Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, Boston, MA, USA.
Mol Cell Biol. 2010 Jul;30(13):3187-205. doi: 10.1128/MCB.00227-10. Epub 2010 Apr 19.
Mammals compensate for unequal X-linked gene dosages between the sexes by inactivating one X chromosome in the female. In marsupials and in the early mouse embryo, X chromosome inactivation (XCI) is imprinted to occur selectively on the paternal X chromosome (X(P)). The mechanisms and events underlying X(P) imprinting remain unclear. Here, we find that the imprinted X(P) can be functionally divided into two domains, one comprising traditional coding genes (genic) and the other comprising intergenic repetitive elements. X(P) repetitive element silencing occurs by the two-cell stage, does not require Xist, and occurs several divisions prior to genic silencing. In contrast, genic silencing initiates at the morula-to-blastocyst stage and absolutely requires Xist. Genes translocate into the presilenced repeat region as they are inactivated, whereas active genes remain outside. Thus, during the gamete-embryo transition, imprinted XCI occurs in two steps, with repeat silencing preceding genic inactivation. Nucleolar association may underlie the epigenetic asymmetry of X(P) and X(M). We hypothesize that transgenerational information (the imprint) is carried by repeats from the paternal germ line or that, alternatively, repetitive elements are silenced at the two-cell stage in a parent-of-origin-specific manner. Our model incorporates aspects of the so-called classical, de novo, and preinactivation hypotheses and suggests that Xist RNA functions relatively late during preimplantation mouse development.
哺乳动物通过在雌性中失活一条 X 染色体来补偿性染色体之间的不等基因剂量。在有袋动物和早期小鼠胚胎中，X 染色体失活 (XCI) 被印记为选择性地发生在父本 X 染色体 (X(P)) 上。X(P) 印记发生的机制和事件仍不清楚。在这里，我们发现被印记的 X(P) 可以在功能上分为两个区域，一个区域包含传统的编码基因（基因），另一个区域包含基因间重复元件。X(P) 重复元件的沉默发生在二细胞阶段，不需要 Xist，并且发生在基因沉默之前的几个分裂中。相比之下，基因沉默在桑葚胚到囊胚阶段开始，并绝对需要 Xist。基因在失活时转移到预先沉默的重复区域，而活跃的基因则留在外面。因此，在配子-胚胎过渡期间，印记 XCI 分两步进行，重复沉默先于基因失活。核仁关联可能是 X(P) 和 X(M) 表观遗传不对称的基础。我们假设跨代信息（印记）是由父本生殖系中的重复序列携带的，或者替代性地，重复元件在二细胞阶段以亲本特异性的方式沉默。我们的模型结合了所谓的经典、从头和预失活假说的各个方面，并表明 Xist RNA 在小鼠植入前发育的相对晚期起作用。
