Extended Data Table 1 |.
Correlation data analysis of 5hmC in diabetes, glucose/TET2 co-regulated genes and metformin impact on blood glucose
| a | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Correlation between 5hmC and various health parameters. | |||||||||||
| Health Parameters | Beta Coefficient | P-value | |||||||||
| Presence of diabetes | −13.51 | 0.0001 | |||||||||
| BMI | −0.8 | <0.0001 | |||||||||
| Age | −0.51 | <0.0001 | |||||||||
| Systolic blood pressure | −0.33 | 0.007 | |||||||||
| HbAlC | −0.23 | <0.05 | |||||||||
|
b | |||||||||||
| Downregulated in Normal-g vs.High-g | CYB561D1 | FDXl | FAM195A | TACC3 | NUP85 | HSPH1 | HAUS7 | IMPDH1 | ZNF408 | SLC25A19 | |
| GTSE1 | RPL13P5 | CDC73 | PLEKHB2 | SLC25A15 | FOXM1 | ESF1 | NUDT19 | NOP2 | NCAPH | ||
| LSM10 | REX04 | MCM7 | NR3C1 | PDCD7 | C12orf44 | TCOF1 | WASF1 | LYPD1 | PAN3 | ||
| MRPL47 | MRPL35 | HOXB2 | RALA | TIPIN | GNG10 | BRI3BP | NOP14 | RPS27L | TMEM98 | ||
| RINT1 | STOM | SOCS7 | SASS6 | GTF2E2 | ITGAE | Clorfl09 | XP04 | CEP55 | FAM73B | ||
| NME7 | ANKRD33B | DOLPP1 | ORC4 | MRPL46 | WDR77 | EP400 | TMEM201 | TEAD4 | HHEX | ||
| TSR1 | CXorf40A | NIPA2 | EXOl | ZZZ3 | ARMC6 | PNP | GLRX2 | ACOT9 | IQCB1 | ||
| SVIP | UNC119 | KIF14 | GPNMB | HSPA9 | TMEM55B | CRADD | QRICH1 | MFHAS1 | MT1H | ||
| M6PR | RFC4 | SPAG5 | CENPA | C15orf61 | SNRPA1 | GABPB1 | MCM6 | C19orf48 | MAP4K3 | ||
| C5orf30 | BCL2L12 | KIFC1 | LCLAT1 | DSCC1 | BRIX1 | TOMM22 | BUB1B | EXOSC8 | CRY1 | ||
| NSUN5P2 | C10orf32 | RAN | ZNF576 | MY019 | KIAA0101 | ORC6 | NCAPD3 | HOXCIO | C9orf40 | ||
| CHEK1 | PIGU | DSN1 | FGF13 | ACYP1 | OPHN1 | LSG1 | TAF5 | HYI | AMOTL2 | ||
| SHROOM2 | TCEAL8 | MDH1 | DARS2 | CHST10 | C2orf47 | STRA13 | RNF26 | RNASEH2C | EPHA2 | ||
| YRDC | SETD8 | WDR36 | IP05 | ADM | TRMT11 | UBE2C | MRPL15 | RNMTL1 | GLRX5 | ||
| RWDD3 | GADD45A | ANP32B | RAD54L2 | SERTAD2 | ADO | RFC3 | TSNAX | RRS1 | |||
| MTPAP | C16orf80 | H2AFX | PPID | METRNL | KIAA0947 | ZNF330 | Clorfll2 | MCM3 | |||
| MSTOl | CDC5L | FOXD1 | RNF149 | RRP7A | PPP6C | FST | CKS1B | SERTAD1 | |||
| VARS2 | DDX5 | DUS1L | PDRG1 | CCT3 | LRRC58 | DCTPP1 | ANAPC4 | CHKA | |||
| EZR | OSBPL3 | KIAA1033 | Cllorf31 | CENPN | Clorf9 | P2RX5 | CRNKL1 | SUV39H1 | |||
| TFDP1 | DUT | TGS1 | CTCF | LI MAI | NSUN2 | DDX46 | MMGT1 | ABL2 | |||
| MAD2L1BP | CDC45 | UBE2T | CCNB1 | ETF1 | EIF3B | HOXB7 | SRRM1 | HIST1H2BK | |||
