Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, UK.
Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10484-9. doi: 10.1073/pnas.1002325107. Epub 2010 May 18.
A longstanding question in centromere biology has been the organization of CENP-A-containing chromatin and its implications for kinetochore assembly. Here, we have combined genetic manipulations with deconvolution and super-resolution fluorescence microscopy for a detailed structural analysis of chicken kinetochores. Using fluorescence microscopy with subdiffraction spatial resolution and single molecule sensitivity to map protein localization in kinetochore chromatin unfolded by exposure to a low salt buffer, we observed robust amounts of H3K9me3, but only low levels of H3K4me2, between CENP-A subdomains in unfolded interphase prekinetochores. Constitutive centromere-associated network proteins CENP-C and CENP-H localize within CENP-A-rich subdomains (presumably on H3-containing nucleosomes) whereas CENP-T localizes in interspersed H3-rich blocks. Although interphase prekinetochores are relatively more resistant to unfolding than sur-rounding pericentromeric heterochromatin, mitotic kinetochores are significantly more stable, reflecting mitotic kinetochore maturation. Loss of CENP-H, CENP-N, or CENP-W had little or no effect on the unfolding of mitotic kinetochores. However, loss of CENP-C caused mitotic kinetochores to unfold to the same extent as their interphase counterparts. Based on our results we propose a new model for inner centromeric chromatin architecture in which chromatin is folded as a layered boustrophedon, with planar sinusoids containing interspersed CENP-A-rich and H3-rich subdomains oriented toward the outer kinetochore. In mitosis, a CENP-C-dependent mechanism crosslinks CENP-A blocks of different layers together, conferring extra stability to the kinetochore.
中心体生物学中的一个长期问题是含有 CENP-A 的染色质的组织及其对动粒组装的影响。在这里,我们结合遗传操作与去卷积和超分辨率荧光显微镜,对鸡动粒进行了详细的结构分析。利用具有亚衍射空间分辨率和单分子灵敏度的荧光显微镜,在暴露于低盐缓冲液后对动粒染色质进行解折叠,我们观察到在解折叠的间期前期动粒中,H3K9me3 大量存在,但在 CENP-A 亚域之间存在的 H3K4me2 水平较低。组成性着丝粒相关网络蛋白 CENP-C 和 CENP-H 定位于富含 CENP-A 的亚域(推测位于含有 H3 的核小体上),而 CENP-T 定位于散布的富含 H3 的块中。尽管间期前期动粒相对于周围着丝粒异染色质较不易解折叠,但有丝分裂动粒更稳定,反映出有丝分裂动粒的成熟。缺失 CENP-H、CENP-N 或 CENP-W 对有丝分裂动粒的解折叠几乎没有影响。然而,缺失 CENP-C 会导致有丝分裂动粒解折叠的程度与间期动粒相同。基于我们的结果,我们提出了一个新的内着丝粒染色质结构模型,其中染色质作为层状的正反交错结构折叠,含有散布的富含 CENP-A 和富含 H3 的亚域的平面正弦波朝向动粒的外部。在有丝分裂过程中,一种依赖于 CENP-C 的机制将不同层的 CENP-A 块交联在一起,赋予动粒额外的稳定性。