Epigenetic regulation of the intestinal epithelium

Cellular and Molecular Life Sciences

Volumn 72, Issue 21, 2015, Pages 4139-4156

  Elliott, Ellen N ^a   Kaestner, Klaus H ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Colorectal cancer; DNA methylation; Epigenetics; Intestinal epithelium

Indexed keywords

DNA METHYLTRANSFERASE 1; DNA METHYLTRANSFERASE 3A; DNA METHYLTRANSFERASE 3B; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR CDX2; CHROMATIN; HISTONE; NOTCH RECEPTOR; NUCLEOSOME;

CELL DIFFERENTIATION; CELL PROLIFERATION; CHROMATIN ASSEMBLY AND DISASSEMBLY; CHROMOSOMAL INSTABILITY; COLORECTAL DISEASE; DNA METHYLATION; EPIGENETICS; FAMILIAL COLON POLYPOSIS; HETEROZYGOSITY LOSS; HISTONE MODIFICATION; HOMEOSTASIS; HUMAN; INTESTINAL STEM CELL; INTESTINE CRYPT; INTESTINE EPITHELIUM; INTESTINE EPITHELIUM CELL; INTESTINE VILLUS; MICROSATELLITE INSTABILITY; MISMATCH REPAIR; MOUSE MODEL; NEXT GENERATION SEQUENCING; NONHUMAN; NOTCH SIGNALING PATHWAY; NUCLEOSOME; REVIEW; SIGNAL TRANSDUCTION; STEM CELL NICHE; TRANSCRIPTION REGULATION; WNT SIGNALING PATHWAY; ANIMAL; CHROMATIN; COLORECTAL TUMOR; CYTOLOGY; ENTEROPATHY; EXPERIMENTAL NEOPLASM; GENETIC EPIGENESIS; GENETICS; INTESTINE MUCOSA; MAMMAL; METABOLISM; MOUSE; PATHOLOGY; PHYSIOLOGY; STEM CELL; ULTRASTRUCTURE;

ANIMALS; CELL DIFFERENTIATION; CHROMATIN; COLORECTAL NEOPLASMS; DNA METHYLATION; EPIGENESIS, GENETIC; HISTONES; HUMANS; INTESTINAL DISEASES; INTESTINAL MUCOSA; MAMMALS; MICE; NEOPLASMS, EXPERIMENTAL; NUCLEOSOMES; RECEPTORS, NOTCH; STEM CELLS; TRANSCRIPTION FACTORS; WNT SIGNALING PATHWAY;

EID: 84944151101     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-015-1997-9     Document Type: Review

References (193)

1. Waddington CH (2012) The epigenotype. 1942. Int J Epidemiol 41:10-13
2. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A (2009) An operational definition of epigenetics. Genes Dev 23:781-783
3. Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447:407-412
4. Sandoval J, Esteller M (2012) Cancer epigenomics: beyond genomics. Curr Opin Genet Dev 22:50-55
5. You JS, Jones PA (2012) Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 22:9-20
6. Runtsch MC, Round JL, O'Connell RM (2014) MicroRNAs and the regulation of intestinal homeostasis. Front Genet 5:347
7. Slaby O, Svoboda M, Michalek J, Vyzula R (2009) MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer 8:102
8. Croce CM (2009) Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10:704-714
9. Suzuki H, Maruyama R, Yamamoto E, Kai M (2013) Epigenetic alteration and microRNA dysregulation in cancer. Front Genet 4:258
10. Schetter AJ, Okayama H, Harris CC (2012) The role of microRNAs in colorectal cancer. Cancer J 18:244-252
11. Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389:251-260
12. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074-1080
13. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693-705
14. Kim TH, Barrera LO, Zheng M et al (2005) A high-resolution map of active promoters in the human genome. Nature 436:876-880
15. Barski A, Cuddapah S, Cui K et al (2007) High-resolution profiling of histone methylations in the human genome. Cell 129:823-837
16. Krivtsov AV, Armstrong SA (2007) MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7:823-833
17. Thirman MJ, Gill HJ, Burnett RC et al (1993) Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations. N Engl J Med 329:909-914
18. Venkatesh S, Smolle M, Li H et al (2012) Set2 methylation of histone H3 lysine 36 suppresses histone exchange on transcribed genes. Nature 489:452-455
19. Li F, Mao G, Tong D et al (2013) The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell 153:590-600
20. Luco RF, Pan Q, Tominaga K, Blencowe BJ, Pereira-Smith OM, Misteli T (2010) Regulation of alternative splicing by histone modifications. Science 327:996-1000
21. Creyghton MP, Cheng AW, Welstead GG et al (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA 107:21931-21936
22. Tie F, Banerjee R, Stratton CA et al (2009) CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing. Development 136:3131-3141
23. Ong CT, Corces VG (2011) Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet 12:283-293
24. Sheaffer KL, Kim R, Aoki R et al (2014) DNA methylation is required for the control of stem cell differentiation in the small intestine. Genes Dev 28:652-664
25. Lister R, Pelizzola M, Dowen RH et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315-322
