Munakata Yasuhisa, Hu Mengwen, Kitamura Yuka, Bynder Adam L, Fritz Amelia S, Schultz Richard M, Namekawa Satoshi H
Department of Microbiology and Molecular Genetics, University of California, Davis, CA 95616, USA.
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
bioRxiv. 2024 Aug 13:2024.08.12.607691. doi: 10.1101/2024.08.12.607691.
The ovarian reserve defines female reproductive lifespan, which in humans spans decades due to the maintenance of meiotic arrest in non-growing oocytes (NGO) residing in primordial follicles. Unknown is how the chromatin state of NGOs is established to enable long-term maintenance of the ovarian reserve. Here, we show that a chromatin remodeler, CHD4, a member of the Nucleosome Remodeling and Deacetylase (NuRD) complex, establishes chromatin states required for formation and maintenance of the ovarian reserve. Conditional loss of CHD4 in perinatal mouse oocytes results in acute death of NGOs and depletion of the ovarian reserve. CHD4 establishes closed chromatin at regulatory elements of pro-apoptotic genes to prevent cell death and at specific genes required for meiotic prophase I to facilitate the transition from meiotic prophase I oocytes to meiotic arrested NGOs. In addition, CHD4 establishes closed chromatin at the regulatory elements of pro-apoptotic genes in male germ cells, allowing male germ cell survival. These results demonstrate a role for CHD4 in defining a chromatin state that ensures germ cell survival, thereby enabling the long-term maintenance of both female and male germ cells.
卵巢储备决定了女性的生殖寿命，在人类中，由于原始卵泡中未生长的卵母细胞（NGO）处于减数分裂停滞状态，生殖寿命可长达数十年。NGO的染色质状态是如何建立以实现卵巢储备的长期维持尚不清楚。在这里，我们表明一种染色质重塑因子CHD4，即核小体重塑和去乙酰化酶（NuRD）复合物的成员，建立了卵巢储备形成和维持所需的染色质状态。围产期小鼠卵母细胞中CHD4的条件性缺失导致NGO急性死亡和卵巢储备耗竭。CHD4在促凋亡基因的调控元件处建立封闭染色质以防止细胞死亡，并在减数分裂前期I所需的特定基因处建立封闭染色质，以促进从减数分裂前期I卵母细胞向减数分裂停滞的NGO的转变。此外，CHD4在雄性生殖细胞中促凋亡基因的调控元件处建立封闭染色质，从而使雄性生殖细胞得以存活。这些结果证明了CHD4在定义一种确保生殖细胞存活的染色质状态中的作用，从而实现雌性和雄性生殖细胞的长期维持。
