Gender-specific postnatal demethylation and establishment of epigenetic memory.
DNA methylation patterns are set up in a relatively fixed programmed manner during normal embryonic development and are then stably maintained. Using genome-wide analysis, we discovered a postnatal pathway involving gender-specific demethylation that occurs exclusively in the male liver. This demodification is programmed to take place at tissue-specific enhancer sequences, and our data show that the methylation state at these loci is associated with and appears to play a role in the transcriptional regulation of nearby genes. This process is mediated by the secretion of testosterone at the time of sexual maturity, but the resulting methylation profile is stable and therefore can serve as an epigenetic memory even in the absence of this inducer. These findings add a new dimension to our understanding of the role of DNA methylation in vivo and provide the foundations for deciphering how environment can impact on the epigenetic regulation of genes in general.
Department of Developmental Biology and Cancer Research, Hebrew University Medical School, Jerusalem 91120, Israel;
Yitzhak
Y
Reizel
Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel;
Adam
A
Spiro
Department of Developmental Biology and Cancer Research, Hebrew University Medical School, Jerusalem 91120, Israel;
Ofra
O
Sabag
Department of Developmental Biology and Cancer Research, Hebrew University Medical School, Jerusalem 91120, Israel;
Yael
Y
Skversky
Department of Developmental Biology and Cancer Research, Hebrew University Medical School, Jerusalem 91120, Israel;
Merav
M
Hecht
Department of Developmental Biology and Cancer Research, Hebrew University Medical School, Jerusalem 91120, Israel;
Ilana
I
Keshet
Bioinformatics and Computational Biology Research Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Benjamin P
BP
Berman
Department of Developmental Biology and Cancer Research, Hebrew University Medical School, Jerusalem 91120, Israel; cedar@mail.huji.ac.il.
Howard
H
Cedar
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D002369:Castration; D019175:DNA Methylation / Q000187:drug effects; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012727:Sex Characteristics; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology
D000728:Androgens; D006657:Histones; D013739:Testosterone
DNA methylation; epigenetic memory; gender-specific genes; gene expression; liver