26. Stadler MB, Murr R, Burger L et al (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480:490-495
27. Ziller MJ, Gu H, Müller F et al (2013) Charting a dynamic DNA methylation landscape of the human genome. Nature 500:477-481
28. Margueron R, Reinberg D (2011) The Polycomb complex PRC2 and its mark in life. Nature 469:343-349
29. Zee BM, Levin RS, Xu B, LeRoy G, Wingreen NS, Garcia BA (2010) In vivo residue-specific histone methylation dynamics. J Biol Chem 285:3341-3350
30. Peters AH, Kubicek S, Mechtler K et al (2003) Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol Cell 12:1577-1589
31. Boyer LA, Plath K, Zeitlinger J et al (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441:349-353
32. Shen X, Liu Y, Hsu YJ et al (2008) EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell 32:491-502
33. Pasini D, Bracken AP, Hansen JB, Capillo M, Helin K (2007) The polycomb group protein Suz12 is required for embryonic stem cell differentiation. Mol Cell Biol 27:3769-3779
34. Faust C, Schumacher A, Holdener B, Magnuson T (1995) The eed mutation disrupts anterior mesoderm production in mice. Development 121:273-285
35. O'Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T (2001) The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol 21:4330-4336
36. Margueron R, Reinberg D (2010) Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet 11:285-296
37. Bilodeau S, Kagey MH, Frampton GM, Rahl PB, Young RA (2009) SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes Dev 23:2484-2489
38. Smith ZD, Meissner A (2013) DNA methylation: roles in mammalian development. Nat Rev Genet 14:204-220
39. Takai D, Jones PA (2002) Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci USA 99:3740-3745
40. Saxonov S, Berg P, Brutlag DL (2006) A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci USA 103:1412-1417
41. Okano M, Xie S, Li E (1998) Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 19:219-220
42. Leonhardt H, Page AW, Weier HU, Bestor TH (1992) A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71:865-873
43. Jones PA, Liang G (2009) Rethinking how DNA methylation patterns are maintained. Nat Rev Genet 10:805-811
44. Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915-926
45. Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247-257
46. Jackson M, Krassowska A, Gilbert N et al (2004) Severe global DNA hypomethylation blocks differentiation and induces histone hyperacetylation in embryonic stem cells. Mol Cell Biol 24:8862-8871
47. Tsumura A, Hayakawa T, Kumaki Y et al (2006) Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells 11:805-814
48. Liao J, Karnik R, Gu H et al (2015) Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat Genet 47:469-478
49. Nichols J, Smith A (2009) Naive and primed pluripotent states. Cell Stem Cell 4:487-492
50. Irizarry RA, Ladd-Acosta C, Wen B et al (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41:178-186
51. Tate PH, Bird AP (1993) Effects of DNA methylation on DNA-binding proteins and gene expression. Curr Opin Genet Dev 3:226-231
52. Jones PL, Veenstra GJ, Wade PA et al (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19:187-191
53. Nan X, Ng HH, Johnson CA et al (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386-389
54. Viré E, Brenner C, Deplus R et al (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871-874
55. Bartolomei MS, Zemel S, Tilghman SM (1991) Parental imprinting of the mouse H19 gene. Nature 351:153-155
56. Holliday R, Pugh JE (1975) DNA modification mechanisms and gene activity during development. Science 187:226-232
57. Venolia L, Gartler SM (1983) Comparison of transformation efficiency of human active and inactive X-chromosomal DNA. Nature 302:82-83
58. Li E, Beard C, Jaenisch R (1993) Role for DNA methylation in genomic imprinting. Nature 366:362-365
59. Plasschaert RN, Bartolomei MS (2014) Genomic imprinting in development, growth, behavior and stem cells. Development 141:1805-1813
60. Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28:1057-1068
61. Schuettengruber B, Martinez AM, Iovino N, Cavalli G (2011) Trithorax group proteins: switching genes on and keeping them active. Nat Rev Mol Cell Biol 12:799-814
62. Lessard JA, Crabtree GR (2010) Chromatin regulatory mechanisms in pluripotency. Annu Rev Cell Dev Biol 26:503-532
