本文關鍵詞： Kat8 H4K16ac 卵母細胞 卵泡 生育力 活性氧　出處：《中國科學技術大學》2017年博士論文　論文類型：學位論文

【摘要】：卵泡發(fā)育的正常進行對于雌性生育能力的維持十分重要。卵泡發(fā)育是一個復雜的生物學過程,其間涉及到細胞的生長、增殖及分化等方面,需要基因的精確調(diào)控。組蛋白乙酰化是一種重要的基因調(diào)控方式,乙�；D移酶和去乙�；改軌蛲ㄟ^改變組蛋白與DNA的結合能力改變?nèi)旧|(zhì)的狀態(tài),進而對基因的轉錄進行調(diào)控。賴氨酸(K)乙�；D移酶KAT8,作為果蠅中X染色體劑量補償系統(tǒng)中的重要組成部分,負責組蛋白H4第十六位賴氨酸大部分的乙酰化。我們發(fā)現(xiàn)Kat8在小鼠卵母細胞及顆粒細胞中均有所表達,并且高表達于生發(fā)泡期卵母細胞胞核。接下來我們進一步利用條件性敲除小鼠模型研究了Kat8在小鼠卵泡發(fā)育過程中的功能,結果表明卵母細胞特異敲除Kat8后小鼠不育,次級及腔前卵泡的發(fā)育受阻,閉鎖卵泡數(shù)目增多,大量卵母細胞出現(xiàn)嚴重的DNA損傷和凋亡,而顆粒細胞的增殖并未受到明顯影響。Kat8敲除的卵母細胞組蛋白H4第十六位賴氨酸乙�；乃斤@著下調(diào),細胞內(nèi)異染色質(zhì)的形態(tài)明顯異常,卵母細胞中抗氧化基因Prdx1、Prdx2、Gpx1及Gpx4的表達顯著下調(diào),活性氧水平明顯升高。向敲除小鼠注射抗氧化劑N-乙酰半胱氨酸可以促進敲除鼠的卵子發(fā)生和卵泡發(fā)育,同時降低卵母細胞活性氧、DNA損傷及凋亡水平。KAT8可以直接結合在抗氧化基因的啟動子區(qū)域,調(diào)控這些基因表達。而顆粒細胞敲除Kat8對小鼠的生育力及卵泡發(fā)育并無明顯影響。綜上所述,我們的研究結果表明卵母細胞內(nèi)KAT8通過調(diào)控細胞內(nèi)抗氧化基因的表達降低了卵母細胞的活性氧水平,進而減少了卵母細胞的凋亡,提高了卵泡的存活能力,維持了雌性的正常生育力。KAT8是迄今為止首個報道的在小鼠卵泡發(fā)育過程中所必需的乙�；D移酶,同時本研究為卵泡發(fā)育障礙引起的不孕癥的診斷、治療提供了重要的科學依據(jù)。
[Abstract]:The normal development of follicles is very important for the maintenance of female fertility. Follicular development is a complex biological process, which involves cell growth, proliferation and differentiation. Histone acetylation is an important gene regulation. Acetyltransferase and deacetylase can change the chromatin state by changing the binding ability of histone to DNA. Lysine K) acetyltransferase KAT8 is an important part of the dose compensation system of X chromosome in Drosophila. Responsible for most of the acetylation of lysine at histone H4 16th. We found that Kat8 was expressed in mouse oocytes and granulosa cells. And high expression in the blastocyst oocyte nucleus. Then we further use the conditional knockout mouse model to study the function of Kat8 in the development of mouse follicles. The results showed that after specific knockout of oocytes in Kat8 mice, the development of secondary and preantral follicles was blocked, the number of atresia follicles increased, and a large number of oocytes showed severe DNA damage and apoptosis. However, the proliferation of granulosa cells was not significantly affected by. Kat8 knockout oocyte histone H4 16th site lysine acetylation level was significantly down-regulated, and the morphology of heterochromatin was significantly abnormal. The expression of antioxidation gene Prdx1, Prdx2, Gpx1 and Gpx4 was significantly down-regulated in oocytes. The level of reactive oxygen species (Ros) was significantly increased. The injection of N- acetylcysteine into knockout mice could promote oogenesis and follicle development in knockout mice and decrease reactive oxygen species (Ros) in oocytes at the same time. The level of DNA damage and apoptosis. KAT8 can directly bind to the promoter region of antioxidant gene. Regulation of these genes expression. Granulosa cell knockout Kat8 has no significant effect on the fertility and follicular development of mice. Our results suggest that KAT8 in oocytes can reduce reactive oxygen species (Ros) levels in oocytes by regulating the expression of antioxidant genes in oocytes and thus reduce the apoptosis of oocytes. KAT8 is the first reported acetyltransferase necessary in mouse follicular development. At the same time, this study provides an important scientific basis for the diagnosis and treatment of infertility caused by follicular dysplasia.
【學位授予單位】：中國科學技術大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：Q492.5

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