Format

Send to

Choose Destination
Sci Rep. 2016 Aug 9;6:31088. doi: 10.1038/srep31088.

Stochastic anomaly of methylome but persistent SRY hypermethylation in disorder of sex development in canine somatic cell nuclear transfer.

Author information

1
Sooam Biotech Research Foundation, Seoul 152-904, Korea.
2
BGI-Shenzhen, Shenzhen, China.
3
Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.
4
Animal Bioscience and Biotechnology Laboratory, United States Department of Agriculture, Beltsville, MD, 20705, USA.
5
Department of Animal and Avian Sciences, University of Maryland, College Park, MD, 20742, USA.
6
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Korea.
7
College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea.
8
College of Animal Sciences, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea.

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.

PMID:
27501986
PMCID:
PMC4977463
DOI:
10.1038/srep31088
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center