| ASNSD1 | UBR7 | BTAF1 | COIL | FLRT3 | CASP7 | CDC26 | TIPARP | POLA1 | |||
| ZNF783 | CKAP2L | PTPLB | PCID2 | ZNF721 | ZC3HC1 | SDC1 | EMP1 | ERCC6L | |||
| COXIO | ARL4A | PPAT | POGK | DHX33 | SRXN1 | RBM25 | NOL11 | POLE2 | |||
| RBM22 | C20orf20 | TYW3 | NUP50 | IRS2 | ZWINT | PAK1IP1 | URM1 | ZNF274 | |||
| PNN | NUBP1 | DNAJB14 | LZIC | TMEM97 | PRIM1 | CDCA3 | BYSL | CDCA5 | |||
| SMC2 | SMNDC1 | UTP20 | SRRM2 | WDR45L | BAZ1A | AGPAT9 | PIGW | ATAD5 | |||
| MPHOSPH10 | MKI67 | ADCY6 | BTBD6 | LIG1 | FLNB | CCNT1 | MSL1 | WDR85 | |||
| CCDC101 | ACBD3 | SHQ1 | DCLRE1A | UQCRFS1 | MYBL2 | FANCI | BLM | C8orf73 | |||
| TIGD5 | NANP | CHERP | NAA40 | POP7 | CPSF7 | POLR3K | PFAS | ATP6V0E2 | |||
| Upregulated in Normal-g vs.High-g | ERCC5 | SERPINB1 | ZCCHC24 | KDM5B | PSIP1 | GLG1 | LGALS1 | NEU1 | PSAP | RASA1 | PPA1 |
| PAN2 | YPEL5 | TNC | PCY0X1 | IMPACT | NES | TULP3 | ETV4 | DHX32 | DYNLT1 | UBAC2 | |
| C3orf32 | RABAC1 | STX18 | RALY | NDUFA9 | SPA17 | SLK | CXXC5 | GTSF1 | MAN2B1 | DNASE2 | |
| PRKCD | BUD13 | MAGED2 | PIGH | CCDC104 | BRMS1 | PLDN | SNX1 | GPX4 | ARAP1 | SF3B14 | |
| SH3BP5 | STOML2 | FAM60A | WDR45 | HEBP1 | ATRN | SPSB2 | SHISA5 | CD97 | NGFRAP1 | ||
| DALRD3 | EMP3 | CALHM2 | PKIG | LDLRAP1 | AP3B1 | SYTL5 | GDE1 | PLA2G12A | RWDD4 | ||
| B4GALT2 | MLKL | APOA1BP | CREBL2 | STX16 | BAX | RDH11 | PIM3 | EIF5A | MECR | ||
| TLCD1 | NRIP1 | COL16A1 | AKR1A1 | GNAI2 | CTSB | PYCRL | GOLGA5 | CCNG1 | PFDN1 | ||
| GGPS1 | PLOD1 | TOR1B | MRC2 | COX17 | NAPRT1 | ZNF512B | PLP1 | KDELR3 | C17orf48 | ||
| MAML2 | SPATA20 | CYBA | POLR2G | UQCRQ | BSG | LHFPL2 | UPRT | IDE | PFDN5 | ||
| TMEM181 | TRIOBP | BLMH | SCO 2 | TAF6 | PREX1 | LOC401397 | POT1 | AMFR | POR | ||
| SPESP1 | C21orf33 | G6PD | LOC645212 | SNX30 | TMEM41B | HAGHL | RALGDS | LEPREL4 | LGALS3 | ||
| ELP4 | RPS6KB2 | KIAA0319L | SLC26A2 | TCF7L2 | PACSIN3 | FAM116A | GTF2A1 | SDHA | CDK5 | ||
| GBAS | HOXA5 | NFU1 | FAF2 | LGALS8 | TSHZ1 | RBL2 | GLT25D1 | GNAQ | MFSD10 | ||
| LOC147727 | NT5E | HAPLN1 | ACADVL | ZYG11B | DCP1A | HIBCH | LAMBI | SH3GLB1 | VPS11 | ||
| SLC39A1 | CEP192 | CKB | KCTD3 | ARL2 | PRKCI | ATG4A | SLC25A6 | TTC13 | HINT2 | ||
| C10orfl25 | TPD52L1 | C6orf70 | SLU7 | DAP | CAB39 | IGF2BP3 | EIF2A | IFI30 | VPS4A | ||
| 0CEL1 | PAPSS2 | S100A3 | SCAMPI | NRAS | CETN3 | EAPP | FAM108C1 | TTC32 | ESYT1 | ||
| CYFIP1 | PPP1CA | MANSC1 | SMYD3 | ABR | BCKDK | IL13RA2 | ATP5A1 | IGBP1 | MLL5 | ||
