Whole Genome DNA Methylation Analysis of Active Pulmonary Tuberculosis Disease Identifies Novel Epigenotypes: PARP9/miR-505/RASGRP4/GNG12 Gene Methylation and Clinical Phenotypes
Abstract
:1. Introduction
2. Results
2.1. Demographics of the Participants
2.2. Whole Genome DNA Methylation Profiles of the Discovery Cohort
2.3. Enrichment Pathway Analysis of the Differentially Methylated Genes
2.4. Differential DNA Methylation Levels of the PARP9, MIR505, RASGRP4, and GNG12 Genes in Active TB Patients Versus HS in the Validation Cohort
2.5. Association of Aberrant DNA Methylation Levels of the GNG12, WIPI2, MRPS18B, and FOXO3 Genes with One-Year Survival in TB Patients in the Validation Cohort
2.6. Aberrant DNA Methylaion Levels of the MRPS18B, RASGRP4, and RPTOR Genes in TB Patients with High Bacterial Burden or Pleural Involvement
2.7. Reversion of Altered DNA Methylation Levels of the CCR6 and RASGRP4 Genes in Active TB Patients after Anti-TB Treatment in the Validation Cohort
2.8. Effects of In Vitro Mtb-Specific Antigen Stimuli on DNA Methylation Levels and Gene Expressions of the 9 Candidate Genes
3. Discussion
4. Materials and Methods
4.1. Study Subjects
4.2. Genome-Wide DNA Methylation Assay and Data Analysis
4.3. Measurement of DNA Methylation and Gene Expression Levels of Selected Genes in the PBMC Samples from the Validation COHORT
4.4. In Vitro Cell Culture Model under Specific TB Antigen Stimuli
4.5. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
Mtb | mycobacterium tuberculosis |
CpG | cytosine guanine di-nucleotides |
PBMC | peripheral blood mononuclear cell |
LD | linear dichroism |
HS | healthy subject |
AFB | acid fast bacilli |
CXR | chest X-radiograph |
PCR | polymerase chain reaction |
ESAT-6 | early secretory antigen target 6 |
CFP-10 | culture filtrate antigenic protein 10 |
LPS | lipopolysaccharide |
DML | differentially methylated loci |
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Characteristics | Discovery Cohort | Validation Cohort | ||||
---|---|---|---|---|---|---|
TB patients N = 12 | Healthy Subjects N = 6 | p Value * | TB Patients N = 64 | Healthy Subjects N = 24 | p Value * | |
Age, years | 65.8 ± 12.1 | 64.3 ± 4.7 | 0.775 | 62.7 ± 14.3 | 62.9 ± 8.4 | 0.939 |
Male sex, n (%) | 12 (100) | 6 (100) | 0.587 | 46 (71.9) | 17 (70.8) | 0.923 |
Co-morbidity, n (%) | ||||||
Hypertension | 2 (16.7) | 0 (0) | 0.289 | 12 (18.8) | 3 (12.5) | 0.487 |
Diabetes mellitus | 4 (33.3) | 1 (16.7) | 0.457 | 22 (34.4) | 7 (29.2) | 0.643 |
COPD/Asthma | 3 (25) | 0 (0) | 0.18 | 7 (10.9) | 4 (16.7) | 0.469 |
Chronic hepatitis | 1 (8.3) | 2 (33.3) | 0.187 | 12 (18.8) | 3 (12.5) | 0.487 |
