Analysis of aging-related epigenetic modifications in murine male germline cells

概要

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学
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位 論 文 要 約
A b s t r a c t ）

博士論文題目 Title of dissertation

Analysis of aging-related epigenetic modifications in murine male germline cells
(マウス雄性生殖細胞系列の加齢によるエピゲノム変化の解析)

東北大学大学院医学系研究科
講座
氏名 Name

医科学専攻

発生発達神経科学分野
舘花

美沙子

Epidemiological studies have shown that advanced paternal age is a risk for neurodevelopmental
disorders, such as autism, in offspring. Recent studies indicate that factors other than de novo mutations
caused by paternal aging can affect health and disease of the offspring. Here, I focused on age-related
epigenetic modifications in male germline cells that might influence developmental programs in offspring.
First, patterns of histone modification in male germline cells were qualitatively and semi-quantitatively
analyzed throughout spermatogenesis by immunostaining of the testes from young and aged mice.
Several histone modifications in the aged testis showed higher or lower levels than in the young testis.
Furthermore, H3K4me2 and H3K27ac (active marks) were found to accumulate at the XY body during
meiosis, and their accumulation levels changed due to aging, suggesting that they may differentially affect
the sex chromosome inactivation during meiosis. In addition, several histone modifications, including
H3K79me3, accumulated on sex chromosomes after meiosis. Next, since a previous study in my
laboratory has shown that hypomethylated regions in the sperm DNA from aged mice contain
REST/NRSF binding motifs in common, I also examined the localization of an epigenetic molecule,
REST/NRSF, in the testis by immunostaining using an epitope tag knock-in mouse line. REST/NRSF
signals were detected in Sertoli cells and spermatogonia. The number of REST/NRSF expressing cell
decreased dramatically during early postnatal stages, but did not change with age. However, it seems that
REST/NRSF was expressed in a longer period in differentiating spermatogonia in the testis of aged mice.
Finally, in order to search another epigenetic alteration, I analyzed micro RNAs (miRNAs) of sperm using
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a commercial microarray. The expression of miRNAs associated with apoptosis increased in the sperm
from aged mice. In addition, miRNAs, which have already been shown to be upregulated in autism
patients, were also shown increased expression in the sperm derived from aged mice. Taken together,
these results indicate that several epigenetic alterations were detected in male germline cells from aged
mice. These alterations during spermatogenesis could affect sperm quality and subsequent development
of the offspring. Further validation is needed to examine the effects on the next generation in detail. ...