Genetic Analysis of Cardiac Growth

摘要： 在发育过程中，细胞分裂(增殖或增殖)与积累的 细胞团(肥大)，以确保心肌细胞大小恒定；然而，在成人心肌细胞中 (ACM)，相似的生长信号主要诱导肥大生长而不增殖，即使许多 相同的信号通路被激活。在分子水平上，虽然增生性生长与 随着一组由E2F转录因子家族调控的细胞周期基因的表达，这些 在肥大的心肌细胞中，基因没有上调。尽管许多描述性研究的特点是 ACM对各种刺激反应退出G1或分裂的能力有限，几乎没有数据来 解释为什么大多数中医在受到刺激时没有进入S阶段。我们已经确定了一部小说 急性髓细胞白血病中G2M/胞质分裂基因沉默的机制：Rb-E2F的组蛋白甲基化调控 细胞周期基因。我们发现两个主要的组蛋白修饰与稳定的基因沉默有关 在ACM中上调，并针对依赖E2F的细胞周期基因。我们建议测试一下 这些表观遗传标记的重要性以及它们是否针对RB依赖于E2F的细胞周期基因 体内的家庭成员。在转基因小鼠中重新激活细胞周期基因与 特异组蛋白去甲基酶的重新表达，通常只有在增殖的胎儿心脏中才能看到 心肌细胞不肥大。有趣的是，这些表观遗传变化可能是可逆的 这表明这可能是一种治疗途径，可以“重塑”或“重新编程”ACM，以恢复其 增殖潜力。我们将通过以下方式探讨组蛋白甲基化在限制ACM增殖中的重要性 确定逆转H3K9和H3K27组蛋白甲基化是否将肥厚性储存库转化为 成人心肌细胞的增殖(目标1)，确定靶向组蛋白甲基化的因素 ACM及其在沉默细胞周期基因和防止增殖中的作用(AIM2)及其确定如何 组蛋白甲基化重塑发生在急性髓细胞白血病及其生理学意义(目标3)。

Abstract: During development, cell division (proliferation or hyperplasia) is tightly coupled to the accumulation of cell mass (hypertrophy) to ensure that myocyte size is constant; however, in adult cardiac myocytes (ACMs), similar growth signals primarily induce hypertrophic growth without proliferation even though many of the same signaling pathways are activated. At a molecular level, while hyperplastic growth is associated with the expression of a panel of cell cycle genes regulated by the E2F family of transcription factors, these genes are not upregulated in hypertrophic myocytes. Despite numerous descriptive studies characterizing the limited ability of ACMs to exit G1 or divide in response to various stimuli, almost no data exists to explain why the majority of ACMs do not enter S phase when stimulated. We have identified a novel mechanism for silencing G2M/cytokinesis genes in ACMs; namely, histone methylation of Rb-E2F regulated cell cycle genes. We show that the two major histone modifications associated with stable gene silencing are upregulated in ACMs and targeted to E2F-dependent cell cycle genes. We propose to test if the importance of these epigenetic marks and if they are targeted to E2F-dependent cell cycle genes by Rb family members in vivo. Genetically reactivating cell cycle genes in transgenic mice is associated with the reexpression of specific histone demethylases, something normally seen only in proliferating fetal cardiac myocytes not hypertrophy. Interestingly, the fact that these epigenetic changes might be reversible suggests that this might be a therapeutic avenue to "remodel" or "reprogram" ACMs to restore their proliferative potential. We will explore the importance of histone methylation in limiting ACM proliferation by determining if reversing H3K9 and H3K27 histone methylation converts a hypertrophic reposnse to hyperplasia in adult cardiac myocytes (Aim 1), determining the factors that target histone methylations in ACMs and their role in silencing cell cycle genes and preventing proliferation (Aim2) and determining how histone methylation remodeling occurs in ACMs and its physiologic significance (Aim 3).