63. Lessard J, Wu JI, Ranish JA et al (2007) An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55:201-215
64. Reisman D, Glaros S, Thompson EA (2009) The SWI/SNF complex and cancer. Oncogene 28:1653-1668
65. Clapier CR, Cairns BR (2009) The biology of chromatin remodeling complexes. Annu Rev Biochem 78:273-304
66. Xue Y, Wong J, Moreno GT, Young MK, Côté J, Wang W (1998) NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell 2:851-861
67. Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP (1999) Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat Genet 23:62-66
68. Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D (1999) Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev 13:1924-1935
69. Kaji K, Caballero IM, MacLeod R, Nichols J, Wilson VA, Hendrich B (2006) The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat Cell Biol 8:285-292
70. Reynolds N, Salmon-Divon M, Dvinge H et al (2012) NuRD-mediated deacetylation of H3K27 facilitates recruitment of Polycomb Repressive Complex 2 to direct gene repression. EMBO J 31:593-605
71. Croft JA, Bridger JM, Boyle S, Perry P, Teague P, Bickmore WA (1999) Differences in the localization and morphology of chromosomes in the human nucleus. J Cell Biol 145:1119-1131
72. Guelen L, Pagie L, Brasset E et al (2008) Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453:948-951
73. Wen B, Wu H, Shinkai Y, Irizarry RA, Feinberg AP (2009) Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nat Genet 41:246-250
74. Ye Q, Worman HJ (1996) Interaction between an integral protein of the nuclear envelope inner membrane and human chromodomain proteins homologous to Drosophila HP1. J Biol Chem 271:14653-14656
75. Gruenbaum Y, Foisner R (2015) Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. Annu Rev Biochem 84:131-164
76. Kind J, Pagie L, Ortabozkoyun H et al (2013) Single-cell dynamics of genome-nuclear lamina interactions. Cell 153:178-192
77. Peric-Hupkes D, Meuleman W, Pagie L et al (2010) Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol Cell 38:603-613
78. Finlan LE, Sproul D, Thomson I et al (2008) Recruitment to the nuclear periphery can alter expression of genes in human cells. PLoS Genet 4:e1000039
79. Kumaran RI, Spector DL (2008) A genetic locus targeted to the nuclear periphery in living cells maintains its transcriptional competence. J Cell Biol 180:51-65
80. Reddy KL, Zullo JM, Bertolino E, Singh H (2008) Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature 452:243-247
81. Berman BP, Weisenberger DJ, Aman JF et al (2012) Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat Genet 44:40-46
82. Hon GC, Hawkins RD, Caballero OL et al (2012) Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res 22:246-258
83. Hansen KD, Timp W, Bravo HC et al (2011) Increased methylation variation in epigenetic domains across cancer types. Nat Genet 43:768-775
84. Estève PO, Chin HG, Smallwood A et al (2006) Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev 20:3089-3103
85. Smallwood A, Estève PO, Pradhan S, Carey M (2007) Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev 21:1169-1178
86. Dialynas GK, Vitalini MW, Wallrath LL (2008) Linking Heterochromatin Protein 1 (HP1) to cancer progression. Mutat Res 647:13-20
87. Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89-92
88. Gama-Sosa MA, Slagel VA, Trewyn RW et al (1983) The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res 11:6883-6894
89. Cheng H, Leblond CP (1974) Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. I. Columnar cell. Am J Anat 141:461-479
90. Gerbe F, Legraverend C, Jay P (2012) The intestinal epithelium tuft cells: specification and function. Cell Mol Life Sci 69:2907-2917
91. Noah TK, Donahue B, Shroyer NF (2011) Intestinal development and differentiation. Exp Cell Res 317:2702-2710
92. Barker N, van Es JH, Kuipers J et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003-1007
93. Fearon ER (2011) Molecular genetics of colorectal cancer. Annu Rev Pathol 6:479-507
94. van der Flier LG, Haegebarth A, Stange DE, van de Wetering M, Clevers H (2009) OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137:15-17
95. Barker N, van Oudenaarden A, Clevers H (2012) Identifying the stem cell of the intestinal crypt: strategies and pitfalls. Cell Stem Cell 11:452-460
96. Tian H, Biehs B, Warming S et al (2011) A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478:255-259