Chronic kidney disease | 3 (25) | 0 (0) | 0.18 | 8 (12.5) | 1 (4.2) | 0.251 |
Heart failure | 1 (8.3) | 0 (0) | 0.467 | 5 (7.8) | 3 (12.5) | 0.496 |
Alcoholism, n (%) | 1 (8.3) | 0 (0) | 0.467 | 5 (7.8) | 1 (4.2) | 0.546 |
Smoking history, n (%) | 4 (33.3) | 1 (16.7) | 0.457 | 19(29.7) | 6 (25) | 0.664 |
Sputum smear at diagnosis, n (%) | ||||||
Acid fast bacilli 0 | 1 (8.3) | 16 (25) | ||||
Acid fast bacilli 1+ | 1 (8.3) | 14 (21.9) | ||||
Acid fast bacilli 2+ | 0 (0) | 10 (15.6) | ||||
Acid fast bacilli 3+ | 6 (50) | 10 (15.6) | ||||
Acid fast bacilli 4+ | 4 (33.3) | 14 (21.9) | ||||
Drug-resistant TB, n (%) | 4 (33.3) | 11 (17.2) | ||||
CXR at diagnosis, n (%) | ||||||
Far advanced lesions | 9 (75) | 38 (59.4) | ||||
Minimal to moderate | 3 (25) | 26 (40.6) | ||||
Systemic symptoms, n (%) | 21 (25.9) | 13 (23.6) | ||||
Fever | 9 (11.1) | 3 (5.5) | ||||
Body weight loss | 2 (12.7) | 6 (10.9) |
UCSC RefGene Name | UCSC RefGene Accession | UCSCRefGene Group | Chromosome | Mean Difference | p-Value | q Value | Column ID |
---|---|---|---|---|---|---|---|
PLEKHG4B | NM_052909 | Body | 5 | −0.31 | 0.000101145 | 0.443008 | cg18816122 |
LARP4B | NM_015155 | Body | 10 | −0.251 | 0.000571043 | 0.221504 | cg05931497 |
KRT17 | NM_000422 | TSS1500 | 17 | −0.237 | 0.000259746 | 0.221504 | cg08058191 |
KIAA1257 | NM_020741 | Body | 3 | −0.223 | 0.00731796 | 0.443008 | cg25752703 |
ETF1 | NM_004730 | 3’UTR | 5 | −0.213 | 0.00201464 | 0.443008 | cg21141827 |
LRPAP1 | NM_002337 | Body | 4 | −0.211 | 0.00277208 | 0.443008 | cg08472008 |
AATK | NM_001080395 | Body | 17 | −0.207 | 0.00167958 | 0.443008 | cg20814202 |
ELL2 | NM_012081 | Body | 5 | −0.206 | 0.00299245 | 0.443008 | cg16998950 |
ITSN1 | NM_003024 | 5’UTR | 21 | −0.205 | 0.00352359 | 0.443008 | cg16452651 |
LOC100270710 | NR_026754 | TSS200 | 10 | −0.2 | 0.000444703 | 0.221504 | cg27570256 |
ADAP1 | NM_006869 | Body | 7 | −0.196 | 4.12 × 10−5 | 0.110752 | cg18332229 |
KCNQ1 | NM_000218 | Body | 11 | −0.195 | 0.00712947 | 0.110752 | cg03155200 |
FBXO6;FBXO44 | NM_018438 | TSS1500;3’UTR | 1 | −0.194 | 0.00438873 | 0.443008 | cg01554529 |
HDAC4 | NM_006037 | Body | 2 | −0.194 | 0.00271246 | 0.110752 | cg22077197 |
KIFC1 | NM_002263 | TSS1500 | 6 | −0.183 | 0.000102932 | 0.110752 | cg15206171 |
ARNT | NM_178427 | Body | 1 | −0.181 | 3.82 × 10−5 | 0.221504 | cg00944785 |
AUH | NM_001698 | Body | 9 | −0.181 | 0.000697739 | 0.443008 | cg13932501 |
MTHFR | NM_005957 | Body | 1 | −0.181 | 0.000697402 | 0.221504 | cg17514528 |
FLJ22536 | NR_015410 | Body | 6 | −0.178 | 0.00158527 | 0.221504 | cg16804603 |
PRKCZ | NM_001033581 | Body | 1 | −0.176 | 0.0015181 | 0.443008 | cg17435831 |
