Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Nucleic Acids Res. 2011 May;39(10):4048-62. doi: 10.1093/nar/gkq1338. Epub 2011 Jan 25.
The centromere is a highly specialized chromosomal element that is essential for chromosome segregation during mitosis. Centromere integrity must therefore be properly preserved and is strictly dependent upon the establishment and maintenance of surrounding chromatin structure. Here we identify WDHD1, a WD40-domain and HMG-domain containing protein, as a key regulator of centromere function. We show that WDHD1 associates with centromeres in a cell cycle-dependent manner, coinciding with mid-to-late S phase. WDHD1 down-regulation compromises HP1α localization to pericentric heterochromatin and leads to altered expression of epigenetic markers associated with this chromatin region. As a consequence, such reduced epigenetic silencing is manifested in disrupted heterochromatic state of the centromere and a defective mitosis. Moreover, we demonstrate that a possible underlying mechanism of WDHD1's involvement lies in the proper generation of the small non-coding RNAs encoded by the centromeric satellite repeats. This role is mediated at the post-transcriptional level and likely through stabilizing Dicer association with centromeric RNA. Collectively, these findings suggest that WDHD1 may be a critical component of the RNA-dependent epigenetic control mechanism that sustains centromere integrity and genomic stability.
着丝粒是一种高度特化的染色体元件，对于有丝分裂过程中的染色体分离至关重要。因此，着丝粒的完整性必须得到妥善保护，并且严格依赖于周围染色质结构的建立和维持。在这里，我们鉴定出 WDHD1 是一种含有 WD40 结构域和 HMG 结构域的蛋白，是着丝粒功能的关键调节因子。我们发现 WDHD1 以细胞周期依赖性的方式与着丝粒结合，与中晚期 S 期一致。WDHD1 的下调会损害 HP1α 向着丝粒异染色质的定位，并导致与该染色质区域相关的表观遗传标记的表达发生改变。因此，这种减少的表观遗传沉默表现为着丝粒异染色质状态的破坏和有缺陷的有丝分裂。此外，我们证明 WDHD1 参与的一个可能的潜在机制在于由着丝粒卫星重复序列编码的小非编码 RNA 的正确生成。该作用是在转录后水平介导的，可能通过稳定 Dicer 与着丝粒 RNA 的结合。总之，这些发现表明 WDHD1 可能是维持着丝粒完整性和基因组稳定性的 RNA 依赖性表观遗传调控机制的关键组成部分。