97. Takeda N, Jain R, LeBoeuf MR, Wang Q, Lu MM, Epstein JA (2011) Interconversion between intestinal stem cell populations in distinct niches. Science 334:1420-1424
98. + secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 14:1099-1104
99. Kuhnert F, Davis CR, Wang HT et al (2004) Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc Natl Acad Sci USA 101:266-271
100. Pinto D, Gregorieff A, Begthel H, Clevers H (2003) Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17:1709-1713
101. Korinek V, Barker N, Moerer P et al (1998) Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 19:379-383
102. Sato T, van Es JH, Snippert HJ et al (2011) Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469:415-418
103. Durand A, Donahue B, Peignon G et al (2012) Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1). Proc Natl Acad Sci USA 109:8965-8970
104. San Roman AK, Jayewickreme CD, Murtaugh LC, Shivdasani RA (2014) Wnt secretion from epithelial cells and subepithelial myofibroblasts is not required in the mouse intestinal stem cell niche in vivo. Stem Cell Reports 2:127-134
105. Kabiri Z, Greicius G, Madan B et al (2014) Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development 141:2206-2215
106. van der Flier LG, Clevers H (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 71:241-260
107. Lee CS, Kaestner KH (2004) Clinical endocrinology and metabolism. Development of gut endocrine cells. Best Pract Res Clin Endocrinol Metab 18:453-462
108. Cummings DE, Overduin J (2007) Gastrointestinal regulation of food intake. J Clin Invest 117:13-23
109. Kreymann B, Williams G, Ghatei MA, Bloom SR (1987) Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 2:1300-1304
110. Mojsov S, Weir GC, Habener JF (1987) Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest 79:616-619
111. Troughton WD, Trier JS (1969) Paneth and goblet cell renewal in mouse duodenal crypts. J Cell Biol 41:251-268
112. Porter EM, Bevins CL, Ghosh D, Ganz T (2002) The multifaceted Paneth cell. Cell Mol Life Sci 59:156-170
113. Gerbe F, van Es JH, Makrini L et al (2011) Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. J Cell Biol 192:767-780
114. Gerbe F, Brulin B, Makrini L, Legraverend C, Jay P (2009) DCAMKL-1 expression identifies Tuft cells rather than stem cells in the adult mouse intestinal epithelium. Gastroenterology 137:2179-2180 (author reply 2180-2171)
115. Westphalen CB, Asfaha S, Hayakawa Y et al (2014) Long-lived intestinal tuft cells serve as colon cancer-initiating cells. J Clin Invest 124:1283-1295
116. Nakanishi Y, Seno H, Fukuoka A et al (2013) Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat Genet 45:98-103
117. May R, Riehl TE, Hunt C, Sureban SM, Anant S, Houchen CW (2008) Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice. Stem Cells 26:630-637
118. Jensen J, Pedersen EE, Galante P et al (2000) Control of endodermal endocrine development by Hes-1. Nat Genet 24:36-44
119. Zheng X, Tsuchiya K, Okamoto R et al (2011) Suppression of hath1 gene expression directly regulated by hes1 via notch signaling is associated with goblet cell depletion in ulcerative colitis. Inflamm Bowel Dis 17:2251-2260
120. Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY (2001) Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294:2155-2158
121. Shroyer NF, Helmrath MA, Wang VY, Antalffy B, Henning SJ, Zoghbi HY (2007) Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 132:2478-2488
122. VanDussen KL, Samuelson LC (2010) Mouse atonal homolog 1 directs intestinal progenitors to secretory cell rather than absorptive cell fate. Dev Biol 346:215-223
123. van Es JH, van Gijn ME, Riccio O et al (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435:959-963
124. VanDussen KL, Carulli AJ, Keeley TM et al (2012) Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development 139:488-497
125. Riccio O, van Gijn ME, Bezdek AC et al (2008) Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep 9:377-383
126. Carulli AJ, Keeley TM, Demitrack ES, Chung J, Maillard I, Samuelson LC (2015) Notch receptor regulation of intestinal stem cell homeostasis and crypt regeneration. Dev Biol 402:98-108
127. Pellegrinet L, Rodilla V, Liu Z et al (2011) Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 140:1230-1240 (e1231-1237)
128. van Es JH, de Geest N, van de Born M, Clevers H, Hassan BA (2010) Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors. Nat Commun 1:18