ZNF827 | NM_178835 | Body | 4 | −0.176 | 0.00195335 | 0.443008 | cg19116959 |
SBNO2 | NM_014963 | 5’UTR | 19 | −0.175 | 0.00141277 | 0.443008 | cg18004847 |
NID1 | NM_002508 | Body | 1 | −0.174 | 0.00382673 | 0.443008 | cg26837399 |
BCOR | NM_001123384 | 5’UTR | X | −0.173 | 0.00514341 | 0.443008 | cg10055320 |
IPCEF1;OPRM1 | NM_001130699 | Body | 6 | −0.173 | 0.000163433 | 0.110752 | cg27296341 |
CHMP4B | NM_176812 | TSS1500 | 20 | −0.172 | 0.000977403 | 0.443008 | cg03355213 |
NDUFS2 | NM_004550 | 5’UTR | 1 | −0.172 | 0.00099 | 0.221504 | cg05656486 |
TEAD3 | NM_003214 | Body | 6 | −0.172 | 0.00240499 | 0.443008 | cg23254569 |
GFI1 | NM_005263 | TSS1500 | 1 | −0.171 | 0.0036827 | 0.443008 | cg09674502 |
WDFY4 | NM_020945 | TSS200 | 10 | −0.17 | 0.000167422 | 0.110752 | cg04749316 |
ATP5A1;HAUS1 | NM_001001937 | 5’UTR;TSS1500 | 18 | −0.168 | 0.00584364 | 0.221504 | cg18069568 |
PTPN7 | NM_002832 | Body | 1 | −0.168 | 0.00219543 | 0.443008 | cg17932662 |
SRBD1 | NM_018079 | Body | 2 | −0.165 | 0.00426648 | 0.443008 | cg12939390 |
BRF1 | NM_001519 | Body | 14 | −0.164 | 0.00796682 | 0.443008 | cg19676553 |
C21orf56 | NM_032261 | 5’UTR; 1stExon | 21 | −0.164 | 0.000173268 | 0.221504 | cg25545878 |
KLF5 | NM_001730 | Body | 13 | −0.164 | 0.009382 | 0.110752 | cg04339360 |
GSN | NM_001127664; | 5’UTR | 9 | −0.163 | 0.00313606 | 0.443008 | cg13569051 |
RBM47 | NM_001098634 | 5’UTR | 4 | −0.163 | 0.00304298 | 0.110752 | cg20789700 |
TBCD | NM_005993 | Body | 17 | −0.163 | 0.0172711 | 0.443008 | cg06218079 |
TLR4 | NM_138554 | Body;3’UTR | 9 | −0.161 | 0.00184428 | 0.443008 | cg14605396 |
ANKRD34B | NM_001004441 | 5’UTR | 5 | −0.158 | 0.00012512 | 0.110752 | cg24834873 |
DEPDC1 | NM_001114120 | TSS1500 | 1 | −0.158 | 0.000861252 | 0.443008 | cg18167921 |
CLCC1 | NM_001048210 | Body | 1 | −0.157 | 0.00119716 | 0.443008 | cg06756164 |
CUBN | NM_001081 | Body | 10 | −0.157 | 0.00110262 | 0.110752 | cg07732336 |
CSGALNACT1 | NM_018371 | TSS200 | 8 | −0.156 | 0.00218679 | 0.443008 | cg18325192 |
C19orf71 | NM_001135580 | TSS1500 | 19 | −0.155 | 0.0232128 | 0.443008 | cg17344770 |
EDARADD | NM_080738 | Body | 1 | −0.155 | 0.0455698 | 0.443008 | cg15086439 |
MGAT5B | NM_144677 | TSS1500 | 17 | −0.155 | 0.000162922 | 0.443008 | cg25923214 |
SLFN12L | NM_001145027 | Body | 17 | −0.155 | 0.000474321 | 0.443008 | cg11855615 |
SSH1 | NM_001161330 | Body | 12 | −0.155 | 0.00924305 | 0.221504 | cg21224380 |
WBSCR17 | NM_022479 | Body | 7 | −0.153 | 2.51E-05 | 0.221504 | cg16533336 |
HOXB2 | NM_002145 | TSS200 | 17 | −0.152 | 0.000734653 | 0.221504 | cg09313705 |
SPRYD4 | NM_207344 | 3’UTR | 12 | −0.152 | 0.0067393 | 0.110752 | cg17554464 |
INF2 | NM_022489 | 5’UTR | 14 | −0.149 | 0.00905403 | 0.443008 | cg01836137 |
