title: Genome-wide demethylation by 5-aza-2'-deoxycytidine alters the cell fate of stem/progenitor cells.
abstract: DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR) is able to cause DNA demethylation in the genome and induce the expression of silenced genes. Whether DNA demethylation can affect the gene expression of stem/progenitor cells has not been understood. Mouse utricle epithelia-derived progenitor cells (MUCs), which possess stem cell features as previously described, exhibit a potential DNA methylation status in the genome. In this study, MUCs were treated with 5-aza-CdR to determine whether DNMT inhibitor is able to induce the differentiation of MUCs. With 5-aza-CdR treatment for 72 hr, MUCs expressed epithelial genes including Cdh1, Krt8, Krt18, and Dsp. Further, hair cell genes Myo7a and Myo6 increased their expressions in response to 5-aza-CdR treatment. The decrease in the global methylated DNA values after 5-aza-CdR treatment indicated a significant DNA demethylation in the genome of MUCs, which may contribute to remarkably increased expression of epithelial genes and hair cell genes. The progenitor MUCs then turned into an epithelial-like hair cell fate with the expression of both epithelial and hair cell genes. This study suggests that stem cell differentiation can be stimulated by DNA demethylation, which may open avenues for studying stem cell fate induction using epigenetic approaches.
authors.affiliation: Department of Otolaryngology-HNS, Wayne State University School of Medicine, 550 E Canfield St. 258, Lande Detroit, MI, 48201, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Zhengqing
authors.initials: Z
authors.lastname: Hu
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D064200:Cdh1 Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016678:Genome / Q000235:genetics*; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects / Q000378:metabolism; D053533:Keratin-8 / Q000235:genetics; D051379:Mice; D018995:Myosin Heavy Chains / Q000235:genetics; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012444:Saccule and Utricle / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D064200:Cdh1 Proteins; D004791:Enzyme Inhibitors; C577585:Fzr1 protein, mouse; D053533:Keratin-8; C486595:Krt8 protein, mouse; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; C089785:myosin VI; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D018995:Myosin Heavy Chains; D009218:Myosins; D001374:Azacitidine
references.citation: Nat Med. 2003 Oct;9(10):1293-9
references.pmid: 12949502
references.citation: J Neurosci. 1995 Apr;15(4):3013-26
references.pmid: 7722642
references.citation: Hear Res. 2013 Mar;297:106-12
references.pmid: 23370457
references.citation: Stem Cells Dev. 2012 Jul 1;21(10):1812-21
references.pmid: 22014028
references.citation: Stem Cells. 2012 Jan;30(1):69-74
references.pmid: 22102534
references.citation: Genes Chromosomes Cancer. 2009 Sep;48(9):828-41
references.pmid: 19530241
references.citation: Biochimie. 2012 Nov;94(11):2202-11
references.pmid: 22634371
references.citation: BMC Cancer. 2010 Jul 12;10:366
references.pmid: 20618997
references.citation: PLoS One. 2014 Mar 06;9(6):e90846
references.pmid: 24603866
references.citation: Trends Amplif. 2012 Mar;16(1):4-18
references.pmid: 22514095
references.citation: Stem Cells. 2011 Nov;29(11):1645-9
references.pmid: 21948625
references.citation: Mol Cell Biol. 1999 Nov;19(11):7327-35
references.pmid: 10523621
references.citation: Cancer Res. 1998 Jan 1;58(1):95-101
references.pmid: 9426064
references.citation: J Cell Physiol. 2007 Aug;212(2):330-44
references.pmid: 17458893
references.citation: Cancer Res. 2005 Aug 15;65(16):7086-90
references.pmid: 16103056
references.citation: Science. 2001 Aug 10;293(5532):1068-70
references.pmid: 11498573
references.citation: Hear Res. 2009 Mar;249(1-2):15-22
references.pmid: 19185606
references.citation: Development. 2004 Sep;131(17):4119-30
references.pmid: 15319325
references.citation: Hear Res. 2010 Jul;266(1-2):18-25
references.pmid: 20438823
references.citation: Trends Biochem Sci. 2006 Feb;31(2):89-97
references.pmid: 16403636
references.citation: Cancer Sci. 2006 Jan;97(1):64-71
references.pmid: 16367923
references.citation: Clin Epigenetics. 2011 Aug;2(2):339-48
references.pmid: 22704346
references.citation: Regen Med. 2013 May;8(3):309-18
references.pmid: 23627825
references.citation: Clin Cancer Res. 2000 Nov;6(11):4243-8
references.pmid: 11106238
references.citation: J Assoc Res Otolaryngol. 2007 Mar;8(1):18-31
references.pmid: 17171473
references.citation: Leuk Res. 2010 Jul;34(7):899-905
references.pmid: 20381863
references.citation: Annu Rev Neurosci. 2013 Jul 8;36:361-81
references.pmid: 23724999
references.citation: Oncogene. 2002 Aug 12;21(35):5483-95
references.pmid: 12154409
references.citation: Int J Mol Med. 2011 May;27(5):625-35
references.pmid: 21373750
references.citation: Cancer Res. 2002 Feb 15;62(4):961-6
references.pmid: 11861364
references.citation: Gene. 2002 May 1;289(1-2):41-8
references.pmid: 12036582
references.citation: Mol Cell Biol. 2005 Jun;25(11):4727-41
references.pmid: 15899874
references.citation: J Assoc Res Otolaryngol. 2008 Mar;9(1):65-89
references.pmid: 18157569
references.citation: Neuron. 2013 Jan 9;77(1):58-69
references.pmid: 23312516
references.citation: Nature. 2007 May 24;447(7143):396-8
references.pmid: 17522671
references.citation: Nature. 2006 Jun 22;441(7096):984-7
references.pmid: 16791196
references.citation: Pharmacol Ther. 2014 Jun;142(3):339-50
references.pmid: 24384533
references.citation: Microbiol Rev. 1991 Sep;55(3):451-8
references.pmid: 1943996
references.citation: Genes Dev. 2002 Jan 1;16(1):6-21
references.pmid: 11782440
references.citation: Nat Rev Neurosci. 2006 Nov;7(11):837-49
references.pmid: 17053809