Nuclear Architecture and Disease

我们实验室的目的是了解基因组在体内是如何组织的，以及这种组织如何促进基因组在健康和疾病中的功能。我们已经在几个领域取得了重大进展：a)我们已经扩展了我们早期的努力，开发成像方法来可视化活细胞中的基因表达。最近，我们将这些技术应用于胚胎干细胞的基因组分析。我们已经证明，在未分化的干细胞中，基因组的组织方式是不同的，并且它们的物理特性的变化对分化至关重要。这些观察结果对我们理解胚胎干细胞分化和这一过程的控制具有重要意义。B)我们已经确定分子马达是一种新型的肿瘤抑制蛋白。虽然分子马达长期以来一直与细胞分裂过程中适当的染色体分离有关，但我们现在已经证明了一种分子马达hKIF4在防止染色体数目异常方面的关键作用。缺乏hKIF4的细胞容易形成肿瘤，说明染色体数目异常可以触发肿瘤的形成。这些观察结果代表了分子运动和癌症生物学领域的新概念。C)最后，我们正在探索早老性疾病Hutchinson-Gilford Progeria Syndrome （HGPS）的分子机制。这种致命的儿童疾病的遗传原因是细胞核中一种主要结构蛋白的突变。我们已经能够在患者细胞中纠正与这种突变相关的致病的选择性剪接事件，并且能够挽救在患者细胞中观察到的细胞缺陷。此外，我们已经证明，负责这些疾病的相同分子机制也涉及生理衰老。这些观察发现了一种新的衰老途径，并建立了HGPS作为人类衰老研究的模型。这是特别有趣的，因为与大多数其他早衰综合征不同，HGPS的特点是没有肿瘤。我们现在正在探索HGPS作为一个模型系统来探索衰老和癌症之间的联系。

The aim of our laboratory is to understand how genomes are organized in vivo and how this organization contributes to genome function in health and disease. We have made significant progress in several areas: a) We have extended our earlier efforts to develop imaging methods to visualize gene expression in living cells. Recently we have applied these techniques to the analysis of genomes in embryonic stem cells. We have demonstrated that genomes are organized differently in undifferentiated stem cells and that changes in their physical properties are critical for differentiation. These observations have implications for our understanding of embryonic stem cell differentiation and the control of this process. B) We have identified molecular motors as a novel type of tumor-suppressing proteins. While molecular motors have long been implicated in proper chromosome segregation during cell division, we have now documented a critical role for one molecular motor, hKIF4, in preventing aberrant chromosome number. Cells lacking hKIF4 were prone to tumor formation, demonstrating that aberrant chromosome number can trigger tumor formation. These observations represent novel concepts in the field of molecular motor and cancer biology. C) Finally, we are exploring the molecular mechanisms of the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). The genetic cause for this fatal childhood disease is a mutation in one of the major architectural proteins of the cell nucleus. We have been able to correct in patient cells the disease-causing alternative splicing event associated with this mutation and were able to rescue the cellular defects observed in patient cells. In addition we have demonstrated that the same molecular mechanism responsible for the diseases is also involved in physiological aging. These observations have identified a novel aging pathway and have established HGPS as a model for the study of human aging. This is of particular interest since, unlike most other premature aging syndromes, HGPS is characterized by the absence of tumors. We are now exploring HGPS as a model system to explore the link between aging and cancer.