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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate
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Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate

机译:涉及EBF1和FOXO1的正向基因间反馈电路可协调B细胞命运

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摘要

Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1). FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in F0X01 -deficient mice is arrested in the common lymphoid progenitor (CLP) LY6D~+ cell stage. We demonstrate that this phenotype closely resembles the arrest in B-cell development observed in EBF1 -deficient mice. Consistent with these observations, we find that the transcription signatures of FOXO1- and EBF1-deficient LY6D~+ progenitors are strikingly similar; indicating a common set of target genes. Furthermore, we found that depletion of EBF1 expression in LY6D~+ CLPs severely affects FOXQ1 mRNA abundance, whereas depletion of FOXO1 activity in LY6D~+ CLPs ablates EBF1 transcript levels. We generated a global regulatory network from EBF1 and FOXO1 genome-wide transcription factor occupancy and transcription signatures derived from EBF1- and FOXO1-deficient CLPs. This analysis reveals that EBF1 and FOXO1 act in a positive feedback circuitry to promote and stabilize specification to the B-cell lineage.
机译:最近的研究已经确定了许多转录调节因子,包括E2A,早期B细胞因子1(EBF1)。 FOXO1和配对盒基因5(PAX5)促进早期B细胞发育。但是,这种调节剂的结合如何机械地促进B细胞的命运仍然知之甚少。在这里,我们证明F0X01缺陷小鼠中的B细胞发育被阻滞在常见的淋巴祖细胞(CLP)LY6D〜+细胞阶段。我们证明,该表型非常类似于在EBF1缺陷小鼠中观察到的B细胞发育停滞。与这些观察结果一致,我们发现FOXO1和EBF1缺失的LY6D〜+祖细胞的转录特征非常相似;表示一组共同的靶基因。此外,我们发现耗尽LY6D〜+ CLPs中的EBF1表达会严重影响FOXQ1 mRNA的丰度,而耗尽LY6D〜+ CLPs中的FOXO1活性则会消除EBF1转录水平。我们从EBF1和FOXO1全基因组转录因子的占有率以及从EBF1和FOXO1缺陷型CLP衍生的转录特征生成了一个全球监管网络。该分析表明EBF1和FOXO1在正反馈电路中起作用,以促进和稳定B细胞谱系的规格。

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    Departments of Molecular Biology, University of California at San Diego, La Jolla, CA 92093,Department of Laboratory Medicine, Karolinska Institute, 14186 Stockholm, Sweden;

    Departments of Molecular Biology, University of California at San Diego, La Jolla, CA 92093,Department of Experimental Medical Science, Lund University, 22242 Lund, Sweden;

    Department of Clinical and Experimental Sciences, Linkoping University, 58183 Linkoping, Sweden;

    Departments of Molecular Biology, University of California at San Diego, La Jolla, CA 92093;

    Departments of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;

    Departments of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;

    Departments of Molecular Biology, University of California at San Diego, La Jolla, CA 92093;

    Department of Clinical and Experimental Sciences, Linkoping University, 58183 Linkoping, Sweden;

    Departments of Molecular Biology, University of California at San Diego, La Jolla, CA 92093;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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