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Table 1 Molecular signatures observed on chromatin in normal and cancer cells

From: Molecular marks for epigenetic identification of developmental and cancer stem cells

Epigenetic changes Chromatin modification observed in normal cell Modification observed in cancer cell
Type of modification on respective gene Effect of modification Reference Type of cancer Type of modification on respective gene Reference
DNA methylation In hESCs, cancer-related genes, including tumor suppressor genes, are repressed by the establishment of “bivalent chromatin domains” consisting of activating (H3 lysine 27 methylation) and repressing (H3 lysine 4 methylation) histone marks that make them poised for activation. Balance those gene expression or suppression. (Schlesinger et al. 2007; Ohm et al. 2007; Widschwendter et al. 2007) Adult cancer cell In adult cancer cell, the promoter region of the gene immediately hypermethylated and fully stopped them from activation. (Schlesinger et al. 2007; Ohm et al. 2007; Widschwendter et al. 2007)
Class A-I (genes are primarily involved in early differentiation processes and more enriched in Polycomb and bivalent marks) cancer-related genes were not hypermethylated in hESC and normal tissue. Regulation of normal developmetal process (Calvanese et al. 2008) Adult cancer cell. Class-I genes were hypermethylated in adult cancer cell. (Calvanese et al. 2008)
Class A-II genes were sometimes methylated in normal tissue but uncommon in hESC. Methylation may be important for linage specification (Calvanese et al. 2008) Cancer cell These genes were frequently methylated in cancer cell line and it became abnormal when it was not hypermethylated in the corresponding normal tissue. (Calvanese et al. 2008)
Promoter region of Class B-I genes (excluding ASCL2, NPY, and SLC5A8 genes) are frequently hypermethylated in hESCs cells lines but never in normal tissues. DNA methylation maintain pluripotency in cancer sten cell and hESC. (Calvanese et al. 2008) cancer cell Class B-I gene are also hypermethylated in cancer stem-cell line and responsible for their pluripotency. (Calvanese et al. 2008)
Class B-II genes(associated with those linked to lineage specification) are often hypermethylated in hESCs and sometimes methylated in normal tissues Important for linage specification (Calvanese et al. 2008) Cancer cell These genes are also hypermethylated in cancer cell line. Their hypermethylation in cancer were considered aberrant in tumor types when the related gene is completely unmethylated in the normal cell. (Calvanese et al. 2008)
AIM2 and RUNX3, that were hypermethylated and repressed in CD34+ hematopoietic progenitor cells and that became unmethylated and overexpressed in myeloid and lymphoid lineages, respectively Maintain linage specification (Li et al. 2002; Woerner et al. 2007) Gastric cancer, colon cancer Hemizygous deletion and hypermethylation in the promoter region of RUNX3 gene was observed in gastric cancer and in colon cancer promoter region of AIM2 was hypermethylated. (Li et al. 2002; Woerner et al. 2007)
Stat3 and Tcf3 binding site on the upstream (−4,880 to −3,790 bp) of Nanog gene is hypomethylated in ES   (Hattori et al. 2007; Gu et al. 2005; Pereira et al. 2006)    
Gcnf binding site on upstream (−2,050 to −1,800 bp) is hypermethylated in ES   (Hattori et al. 2007)    
Six proximal CpG site of Oct-4, Sox2 and p53 regulator binding site in nenog gene (−1 to −1,000) is completely unmethylate and another ten distal CpG site is 29% methylated. Activate Nanog expression (Kuroda et al. 2005; Lin et al. 2005; Hattori et al. 2007; Rodda et al. 2005)    
Oct-4 gene regulatory region displays quite a unique DNA methylation pattern regulated by specific cis-elements such as Sp1 or Sp3 binding sites. Expression control of the gene (Hattori et al. 2004)    
the SOX2 protein is expressed in normal gastric mucosae Inhibited cell proliferation through cell-cycle (G1) arrest and apoptosis (Otsubo et al. 2008) Gastric cancer Half of the case of gastric cancer (three out of six) promoter region of Sox2 gene is hypermethylated and lowering the expression of SOX2 protein. (Otsubo et al. 2008)
