Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Exp Hematol. 2024 Sep;137:104252. doi: 10.1016/j.exphem.2024.104252. Epub 2024 Jun 12.
Transcriptional mechanisms establish and maintain complex genetic and protein networks to control cell state transitions. The hematopoietic transcription factor GATA1 is a master regulator of erythropoiesis and megakaryopoiesis, and human GATA1 genetic variants cause anemia and megakaryoblastic leukemia. Multiomic analyses revealed that GATA1 controls expression of transporters and metabolic enzymes that dictate intracellular levels of endogenous small molecules, including heme, metal ions, and sphingolipids. Besides its canonical function as a hemoglobin component, heme facilitates or antagonizes GATA1 function to regulate erythropoiesis via mechanisms dependent or independent of the heme-binding transcription factor BTB domain and CNC homology 1 (BACH1). GATA1 regulates the expression of genes encoding heme biosynthetic enzymes and BACH1. GATA1 maintains homeostasis of bioactive ceramides during erythroid differentiation by regulating genes encoding sphingolipid metabolic enzymes. Disrupting ceramide homeostasis impairs critical cytokine signaling and is detrimental to erythroid cells. During erythroid maturation, GATA1 induces a zinc transporter switch that favors export versus import, thus dictating the intracellular zinc level, erythroblast survival, and differentiation. In aggregate, these studies support an emerging paradigm in which GATA factor-dependent transcriptional mechanisms control the intracellular levels of endogenous small molecules and small molecule-dependent feedback loops that serve as vital effectors of transcription factor activity, genome function, and cell state transitions.
转录机制建立和维持复杂的遗传和蛋白质网络，以控制细胞状态的转变。造血转录因子 GATA1 是红细胞生成和巨核细胞生成的主要调节因子，人类 GATA1 遗传变异导致贫血和巨核细胞白血病。多组学分析表明，GATA1 控制着转运蛋白和代谢酶的表达，这些蛋白和酶决定了内源性小分子（包括血红素、金属离子和鞘脂）的细胞内水平。除了作为血红蛋白成分的典型功能外，血红素还通过依赖或不依赖于血红素结合转录因子 BTB 结构域和 CNC 同源性 1（BACH1）的机制，促进或拮抗 GATA1 功能，从而调节红细胞生成。GATA1 调节血红素生物合成酶和 BACH1 的基因表达。GATA1 通过调节编码鞘脂代谢酶的基因来维持红细胞分化过程中生物活性神经酰胺的动态平衡。破坏神经酰胺动态平衡会损害关键细胞因子信号转导，并对红细胞有害。在红细胞成熟过程中，GATA1 诱导锌转运体的转换，有利于出口而不是进口，从而决定细胞内锌水平、成红细胞的存活和分化。总的来说，这些研究支持了一个新兴的范例，即 GATA 因子依赖性转录机制控制内源性小分子的细胞内水平，以及小分子依赖性反馈回路作为转录因子活性、基因组功能和细胞状态转变的重要效应物。
