Transcription Factor Repertoire of Homeostatic Eosinophilopoiesis
Transcription Factor Repertoire of Homeostatic Eosinophilopoiesis
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DOI：
10.4049/jimmunol.1500510
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发表时间：
2015-09-15
影响因子：
4.4
通讯作者：
Fulkerson, Patricia C.
中科院分区：
文献类型：
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作者：
Bouffi, Carine;Kartashov, Andrey V.;Fulkerson, Patricia C.
成熟嗜酸性粒细胞(Eos)的产生是一个紧密协调的过程，目的是维持组织中正常的Eos水平，同时也保持血液中这些复杂和敏感的细胞的数量较少。为了确定小鼠体内稳态嗜酸性粒细胞生成的调节因素，我们采取了一种全球方法来确定在关键发育阶段的稳态期间发生的全基因组转录组和表观基因组的变化，包括Eos谱系承诺和谱系成熟。我们的分析显示，与Eos成熟相关的转录组改变(1199个基因)明显多于与Eos谱系承诺相关的转录组改变(490个基因)，这突显了分化所需的更大的转录投资。Eos家族承诺的祖细胞(EOPs)表达高水平的颗粒蛋白，并含有与成熟静息Eos不同的超微结构颗粒。我们的分析还描绘了一个976基因的Eos谱系转录组，其中包括56个转录因子，其中许多以前从未与Eos相关。EOPs和Eos表达Ikaros转录因子家族成员Helios和Aiolos，它们通过调节染色质结构和DNA可及性来调节基因表达，而不是粒-单核细胞祖细胞或中性粒细胞。表观遗传学研究表明，在Eos发育过程中，活跃的染色质标记在谱系承诺诱导的基因和细胞成熟诱导的基因之间有明显的分布。此外，Aiolos和Helios结合位点显著丰富了EOPs和Eos表达的具有活性染色质的基因，突显了Helios和Aiolos在Eos发育过程中调节基因表达的潜在新作用。
The production of mature eosinophils (Eos) is a tightly orchestrated process with the aim to sustain normal Eos levels in tissues while also maintaining low numbers of these complex and sensitive cells in the blood. To identify regulators of homeostatic eosinophilopoiesis in mice, we took a global approach to identify genome-wide transcriptome and epigenome changes that occur during homeostasis at critical developmental stages, including Eos-lineage commitment and lineage maturation. Our analyses revealed a markedly greater number of transcriptome alterations associated with Eos maturation (1199 genes) than with Eos-lineage commitment (490 genes), highlighting the greater transcriptional investment necessary for differentiation. Eos-lineage-committed progenitors (EoPs) were noted to express high levels of granule proteins and contain granules with an ultrastructure distinct from that of mature resting Eos. Our analyses also delineated a 976-gene Eos-lineage transcriptome that included a repertoire of 56 transcription factors, many of which have never previously been associated with Eos. EoPs and Eos, but not granulocyte-monocyte progenitors or neutrophils, expressed Helios and Aiolos, members of the Ikaros family of transcription factors, which regulate gene expression via modulation of chromatin structure and DNA accessibility. Epigenetic studies revealed a distinct distribution of active chromatin marks between genes induced with lineage commitment and genes induced with cell maturation during Eos development. In addition, Aiolos and Helios binding sites were significantly enriched in genes expressed by EoPs and Eos with active chromatin, highlighting a potential novel role for Helios and Aiolos in regulating gene expression during Eos development.