The sex-determining region Y-box 7 (Sox7) normally express in embryonic stem cell and some differentiated depend on cell type Is a transcription factor, essential for embryonic development and endoderm differentiation   Prostate adenocarcinomas and primary prostate tumors A study shows that in 47% of the prostate adenocarcinomas and 48% of the primary prostate tumors SOX7 gene were downregulated through promoter hypermethylation . (Guo et al. 2008)
    Lung carcinoma SOX7, SOX18 promoter region methylated in lung carcinoma. (Dammann et al. 2005)
    Colorectal cancer SOX17 promoter region hypermethylated in colorectal cancer. (Zhang et al. 2008a)
The sex-determining region Y-box 7 (Sox7) normally express in embryonic stem cell and some differentiated depend on cell type    Colorectal cancer Sox7 promoter region is hypermethylated in colorectal cancer (Zhang et al. 2009)
  sFRPs and DKK1 as secreted Wnt antagonists acting at cell membrane to prevent ligand-receptor interactions and APC degrade b-catenin or export b-catenin from the nuclear to cytoplasm   Colorectal cancer Promoter hypermethylation occurs at sFRPs, DKK1, and APC genes, which are key genes in colorectal cancer development. (Caldwell et al. 2004; Esteller et al. 2000; Aguilera et al. 2006)
In normal embryonic ureteal and bladder cell, only the sixth binding site of CTCF insulator protein on the promoter region of human H19 gene is allele-specific methylation. Controlled the normal expression of H19 gene (Takai et al. 2001) Bladder cancer Aberrant hypomethylation observed at sixth CTCF binding site in parenal allele causes overexperssion of H19. (Takai et al. 2001)
Allele-specific normal methylation pattern at the sixth CTCF binding site at H19 promoter region in normal cell. Controlled the normal expression of H19 gene (Takai et al. 2001) Wilms' tumor and colon cancer Hypermethylation occur at sixth CTCF binding site in maternal allele. (Takai et al. 2001)
Allele-specific normal methylation pattern at the sixth CTCF binding site at H19 promoter region in normal cell. Controlled the normal expression of H19 gene (Takai et al. 2001) Lung cancer Hypomethylation of that site and biallelic expression of H19 gene observe (Takai et al. 2001)
In normal squamous cell, repetitive sequence classes including SINEs, LINEs, subtelomeric repeats, and segmental duplications are hypermethylated.   (Pfeifer and Rauch 2009) Squamous cell tumors In squamous cell tumors, repetitive DNA sequences are hypomethylated at CpG island. (Pfeifer and Rauch 2009)
   (Pfeifer and Rauch 2009)   Multiple methylated CpG islands present in four HOX gene loci on chromosomes 2, 7, 12, and 17, so these are the hotspots region for tumor-associated methylation (Pfeifer and Rauch 2009)
The p57KIP2 gene, a cyclin-dependent kinase inhibitor in the kinase-interacting protein (KIP) family is unmethylated in normal tissue Tumor suppressor gene (Hagiwara et al. 2010) Lymphocytic leukemia and lung cancer DNA methylation inactive this tumor suppressor gene. (Hagiwara et al. 2010; Shen et al. 2003; Pateras et al. 2006)
DNMT3L promoter region is methylated in normal differentiated cell.   (Gokul et al. 2009) Squamous cell carcinoma of cervix and cervical cancer cell Loss of DNA methylation at the DNMT3L promoter region observe in this cancer cell. Overexpression of DNMT3L regulates DNMT3A and DNMT3B activity which result into cell proliferation and induce independent growth (Gokul et al. 2009)
Hypermethylation not observed in normal placenta.   (Zhang et al. 2008b) Choriocarcinoma. seminoma and embryonal carcinoma Minimal promoter and exon 1 regions of Oct4 are both hypermethylated in choriocarcinoma. In gonadal germ cell tumors, specifically seminoma and embryonal carcinoma Oct4 expression become lower. (Zhang et al. 2008b; Lau and Chang 2006)