129. Kazanjian A, Noah T, Brown D, Burkart J, Shroyer NF (2010) Atonal homolog 1 is required for growth and differentiation effects of notch/gamma-secretase inhibitors on normal and cancerous intestinal epithelial cells. Gastroenterology 139:918-928 (928.e911-916)
130. Kim TH, Shivdasani RA (2011) Genetic evidence that intestinal Notch functions vary regionally and operate through a common mechanism of Math1 repression. J Biol Chem 286:11427-11433
131. Fre S, Huyghe M, Mourikis P, Robine S, Louvard D, Artavanis-Tsakonas S (2005) Notch signals control the fate of immature progenitor cells in the intestine. Nature 435:964-968
132. Stanger BZ, Datar R, Murtaugh LC, Melton DA (2005) Direct regulation of intestinal fate by Notch. Proc Natl Acad Sci USA 102:12443-12448
133. Noah TK, Shroyer NF (2013) Notch in the intestine: regulation of homeostasis and pathogenesis. Annu Rev Physiol 75:263-288
134. Blache P, van de Wetering M, Duluc I et al (2004) SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol 166:37-47
135. Fre S, Pallavi SK, Huyghe M et al (2009) Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci USA 106:6309-6314
136. Tian H, Biehs B, Chiu C et al (2015) Opposing activities of notch and wnt signaling regulate intestinal stem cells and gut homeostasis. Cell Rep 11:33-42
137. Gao N, White P, Kaestner KH (2009) Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2. Dev Cell 16:588-599
138. Gao N, Kaestner KH (2010) Cdx2 regulates endo-lysosomal function and epithelial cell polarity. Genes Dev 24:1295-1305
139. Verzi MP, Shin H, Ho LL, Liu XS, Shivdasani RA (2011) Essential and redundant functions of caudal family proteins in activating adult intestinal genes. Mol Cell Biol 31:2026-2039
140. Verzi MP, Shin H, He HH et al (2010) Differentiation-specific histone modifications reveal dynamic chromatin interactions and partners for the intestinal transcription factor CDX2. Dev Cell 19:713-726
141. Verzi MP, Shin H, San Roman AK, Liu XS, Shivdasani RA (2013) Intestinal master transcription factor CDX2 controls chromatin access for partner transcription factor binding. Mol Cell Biol 33:281-292
142. Kim TH, Li F, Ferreiro-Neira I et al (2014) Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity. Nature 506:511-515
143. Nguyen AT, Zhang Y (2011) The diverse functions of Dot1 and H3K79 methylation. Genes Dev 25:1345-1358
144. Okada Y, Feng Q, Lin Y et al (2005) hDOT1L links histone methylation to leukemogenesis. Cell 121:167-178
145. Mahmoudi T, Boj SF, Hatzis P et al (2010) The leukemia-associated Mllt10/Af10-Dot1 l are Tcf4/β-catenin coactivators essential for intestinal homeostasis. PLoS Biol 8:e1000539
146. Ho LL, Sinha A, Verzi M, Bernt KM, Armstrong SA, Shivdasani RA (2013) DOT1L-mediated H3K79 methylation in chromatin is dispensable for Wnt pathway-specific and other intestinal epithelial functions. Mol Cell Biol 33:1735-1745
147. Kaaij LT, van de Wetering M, Fang F et al (2013) DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus. Genome Biol 14:R50
148. Siegel R, Desantis C, Jemal A (2014) Colorectal cancer statistics, 2014. CA Cancer J Clin 64:104-117
149. Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50:113-130
150. Leary RJ, Lin JC, Cummins J et al (2008) Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers. Proc Natl Acad Sci USA 105:16224-16229
151. Wood LD, Parsons DW, Jones S et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108-1113
152. Vogelstein B, Fearon ER, Hamilton SR et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525-532
153. Network CGA (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330-337
154. Vilar E, Gruber SB (2010) Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 7:153-162
155. Aaltonen LA, Peltomäki P, Leach FS et al (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260:812-816
156. Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C (2003) The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer 3:695-701
157. Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386:623-627
158. Cahill DP, Lengauer C, Yu J et al (1998) Mutations of mitotic checkpoint genes in human cancers. Nature 392:300-303
159. Michel LS, Liberal V, Chatterjee A et al (2001) MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409:355-359
160. Galiatsatos P, Foulkes WD (2006) Familial adenomatous polyposis. Am J Gastroenterol 101:385-398
