Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, 00161 Italy; Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, 00161 Italy.
Am J Hum Genet. 2019 Sep 5;105(3):493-508. doi: 10.1016/j.ajhg.2019.07.007. Epub 2019 Aug 22.
Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.
组蛋白介导核 DNA 在染色质中的动态包装，这一过程受到精确调控，以保证基因组的有效压缩和细胞分裂过程中染色体的正确分离，并完成 DNA 复制、转录和修复。由于组蛋白在结构和调节方面发挥着重要作用，组蛋白功能失调或组蛋白水平异常会对多种细胞过程产生严重影响，最终可能影响发育或导致细胞转化，这并不奇怪。最近，涉及 HIST1H1E 端尾的种系移码突变，该突变是连接组蛋白家族中广泛表达的成员，有助于高级染色质折叠，与一个尚未明确的综合征有关，该综合征包括智力障碍。我们报告称，这些突变导致稳定的蛋白存在于细胞核中，与染色质结合，破坏 DNA 的适当压缩，并与特定的甲基化模式相关。表达这些突变蛋白的细胞增殖率和能力显著降低，几乎无法进入 S 期，并加速衰老。值得注意的是，对具有这些突变的大量受试者的临床评估显示，过早衰老表型是该疾病以前未被认识到的特征之一。我们的发现确定了异常染色质重塑、细胞衰老和加速衰老之间的直接联系。
