Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, 200120, Shanghai, China.
Frontier Science Center for Stem Cell Research, Tongji University, 200092, Shanghai, China.
Nat Commun. 2023 Feb 21;14(1):957. doi: 10.1038/s41467-023-36584-z.
Epigenetic reprogramming of the parental genome is essential for zygotic genome activation and subsequent embryo development in mammals. Asymmetric incorporation of histone H3 variants into the parental genome has been observed previously, but the underlying mechanism remains elusive. In this study, we discover that RNA-binding protein LSM1-mediated major satellite RNA decay plays a central role in the preferential incorporation of histone variant H3.3 into the male pronucleus. Knockdown of Lsm1 disrupts nonequilibrium pronucleus histone incorporation and asymmetric H3K9me3 modification. Subsequently, we find that LSM1 mainly targets major satellite repeat RNA (MajSat RNA) for decay and that accumulated MajSat RNA in Lsm1-depleted oocytes leads to abnormal incorporation of H3.1 into the male pronucleus. Knockdown of MajSat RNA reverses the anomalous histone incorporation and modifications in Lsm1-knockdown zygotes. Our study therefore reveals that accurate histone variant incorporation and incidental modifications in parental pronuclei are specified by LSM1-dependent pericentromeric RNA decay.
亲本基因组的表观遗传重编程对于哺乳动物合子基因组激活和随后的胚胎发育至关重要。先前已经观察到组蛋白 H3 变体不对称地掺入亲本基因组中，但潜在的机制仍然难以捉摸。在这项研究中，我们发现 RNA 结合蛋白 LSM1 介导的主要卫星 RNA 降解在组蛋白变体 H3.3 优先掺入雄性原核中起着核心作用。Lsm1 的敲低会破坏非平衡原核组蛋白的掺入和不对称的 H3K9me3 修饰。随后，我们发现 LSM1 主要针对主要卫星重复 RNA (MajSat RNA) 进行降解，并且在 Lsm1 耗尽的卵母细胞中积累的 MajSat RNA 导致 H3.1 异常掺入雄性原核。MajSat RNA 的敲低逆转了 Lsm1 敲低胚胎中的异常组蛋白掺入和修饰。因此，我们的研究表明，准确的组蛋白变体掺入和亲本原核中的偶然修饰是由 LSM1 依赖的着丝粒 RNA 降解指定的。