Histone modification The level of H3-K9 and H3-K27 methylation of the Nanog proximal and distal tissue specific differentially methylated regions (T-DMR) is low in ICM cells then TE cells and differentiated cell. Activate nanog expression in ES cell (Hattori et al. 2007)    
H3-K4 trimethylation and H3-K4 dimethylation level is high at the Nanog proximal and distal T-DMR in ICM then TE cells Assist chromatin relaxation in ICM (Hattori et al. 2007)    
H3-K9 and H3-K27 methylation of Oct4 gene T-DMR is low in both ES and TS cell compare to nanog gene H3-K9 and H3-K27 is not more important for Oct4 gene expression (Hattori et al. 2007)    
H3-K4 tri- and di-methylation level is high at the Oct-4 gene T-DMR in ICM then TE cells Assist chromatin relaxation in ICM (Hattori et al. 2007)    
In normal cell early growth response 1 (EGR1) gene, inhibition is not observed. EGR1 gene expressed. (Lubieniecka et al. 2008) Synovial sarcoma In these cancer cells, H3K27me3 modification and polycomb group protein recruitment occur at the promoter region of the tumor suppressor gene EGR1 by the SS18-SSX protein. 137
In ESCs, Nanog gene H3 and H4 is hyperactylated in the proximal and distal T-DMR then differentiated cell Nanog expression ES cell (Hattori et al. 2007)    
  H3 and H4 is also hyperacetylated in Oct4 gene upstream region. Nanog expression ES cell (Hattori et al. 2007)    
The SOX2 protein is expressed in normal gastric mucosae Inhibited cell proliferation through cell-cycle (G1) arrest and apoptosis (Otsubo et al. 2008) Gastric cancer Some SOX2 expression-negative cases did not show any DNA methylation but they re-establish SOX2 expression after treatment with a histone deacetylase inhibitor TSA in gastric cancer cell line MKN7. It may represent that histone modification also involves in SOX2 expression. (Otsubo et al. 2008)
H3K4 and H3K27 methylation two of the most important histone methylation marks in normal cell. Regulate gene expression (Chi et al. 2010) Human myeloid and lymphoid leukemias H3K4 methylation is increased by the MLL (mixed lineage leukemia) gene rearrangement and increase level of H3K4-specific HMT expression. (Chi et al. 2010; Krivtsov and Armstrong 2007; Milne et al. 2002; Nakamura et al. 2002)
Prostate, breast, colon, skin and lung cancer EZH2, an H3K27-specific methyltransferase, overexpression in various solid tumors may increase the H3K27 methylation and disrupt the normal activity in cancer cell. (Chi et al. 2010)
  LSD1 demethylates H3K4me2/1. Repress the invasiveness and metastasis of breast cancer cells. (Wang et al. 2009b) Breast carcinoma LSD1 downregulates. (Wang et al. 2009b)
Ubiquitination In normal cell, polycomb group protein Bmi1 and histone H2A monoubiquitination suppress oncogene expression.   (Barco et al. 2009) Synovial sarcoma SYT-SSX2 recruitment promotes the displacement and/or degradation of Bmi1 protein and histone H2A hypoubiquitination which is responsible for the reactivation of polycomb-repressed genes. (Barco et al. 2009)
miRNA let-7 has very important role in the maintenance of stemness of stem cell and cancer stem cell. In ESCs, accumulation of let-7 related to the reduction of the level of LIN28, LIN28B and MYC (promote induction of pluripotency). MYC, RAS and HMGA2 oncogene expression and cell-cycle progression controlled by let -7. (Viswanathan et al. 2008; Newman et al. 2008; Johnson et al. 2007; Takamizawa et al. 2004; Lee and Dutta 2007; Mayr et al. 2007; Shell et al. 2007; Hebert et al. 2007; Wang et al. 2007; Johnson et al. 2005; Büssing et al. 2008) Breast cancer cell line, non-small-cell lung carcinoma In cancer, stem-cell let-7 expression is repressed. (Büssing et al. 2008; Yu et al. 2007b)
miR-145 negatively regulate the pluripotency of hESCs. miR-145 directly targeted the 3′ untranslated region of NANOG (in murine ESCs), OCT4, SOX2, KLF4 and inhibit the expression of these protein. Necessary for downregulation of pluripotency genes during differentiation. (Xu et al. 2009) Breast cancer, colorectal cancer, cervical cancer and lung adenocarcinoma miR-145 downregulate (Cho et al. 2009)
  1. See also Supplementary Table-II for Class A-I, Class A-II, Class B-I, and Class B-II genes