title: Maternal diabetes modulates dental epithelial stem cells proliferation and self-renewal in offspring through apurinic/apyrimidinicendonuclease 1-mediated DNA methylation.
abstract: Maternal gestational diabetes mellitus (GDM) has many adverse effects on the development of offspring. Aberrant DNA methylation is a potential mechanism associated with these effects. However, the effects of GDM on tooth development and the underlying mechanisms have not been thoroughly investigated. In the present study, a GDM rat model was established and incisor labial cervical loop tissue and dental epithelial stem cells (DESCs) were harvested from neonates of diabetic and control dams. GDM significantly suppressed incisor enamel formation and DESCs proliferation and self-renewal in offspring. Gene expression profiles showed that Apex1 was significantly downregulated in the offspring of diabetic dams. In vitro, gain and loss of function analyses showed that APEX1 was critical for DESCs proliferation and self-renewal and Oct4 and Nanog regulation via promoter methylation. In vivo, we confirmed that GDM resulted in significant downregulation of Oct4 and Nanog and hypermethylation of their promoters. Moreover, we found that APEX1 modulated DNA methylation by regulating DNMT1 expression through ERK and JNK signalling. In summary, our data suggest that GDM-induced APEX1 downregulation increased DNMT1 expression, thereby inhibiting Oct4 and Nanog expression, through promoter hypermethylation, resulting in suppression of DESCs proliferation and self-renewal, as well as enamel formation.
authors.affiliation: State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.|National Engineering Laboratory for Oral Regenerative Medicine, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.|National Engineering Laboratory for Oral Regenerative Medicine, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.|Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.|National Engineering Laboratory for Oral Regenerative Medicine, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.|Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.
authors.forename: Zhiling
authors.initials: Z
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.|National Engineering Laboratory for Oral Regenerative Medicine, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.|National Engineering Laboratory for Oral Regenerative Medicine, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.|National Engineering Laboratory for Oral Regenerative Medicine, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.|Department of Pedodontics, West China College of Stomatology, Sichuan University, No. 14, 3rd Section, Renmin South Road, Chengdu 610041, P. R. China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.|National Engineering Laboratory for Oral Regenerative Medicine, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.|Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Tian
mesh_terms: D000818:Animals; D001786:Blood Glucose; D049109:Cell Proliferation; D000066673:Cell Self Renewal / Q000235:genetics*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics; D019175:DNA Methylation; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics* / Q000378:metabolism; D003744:Dental Enamel Hypoplasia / Q000235:genetics; D016640:Diabetes, Gestational; D005260:Female; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D009024:Morphogenesis / Q000235:genetics; D000071317:Nanog Homeobox Protein / Q000235:genetics; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D011247:Pregnancy; D051381:Rats; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D014070:Tooth / Q000166:cytology*
chemical_list: D001786:Blood Glucose; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619382:Dnmt1 protein, rat; C470319:Apex1 protein, rat; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase