1. Supplementary Table 2. a The #CpG indicates the number of CpG in the sequence region. b The plus(+) and minus(-) indicate the presence and absence of CpG island, respectively. c The plus(+) and minus(-) indicate the presence and absence of candidate methylated site, respectively. d The minimum P-value shows the most significant p-value in the analyzed region. e The methylation (%) indicates the ratio of methyl CpG sites to all CpG sites.

2. Supplementary Table 3. Features of candidate methylated sites are shown. a The Obs/exp indicates the ratio of observed and expected CpG frequency. b Fold-enrichment was calculated based on population of ENCODE probes extracted randomly.

3. Supplementary Table 4: a The Upstream CMS shows a location of upstream CMS, if any, by a distance from a TSS. b The 5Aza+ indicates GeneChip score with 5Aza-dC treatment. c The 5Aza- indicates GeneChip socre without 5Aza-dC treatment.

4. Supplementary Figure 1: － 5Aza-dC 400 200 100 50 (ng) ＋ Genomic DNA and demethylated DNA were spotted on a nitrocellulose membrane at 50- 400ng. 1 st antibody: anti-methycytosine antibody, 2 nd antibody: HRP anti-rabbit IgG antibody

5. -5-4-3-20 0 -2 -3 -5 -4 Log 10 (P) - Log 10 (P) 32 16 8 4 1 2 123450 MeDIP1 vs.. Control1 ( n = 1 ) Control1 vs. Control2 ( n = 1 ) MeDIPs vs. Controls ( n = 2 ) MeDIP1 vs. Control1 ( n = 1 ) MeDIPs vs. Controls ( n = 2 ) The scanned tiling array data were analyzed with Tiling Array Analysis Software (Affymetrix). The p-values analyzed in those combinations of 2 MeDIPs vs. 2 Controls, MeDIP1 vs. Control1, Control1 vs. Control2 were obtained. a Number of probes less than each threshold p-value was plotted for each result. b The rates of probe numbers due to threshold p-values were plotted. Supplementary Figure 2: AB

6. A Supplementary Figure 3:

10. B

14. C

17. High-resolution mapping of DNA methylation in the ENCODE region. Tracks for CMS (light green bar), -10×log10(p-value) (vertical yellow bar) and CGI (green bar) are shown. a DLD1, b HCT116, b SW480

18. Supplementary Figure 4: Bisulfite sequencing of CMS or non-CMS in HCT116. a Genomic view showing CMS on INHA (top). Tracks for sequenced region (pink bar), CMS (light green bar), -10×log10 (P-value) (vertical yellow bar) and CGI (green bar) are shown. Black horizontal bar indicates P=10 -2. Result of bisulfite sequencing (bottom). Closed circle and open circle indicate methylated CpG and unmethylated CpG, respectively. b TFEB, c CRAT A B C

19. Supplementary Figure 5: Results of bisulfite sequencing are shown described in Supplemental Table 3. Number 16 and 19 are shown in Supplemental Fig. 7, and number 17-18 and 26 are shown in Supplemental Fig 4. Number 28-40 are shown in Fig. 4. Closed circle and open circle indicate methylated CpG and unmethylated CpG, respectively.

20. Supplementary Figure 6: A DLD1_CMS

21. Supplementary Figure 6: B SW480_CM S High-resolution mapping of DNA methylation on the HOXA cluster. Tracks for CMS (light green bar), - 10×log10(p-value) (vertical yellow bar) and CGI (green bar) are shown. a DLD1, b SW480

22. Supplementary Figure 7: A B Comparison of methylation patterns among three colorectal cancer cell lines. a The Venn diagram of CMS in three cell lines. If CMS overlapped at least by one base, we regard them as overlapped CMS. b and c High-resolution mapping of DNA methylation for EXT1 and CFTR, respectively. Tracks for sequenced region (blue bar). CMS and -10 × log10(p-value) are shown in yellow bar for DLD1, green for HCT116, and purple for SW480. Results of sequencing are shown at the bottom. C

23. Supplementary Figure 8: MSP analysis of genes overexpressed after 5Aza-dC treatment. a and b High-resolution mapping of DNA methylation for TKTL1 and EXT1, respectively.

24. TKTL1: transketolase-like 1 SERPINB2: serpin peptidase inhibitor, clade B, member 2 CTAG2: cancer/testis antigen 2 CTAG1B: cancer/testis antigen 1B PDLIM4: PDZ and LIM domain 4 CTGF: connective tissue growth factor CDH2: N-cadherin EXT1: exostoses1 RFPL2: ret finger protein-like 2 AXIN1: axin 1 -10×log(P-value) HCT116_CM S -10×log(P-value) HCT116_CM S -10×log(P-value) HCT116_CM S -10×log(P-value) HCT116_CM S -10×log(P-value) HCT116_CM S -10×log(P-value) HCT116_CM S -10×log(P-value) HCT116_CM S -10×log(P-value) HCT116_CM S -10×log(P-value) HCT116_CM S -10×log(P-value) Supplementary Figure 9: DNA methylation maps of genes 10 top-ranking genes overexpressed after 5Aza-dC treatment are shown. Tracks for CMS (light green bar), -10×log 10 (p-value) (vertical yellow bar) and CGI (green bar), Repeat Masker (black bar) are shown.