2 | Membrane-Bound Glycerophospholipid O-Acyltransferase 2 |
METTL22 | Methyltransferase 22, Kin17 Lysine |
MIC1 | Macrophage Inhibitory Cytokine 1 |
NTRK1 | Neurotrophic Receptor Tyrosine Kinase 1 |
PCDHGC3 | Protocadherin Gamma Subfamily C, 3 |
PDCD1 | Programmed Cell Death 1 |
PHLDA2 | Pleckstrin Homology-Like Domain Family A Member 2 |
PHOX2A | Paired-Like Homeobox 2A |
PNPLA2 | Patatin-Like Domain 2, Triacylglycerol Lipase |
PODXL2 | Podocalyxin Like 2 |
POR | P450 (Cytochrome) Oxidoreductase |
PPARA | Peroxisome Proliferator–Activated Receptor α |
PPP1R3B | Protein Phosphatase 1 Regulatory Subunit 3B |
PROZ | Protein Z, Vitamin K-Dependent Plasma Glycoprotein |
PRTN3 | Proteinase 3 |
PTGDS | Prostaglandin D2 Synthase |
QRFPR | Pyroglutamylated RFamide Peptide Receptor |
RABGEF1 | RAB Guanine Nucleotide Exchange Factor 1 |
RALGDS | Ral Guanine Nucleotide Dissociation Stimulator |
RARB | Retinoic Acid Receptor Beta |
RBFA | Ribosome Binding Factor A |
RIPK4 | Receptor Interacting Serine/Threonine Kinase 4 |
RNASEH2B | Ribonuclease H2 Subunit B |
RPS29 | Ribosomal Protein S29 |
SDC4 | Syndecan 4 |
SERP1 | Stress-Associated Endoplasmic Reticulum Protein 1 |
SHANK3 | SH3 And Multiple Ankyrin Repeat Domains 3 |
SLC25A34 | Solute Carrier Family 25 Member 34 |
SLC38A4 | Solute Carrier Family 38 Member 4 |
SMARCA5 | SNF2 Related Chromatin Remodeling ATPase 5 |
SYT16 | Synaptotagmin 16 |
TBX15 | T-Box Transcription Factor 15 |
TMEM143 | Transmembrane Protein 143 |
TMEM45B | Transmembrane Protein 45B |
TPM1 | Tropomyosin 1 |
TRIB3 | Tribbles Pseudokinase 3 |
TSPAN9 | Tetraspanin 9 |
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HN (n = 4) | LN (n = 4) | p-Value | |||
---|---|---|---|---|---|
Mean | SE | Mean | SE | ||
Age (d) | 260.75 | 1.79 | 258.50 | 1.20 | 0.273 |
BW (kg) | 32.91 | 0.58 | 24.29 | 1.67 | 0.001 |
Liver (g) | 641.73 | 20.69 | 508.12 | 31.58 | 0.006 |
%BW | 1.95 | 0.04 | 2.10 | 0.84 | 0.220 |
DHR * | |||
---|---|---|---|
Histone Mark | Total | Upregulated in LN | Downregulated in LN |
H3K4me3 | 20,823 | 535 | 404 |
H3K27me3 | 35,363 | 1934 | 1909 |
Histone Mark | Gene | Chr. no. | Genomic Region | LN/HN Ratio | p-Value |
---|---|---|---|---|---|
H3K4me3 | ADH4 | 6 | 25,480,605..25,481,355 | 0.264 | 0.000003 |
USP36 | 19 | 53,535,872..53,536,716 | 1.919 | 0.000040 | |
RARB | 27 | 40,353,778..40,354,509 | 3.583 | 0.000047 | |
LOC508098 | 18 | 64,038,284..64,039,133 | 2.210 | 0.000060 | |
LOC617302 | 25 | 2,255,163..2,255,891 | 1.456 | 0.000069 | |
MT1E | 18 | 24,034,824..24,035,551 | 1.626 | 0.000084 | |
SLC38A4 | 5 | 33,400,863..33,401,584 | 1.230 | 0.000100 | |
ZFP36 | 18 | 49,102,226..49,103,204 | 1.189 | 0.000127 | |
PHLDA2 | 29 | 48,689,563..48,690,308 | 1.695 | 0.000146 | |
FADS1 | 29 | 40,350,665..40,351,393 | 0.515 | 0.000164 | |
H3K27me3 | MIC1 | 23 | 27,912,712..27,913,557 | 0.407 | 0.000001 |
UAP1 | 3 | 6,937,706..6,938,669 | 2.958 | 0.000003 | |
LDLRAP1 | 2 | 127,508,220..127,508,996 | 3.158 | 0.000006 | |
PRTN3 | 7 | 43,404,963..43,405,718 | 0.529 | 0.000023 | |
SYT16 | 10 | 73,935,943..73,936,680 | 0.468 | 0.000024 | |
CLK2 | 3 | 15,367,381..15,368,065 | 3.259 | 0.000027 | |
HOXA11 | 4 | 68,857,565..68,858,272 | 0.5 | 0.000065 | |
TBX15 | 3 | 24,130,717..24,131,497 | 0.526 | 0.000065 | |
GFI1 | 3 | 50,944,295..50,945,015 | 0.509 | 0.000080 |
Category | Term | p-Value | FE |
---|---|---|---|
GO_BP | GO:0006357~regulation of transcription from RNA polymerase II promoter | 0.001343 | 2.23 |
GO:0042981~regulation of apoptotic process | 0.010192 | 5.89 | |
GO:0033627~cell adhesion mediated by integrin | 0.021313 | 13.20 | |
