Developmental and species-divergent globin switching are driven by BCL11A.
Developmental and species-divergent globin switching are driven by BCL11A.
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顺式调控元件或反式作用因子的变化对物种间基因表达差异的贡献尚不清楚。哺乳动物的β-珠蛋白基因座已成为发育过程中基因调控的范例。含有人类β-珠蛋白基因的转基因小鼠，包括连锁胚胎(ε)、胎儿(γ)和成人(β)基因，已被用作研究从胎儿到成人血红蛋白的时间转换的模型系统，就像人类所发生的那样。我们发现这些小鼠中的人类γ-珠蛋白基因表现为小鼠胚胎珠蛋白基因，揭示了该模型的局限性，并表明在哺乳动物进化过程中出现了反式作用环境的关键差异。我们发现，BCL11A是一种通过全基因组关联研究确定的人类γ-珠蛋白表达的抑制因子，它在小鼠和人类中的表达不同。在没有BCL11A的情况下，小鼠胚胎珠蛋白和人类γ-珠蛋白基因的发育沉默在小鼠中无法发生。因此，BCL11A是物种分化珠蛋白转换的关键调节因子。通过比较小鼠和人类β-珠蛋白基因调控的个体发育，我们已经表明，反式作用因子表达的变化构成了进化过程中基因表达变化的关键驱动因素。
The contribution of changes in cis-regulatory elements or trans-acting factors to interspecies differences in gene expression is not well understood. The mammalian β-globin loci have served as a paradigm for gene regulation during development. Transgenic mice harboring the human β-globin locus, consisting of the linked embryonic (ε), fetal (γ) and adult (β) genes, have been used as a model system to study the temporal switch from fetal to adult hemoglobin, as occurs in humans. We show that the human γ-globin genes in these mice behave as murine embryonic globin genes, revealing a limitation of the model and demonstrating that critical differences in the trans-acting milieu have arisen during mammalian evolution. We show that the expression of BCL11A, a repressor of human γ-globin expression identified through genome-wide association studies, differs between mouse and human. Developmental silencing of the mouse embryonic globin and human γ-globin genes fails to occur in mice in the absence of BCL11A. Thus, BCL11A is a critical mediator of species-divergent globin switching. By comparing the ontogeny of β-globin gene regulation in mice and humans, we have shown that alterations in expression of a trans-acting factor constitute a critical driver of gene expression changes during evolution.