title: Stochastic anomaly of methylome but persistent SRY hypermethylation in disorder of sex development in canine somatic cell nuclear transfer.
abstract: Somatic cell nuclear transfer (SCNT) provides an excellent model for studying epigenomic reprogramming during mammalian development. We mapped the whole genome and whole methylome for potential anomalies of mutations or epimutations in SCNT-generated dogs with XY chromosomal sex but complete gonadal dysgenesis, which is classified as 78, XY disorder of sex development (DSD). Whole genome sequencing revealed no potential genomic variations that could explain the pathogenesis of DSD. However, extensive but stochastic anomalies of genome-wide DNA methylation were discovered in these SCNT DSD dogs. Persistent abnormal hypermethylation of the SRY gene was observed together with its down-regulated mRNA and protein expression. Failure of SRY expression due to hypermethylation was further correlated with silencing of a serial of testis determining genes, including SOX9, SF1, SOX8, AMH and DMRT1 in an early embryonic development stage at E34 in the XY(DSD) gonad, and high activation of the female specific genes, including FOXL2, RSPO1, CYP19A1, WNT4, ERα and ERβ, after one postnatal year in the ovotestis. Our results demonstrate that incomplete demethylation on the SRY gene is the driving cause of XY(DSD) in these XY DSD dogs, indicating a central role of epigenetic regulation in sex determination.
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.
authors: Young-Hee
authors: YH
authors: Jeong
authors: BGI-Shenzhen, Shenzhen, China.|Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.
authors: Hanlin
authors: H
authors: Lu
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.|Animal Bioscience and Biotechnology Laboratory, United States Department of Agriculture, Beltsville, MD, 20705, USA.|Department of Animal and Avian Sciences, University of Maryland, College Park, MD, 20742, USA.
authors: Chi-Hun
authors: CH
authors: Park
authors: BGI-Shenzhen, Shenzhen, China.
authors: Meiyan
authors: M
authors: Li
authors: BGI-Shenzhen, Shenzhen, China.
authors: Huijuan
authors: H
authors: Luo
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.
authors: Joung Joo
authors: JJ
authors: Kim
authors: BGI-Shenzhen, Shenzhen, China.
authors: Siyang
authors: S
authors: Liu
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.
authors: Kyeong Hee
authors: KH
authors: Ko
authors: BGI-Shenzhen, Shenzhen, China.
authors: Shujia
authors: S
authors: Huang
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.
authors: In Sung
authors: IS
authors: Hwang
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.
authors: Mi Na
authors: MN
authors: Kang
authors: BGI-Shenzhen, Shenzhen, China.|Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.
authors: Desheng
authors: D
authors: Gong
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.
authors: Kang Bae
authors: KB
authors: Park
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.
authors: Eun Ji
authors: EJ
authors: Choi
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.
authors: Jung Hyun
authors: JH
authors: Park
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.
authors: Yeon Woo
authors: YW
authors: Jeong
authors: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Korea.
authors: Changjong
authors: C
authors: Moon
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.|College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea.
authors: Sang-Hwan
authors: SH
authors: Hyun
authors: College of Animal Sciences, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea.
authors: Nam Hyung
authors: NH
authors: Kim
authors: College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea.
authors: Eui-Bae
authors: EB
authors: Jeung
authors: BGI-Shenzhen, Shenzhen, China.
authors: Huanming
authors: H
authors: Yang
authors: Sooam Biotech Research Foundation, Seoul 152-904, Korea.
authors: Woo Suk
authors: WS
authors: Hwang
authors: BGI-Shenzhen, Shenzhen, China.|Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.
authors: Fei
authors: F
authors: Gao
mesh_terms: D000818:Animals; D019976:Cloning, Organism; D019175:DNA Methylation; D004195:Disease Models, Animal; D012734:Disorders of Sex Development / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D044127:Epigenesis, Genetic; D005260:Female; D006059:Gonadal Dysgenesis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008297:Male; D053652:Nuclear Transfer Techniques / Q000009:adverse effects*; D011247:Pregnancy; D019849:Sex Determination Processes; D051876:Sex-Determining Region Y Protein / Q000235:genetics*; D013269:Stochastic Processes; D013737:Testis / Q000196:embryology / Q000378:metabolism; D014998:Y Chromosome / Q000235:genetics
chemical_list: D051876:Sex-Determining Region Y Protein