| BBS2 | MYH10 | ATP6AP1 | CLIP4 | PMVK | TBCE | SCANDI | SLC44A1 | UGGT1 | MGAT4B | ||
| HMGCL | AMOTL1 | PRKAR1A | MYBBP1A | MBTPS1 | RB1CC1 | CD70 | TMEM192 | FAM82A2 | RAB11FIP5 | ||
| FZD7 | SNHG8 | HSD17B8 | HTRA2 | TWF2 | SV2A | ARL6IP5 | DTX3L | PRPSAP2 | KIAA1143 | ||
| OSTF1 | SIDT2 | DECR1 | RFXANK | Clorf85 | TSPAN31 | LOC152217 | LCMT1 | ATG9A | AP2B1 | ||
| C6orfl20 | KIAA1191 | SNX10 | SLC25A46 | C5orf54 | EIF4B | TTC19 | AGGF1 | ZMYND8 | SDHC | ||
| FAM125A | C4orf52 | POLR3GL | MTFMT | ROBOl | BCKDHA | NDRG3 | DHX40 | SRP14 | MTAP | ||
| FKBP2 | SFRP1 | ALKBH6 | ARPC1B | EMD | HADH | VPS29 | FKBP11 | FAM86A | TMEM14C | ||
| COG4 | FAM174A | PTGFRN | ZKSCAN1 | MTR | CBR3 | NDUFB5 | UBE2L6 | NECAP1 | DHX16 | ||
| MXI1 | NFATC2 | MPV17 | KCNN4 | PPP1R7 | GABARAP | EDEM1 | ACVR1 | VPS72 | EPS15 | ||
| FAM114A1 | SH3BGRL3 | PTPN14 | RNF181 | SERINC1 | FADS3 | CRELD2 | LOC642361 | AKR7A2 | HOXB3 | ||
| TCTN3 | RIN1 | C4orf48 | DSG2 | TSPAN14 | COX7A2 | RNF123 | ALDH2 | NT5DC1 | BNIP3 | ||
|
c | |||||||||||
| Status | Tumor | Metformin | Average Blood Glucose (mM) | Status | Tumor | Metformin | Average Blood Glucose (mM) | ||||
| Non-diabetic | TET2 | − | 6.30±0.59 | Diabetic | TET2 | − | 12.94±2.27 | ||||
| TET2 | + | 5.65±0.73 | TET2 | + | 14.16±3.76 | ||||||
| Mock | − | 5.40±0.84 | Mock | − | 14.08±3.49 | ||||||
| Mock | + | 5.60±0.69 | Mock | + | 14.76±2.90 | ||||||
a, Univariate regression analysis showing presence of diabetes, BMI, age, systolic blood pressure, and HbA1c in association with 5hmC. These health parameters, particularly the presence of diabetes and HbA1c, are negatively correlated with 5hmC. n = 28 healthy donors and 29 diabetic patients. Two-sided t-test.
b, Glucose-modulated and TET2 dependent genes. Five hundred and eighty-five genes that are up- or downregulated in normal glucose compared to high glucose in A2058-TET2WT cells are listed. These genes had differential expression under normal glucose versus high glucose in A2058-TET2WT cells only, and not in A2058-TET2M or mock cells. These genes are defined as glucose-modulated and TET2-dependent. Expression profile of these genes is shown in Fig. 1h.
c, Blood glucose levels in diabetic and non-diabetic mice treated with or without metformin. Blood glucose levels were measured on the last day of experiment. Metformin treatment did not alter blood glucose levels in either diabetic or non-diabetic mice. n = 4–5, data shown as mean ± s.d.