161. Su LK, Kinzler KW, Vogelstein B et al (1992) Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256:668-670
162. + in intestinal adenomas from Min mice. Cancer Res 54:5947-5952
163. Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP (1985) Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228:187-190
164. Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M (1988) Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res 48:1159-1161
165. Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R (1998) DNA hypomethylation leads to elevated mutation rates. Nature 395:89-93
166. Nakamura N, Takenaga K (1998) Hypomethylation of the metastasis-associated S100A4 gene correlates with gene activation in human colon adenocarcinoma cell lines. Clin Exp Metastasis 16:471-479
167. Lengauer C, Kinzler KW, Vogelstein B (1997) DNA methylation and genetic instability in colorectal cancer cells. Proc Natl Acad Sci U S A 94:2545-2550
168. Chen T, Hevi S, Gay F et al (2007) Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells. Nat Genet 39:391-396
169. Spada F, Haemmer A, Kuch D et al (2007) DNMT1 but not its interaction with the replication machinery is required for maintenance of DNA methylation in human cells. J Cell Biol 176:565-571
170. Cui H, Horon IL, Ohlsson R, Hamilton SR, Feinberg AP (1998) Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nat Med 4:1276-1280
171. Jones S, Li M, Parsons DW et al (2012) Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum Mutat 33:100-103
172. Suzuki H, Watkins DN, Jair KW et al (2004) Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36:417-422
173. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96:8681-8686
174. Weisenberger DJ, Siegmund KD, Campan M et al (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38:787-793
175. Issa JP (2004) CpG island methylator phenotype in cancer. Nat Rev Cancer 4:988-993
176. Nosho K, Shima K, Irahara N et al (2009) DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer. Clin Cancer Res 15:3663-3671
177. Eads CA, Danenberg KD, Kawakami K, Saltz LB, Danenberg PV, Laird PW (1999) CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res 59:2302-2306
178. Hinoue T, Weisenberger DJ, Lange CP et al (2012) Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res 22:271-282
179. Akhtar-Zaidi B, Cowper-Sal-lari R, Corradin O et al (2012) Epigenomic enhancer profiling defines a signature of colon cancer. Science 336:736-739
180. Ohm JE, McGarvey KM, Yu X et al (2007) A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39:237-242
181. Keshet I, Schlesinger Y, Farkash S et al (2006) Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat Genet 38:149-153
182. De Carvalho DD, Sharma S, You JS et al (2012) DNA methylation screening identifies driver epigenetic events of cancer cell survival. Cancer Cell 21:655-667
183. Schlesinger Y, Straussman R, Keshet I et al (2007) Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 39:232-236
184. Widschwendter M, Fiegl H, Egle D et al (2007) Epigenetic stem cell signature in cancer. Nat Genet 39:157-158
185. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546-1558
186. Moser AR, Pitot HC, Dove WF (1990) A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247:322-324
187. N/+ reduces the net growth rate and multiplicity of intestinal adenomas in C57BL/6-multiple intestinal neoplasia (Min)/+mice independently of p53 but demonstrates strong synergy with the modifier of Min 1(AKR) resistance allele. Cancer Res 60:3965-3970
188. Eads CA, Nickel AE, Laird PW (2002) Complete genetic suppression of polyp formation and reduction of CpG-island hypermethylation in Apc(Min/+) Dnmt1-hypomorphic Mice. Cancer Res 62:1296-1299
189. Yamada Y, Jackson-Grusby L, Linhart H et al (2005) Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc Natl Acad Sci USA 102:13580-13585
190. Linhart HG, Lin H, Yamada Y et al (2007) Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev 21:3110-3122
191. Lin H, Yamada Y, Nguyen S et al (2006) Suppression of intestinal neoplasia by deletion of Dnmt3b. Mol Cell Biol 26:2976-2983
192. Elliott EN, Sheaffer KL, Schug J, Stappenbeck TS, Kaestner KH (2015) Dnmt1 is essential to maintain progenitors in the perinatal intestinal epithelium. Development 142:2163-2172
193. Perreault N, Sackett SD, Katz JP, Furth EE, Kaestner KH (2005) Foxl1 is a mesenchymal Modifier of Min in carcinogenesis of stomach and colon. Genes Dev 19:311-315