Gnanapragasam Merlin Nithya, Bieker James J
aDepartment of Cell, Developmental, and Regenerative Biology bBlack Family Stem Cell Institute cTisch Cancer Center dMindich Child Health and Development Institute, Mount Sinai School of Medicine, New York, USA.
Curr Opin Hematol. 2017 May;24(3):183-190. doi: 10.1097/MOH.0000000000000327.
Transcriptional regulators provide the molecular and biochemical basis for the cell specific properties and characteristics that follow from their central role in establishing tissue-restricted expression. Precise and sequential control of terminal cell divisions, nuclear condensation, and enucleation are defining characteristics within erythropoietic differentiation. This review is focused on KLF1, a central global regulator of this process.
Studies in the past year have brought a number of proteins that are targets of KLF1 regulation into focus with respect to their roles in terminal erythroid differentiation. Many of these are involved in fine control of the cell cycle at both early (E2F2, Cyclin A2) and later (p18, p27, p19) stages of differentiation, or are directly involved in enucleation (p18, p27). Dramatic biophysical changes controlled at the nuclear lamin by caspase 3 enable histone release and nuclear condensation, whereas dematin association with structural proteins alters the timing of enucleation. Conditional ablation of mDia2 has established its role in late stage cell cycle and enucleation.
Transcription factors such as KLF1, along with epigenetic modifiers, play crucial roles in establishing the proper onset and progression of terminal differentiation events. Studies from the past year show a remarkable multifaceted convergence on cell cycle control, and establish that the orthochromatic erythroblast stage is a critical nodal point for many of the effects on enucleation. These studies are relevant to understanding the underlying causes of anemia and hematologic disease where defective enucleation predicts a poor clinical outcome.
转录调节因子为细胞特异性特性提供了分子和生化基础，这些特性源于它们在建立组织限制性表达中的核心作用。终末细胞分裂、核浓缩和去核的精确且有序的控制是红细胞生成分化的决定性特征。本综述聚焦于KLF1，它是这一过程的核心全局调节因子。
过去一年的研究使许多作为KLF1调节靶点的蛋白质在终末红细胞分化中的作用成为焦点。其中许多蛋白质参与了分化早期（E2F2、细胞周期蛋白A2）和晚期（p18、p27、p19）对细胞周期的精细调控，或者直接参与去核过程（p18、p27）。半胱天冬酶3对核纤层蛋白的控制引发的显著生物物理变化可导致组蛋白释放和核浓缩，而珠蛋白与结构蛋白的结合会改变去核的时间。条件性敲除mDia2已证实其在细胞周期后期和去核过程中的作用。
KLF1等转录因子与表观遗传修饰因子一起，在建立终末分化事件的正确起始和进程中发挥关键作用。过去一年的研究在细胞周期控制方面呈现出显著的多方面趋同，并确定正染红细胞阶段是许多影响去核过程的关键节点。这些研究对于理解贫血和血液系统疾病的潜在病因具有重要意义，在这些疾病中，去核缺陷预示着临床预后不良。