MIR223 | NR_029637 | TSS200 | X | −0.149 | 0.000317282 | 0.110752 | cg19127840 |
RNASE3 | NM_002935 | 5’UTR | 14 | −0.149 | 0.000488913 | 0.221504 | cg09842118 |
AOAH | NM_001637 | Body | 7 | −0.148 | 0.00129482 | 0.221504 | cg00390511 |
PARP9;DTX3L | NM_001146106 | 5’UTR; TSS1500 | 3 | −0.148 | 0.00594526 | 0.110752 | cg22930808 |
MRPS18B;PPP1R10 | NM_014046;NM_002714 | Body;TSS1500 | 6 | 0.113 | 0.000298705 | 0.221504 | cg04176995 |
ABCC1 | NM_019862 | Body | 16 | 0.116 | 1.33 × 10−5 | 0.110752 | cg04981696 |
ERH; SLC39A9 | NM_004450 | 1stExon;5’UTR;TSS1500 | 14 | 0.116 | 5.09 × 10−5 | 0.221504 | cg04509559 |
BPI | NM_001725 | TSS200 | 20 | 0.117 | 0.000144623 | 0.443008 | cg01948217 |
EIF2C2 | NM_012154 | Body | 8 | 0.123 | 0.00544777 | 0.443008 | cg19352830 |
PLAG1;CHCHD7 | NM_001114635 | 5’UTR;TSS1500; | 8 | 0.124 | 2.14 × 10−5 | 0.110752 | cg01994308 |
LOC400759 | NR_003133 | TSS1500 | 1 | 0.138 | 3.85 × 10−6 | 0.110752 | cg13454346 |
HSPA8 | NM_006597 | Body | 11 | 0.139 | 0.00331157 | 0.221504 | cg03309938 |
LIME1 | NM_017806 | TSS1500 | 20 | 0.139 | 2.92 × 10−6 | 0.110752 | cg14977069 |
CPT1A | NM_001876;NM_001031847 | 5’UTR;5’UTR | 11 | 0.152 | 7.96 × 10−6 | 0.110752 | cg19081843 |
RPTOR | NM_001163034 | Body | 17 | 0.164 | 0.000764449 | 0.443008 | cg10035831 |
MICAL3 | NM_015241 | TSS200 | 22 | 0.18 | 1.51 × 10−5 | 0.000394 | cg05367846 |
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Chen, Y.-C.; Hsiao, C.-C.; Chen, T.-W.; Wu, C.-C.; Chao, T.-Y.; Leung, S.-Y.; Eng, H.-L.; Lee, C.-P.; Wang, T.-Y.; Lin, M.-C. Whole Genome DNA Methylation Analysis of Active Pulmonary Tuberculosis Disease Identifies Novel Epigenotypes: PARP9/miR-505/RASGRP4/GNG12 Gene Methylation and Clinical Phenotypes. Int. J. Mol. Sci. 2020, 21, 3180. https://doi.org/10.3390/ijms21093180
Chen Y-C, Hsiao C-C, Chen T-W, Wu C-C, Chao T-Y, Leung S-Y, Eng H-L, Lee C-P, Wang T-Y, Lin M-C. Whole Genome DNA Methylation Analysis of Active Pulmonary Tuberculosis Disease Identifies Novel Epigenotypes: PARP9/miR-505/RASGRP4/GNG12 Gene Methylation and Clinical Phenotypes. International Journal of Molecular Sciences. 2020; 21(9):3180. https://doi.org/10.3390/ijms21093180
Chicago/Turabian StyleChen, Yung-Che, Chang-Chun Hsiao, Ting-Wen Chen, Chao-Chien Wu, Tung-Ying Chao, Sum-Yee Leung, Hock-Liew Eng, Chiu-Ping Lee, Ting-Ya Wang, and Meng-Chih Lin. 2020. "Whole Genome DNA Methylation Analysis of Active Pulmonary Tuberculosis Disease Identifies Novel Epigenotypes: PARP9/miR-505/RASGRP4/GNG12 Gene Methylation and Clinical Phenotypes" International Journal of Molecular Sciences 21, no. 9: 3180. https://doi.org/10.3390/ijms21093180