GO:0016477~cell migration | 0.031975 | 4.16 | |
GO:0045893~positive regulation of transcription, DNA-templated | 0.034545 | 3.31 | |
GO:0071376~cellular response to corticotropin-releasing hormone stimulus | 0.039141 | 49.87 | |
GO:0035767~endothelial cell chemotaxis | 0.045515 | 42.74 | |
GO:0032869~cellular response to insulin stimulus | 0.048273 | 8.47 | |
KEGG_PATH | bta04927:Cortisol synthesis and secretion | 0.000828 | 11.59 |
bta04934:Cushing syndrome | 0.003415 | 5.79 | |
bta04925:Aldosterone synthesis and secretion | 0.003494 | 7.85 | |
bta05166:Human T-cell leukemia virus 1 infection | 0.003907 | 4.55 | |
bta05163:Human cytomegalovirus infection | 0.005195 | 4.29 | |
bta05205:Proteoglycans in cancer | 0.010665 | 4.41 | |
bta05207:Chemical carcinogenesis—receptor activation | 0.013152 | 4.19 | |
bta03320:PPAR signaling pathway | 0.015762 | 7.44 | |
bta05200:Pathways in cancer | 0.023839 | 2.50 | |
bta04928:Parathyroid hormone synthesis, secretion, and action | 0.031038 | 5.74 |
Category | Term | p-Value | FE |
---|---|---|---|
GO_BP | GO:0006357~regulation of transcription from RNA polymerase II promoter | <0.000001 | 3.58 |
GO:0030182~neuron differentiation | <0.000001 | 9.61 | |
GO:0009952~anterior/posterior pattern specification | <0.000001 | 10.47 | |
GO:0045944~positive regulation of transcription from RNA polymerase II promoter | <0.000001 | 3.21 | |
GO:0035115~embryonic forelimb morphogenesis | <0.000001 | 19.57 | |
GO:0048706~embryonic skeletal system development | <0.000001 | 18.85 | |
GO:0048704~embryonic skeletal system morphogenesis | <0.000001 | 14.14 | |
GO:0001764~neuron migration | 0.000002 | 7.32 | |
GO:0030154~cell differentiation | 0.000006 | 3.21 | |
GO:0045893~positive regulation of transcription, DNA-templated | 0.000007 | 3.76 | |
KEGG_PATH | bta04020:Calcium signaling pathway | 0.000001 | 4.19 |
bta05200:Pathways in cancer | 0.000002 | 2.93 | |
bta04310:Wnt signaling pathway | 0.000027 | 4.54 | |
bta04916:Melanogenesis | 0.000040 | 5.99 | |
bta04015:Rap1 signaling pathway | 0.000046 | 3.98 | |
bta04724:Glutamatergic synapse | 0.000096 | 5.36 | |
bta05224:Breast cancer | 0.000162 | 4.48 | |
bta05207:Chemical carcinogenesis—receptor activation | 0.000204 | 3.67 | |
bta04727:GABAergic synapse | 0.000679 | 5.37 | |
bta05226:Gastric cancer | 0.000858 | 3.99 |
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Muroya, S.; Ojima, K.; Shimamoto, S.; Sugasawa, T.; Gotoh, T. Promoter H3K4me3 and Gene Expression Involved in Systemic Metabolism Are Altered in Fetal Calf Liver of Nutrient-Restricted Dams. Int. J. Mol. Sci. 2025, 26, 7540. https://doi.org/10.3390/ijms26157540
Muroya S, Ojima K, Shimamoto S, Sugasawa T, Gotoh T. Promoter H3K4me3 and Gene Expression Involved in Systemic Metabolism Are Altered in Fetal Calf Liver of Nutrient-Restricted Dams. International Journal of Molecular Sciences. 2025; 26(15):7540. https://doi.org/10.3390/ijms26157540
Chicago/Turabian StyleMuroya, Susumu, Koichi Ojima, Saki Shimamoto, Takehito Sugasawa, and Takafumi Gotoh. 2025. "Promoter H3K4me3 and Gene Expression Involved in Systemic Metabolism Are Altered in Fetal Calf Liver of Nutrient-Restricted Dams" International Journal of Molecular Sciences 26, no. 15: 7540. https://doi.org/10.3390/ijms26157540
APA StyleMuroya, S., Ojima, K., Shimamoto, S., Sugasawa, T., & Gotoh, T. (2025). Promoter H3K4me3 and Gene Expression Involved in Systemic Metabolism Are Altered in Fetal Calf Liver of Nutrient-Restricted Dams. International Journal of Molecular Sciences, 26(15), 7540. https://doi.org/10.3390/ijms26157540