Mammalian Genome

, Volume 23, Issue 5–6, pp 336–345 | Cite as

Bridging sequence diversity and tissue-specific expression by DNA methylation in genes of the mouse prolactin superfamily

  • Koji Hayakawa
  • Momo O. Nakanishi
  • Jun Ohgane
  • Satoshi Tanaka
  • Mitsuko Hirosawa
  • Michael J. Soares
  • Shintaro Yagi
  • Kunio Shiota


Much of the DNA in genomes is organized within gene families and hierarchies of gene superfamilies. DNA methylation is the main epigenetic event involved in gene silencing and genome stability. In the present study, we analyzed the DNA methylation status of the prolactin (PRL) superfamily to obtain insight into its tissue-specific expression and the evolution of its sequence diversity. The PRL superfamily in mice consists of two dozen members, which are expressed in a tissue-specific manner. The genes in this family have CpG-less sequences, and they are located within a 1-Mb region as a gene cluster on chromosome 13. We tentatively grouped the family into several gene clusters, depending on location and gene orientation. We found that all the members had tissue-dependent differentially methylated regions (T-DMRs) around the transcription start site. The T-DMRs are hypermethylated in nonexpressing tissues and hypomethylated in expressing cells, supporting the idea that the expression of the PRL superfamily genes is subject to epigenetic regulation. Interestingly, the DNA methylation patterns of T-DMRs are shared within a cluster, while the patterns are different among the clusters. Finally, we reconstituted the nucleotide sequences of T-DMRs by converting TpG to CpG based on the consideration of a possible conversion of 5-methylcytosine to thymine by spontaneous deamination during the evolutionary process. On the phylogenic tree, the reconstituted sequences were well matched with the DNA methylation pattern of T-DMR and orientation. Our study suggests that DNA methylation is involved in tissue-specific expression and sequence diversity during evolution.



This research was funded by grants from Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan (21221008 to Kunio Shiota), and the National Institute of Biomedical Innovation (NIBIO), Japan. We thank Dr. Naoko Hattori and Dr. Shinya Sato for their helpful suggestions regarding analysis.

Conflicts of interest

The authors have no conflicts of interest to declare.

Supplementary material

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Supplementary material 1 (XLS 35 kb)
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Supplementary material 2 (DOC 29 kb)
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Supplementary material 3: Supplementary Fig. 1: LINE-rich/SINE-poor proportions in mouse PRL superfamily gene cluster. Repeat markers were visualized by USCS genome browser (mm8) (TIFF 2322 kb)
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Supplementary material 4 (TIFF 5707 kb)
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Supplementary material 5 (TIFF 5927 kb)
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Supplementary material 6 (TIFF 4012 kb)
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Supplementary material 7 (TIFF 804 kb)


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Koji Hayakawa
    • 1
  • Momo O. Nakanishi
    • 1
  • Jun Ohgane
    • 1
    • 3
  • Satoshi Tanaka
    • 1
  • Mitsuko Hirosawa
    • 1
  • Michael J. Soares
    • 2
  • Shintaro Yagi
    • 1
  • Kunio Shiota
    • 1
  1. 1.Laboratory of Cellular Biochemistry, Department of Animal Resource, Sciences/Veterinary Medical SciencesThe University of TokyoTokyoJapan
  2. 2.Institute for Reproductive Health and Regenerative Medicine, Department Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityUSA
  3. 3.Laboratory of Genomic Function Engineering, Department of Life Sciences, School of AgricultureMeiji UniversityKawasakiJapan

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