Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1.
Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1.
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DOI：
10.3389/fimmu.2017.00383
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发表时间：
2017
影响因子：
7.3
通讯作者：
Garrett-Sinha LA
中科院分区：
文献类型：
--
作者：
Saelee P;Kearly A;Nutt SL;Garrett-Sinha LA
转录因子Ets1在B淋巴细胞中高表达。Ets1的缺失导致B细胞过早分化为抗体分泌细胞（ASCs），分泌自身抗体，并导致自身免疫性疾病的发生。尽管Ets1在B细胞生物学中很重要，但在这些细胞中已知的Ets1靶基因很少。为了更全面地了解Ets1在调节B细胞分化中的功能，我们在原代小鼠B细胞中进行了Ets1 ChIP-seq，以鉴定bbb10000个结合位点，其中许多位点位于对B细胞活化和分化起重要作用的基因附近。尽管Ets1与基因组中的许多位点结合，但缺乏Ets1的B细胞的基因表达变化证明，只有不到5%的位点需要Ets1进行调控。表达改变的基因队列包括许多与自身免疫性疾病易感性相关的基因。我们将注意力集中在四个这样的Ets1靶基因Ptpn22、Stat4、Egr1和Prdm1上，以评估它们如何在限制ASC形成的Ets1功能中发挥作用。我们发现这些特定靶点的失调不能解释在没有Ets1的情况下ASC分化的改变。我们已经确定了B细胞中Ets1的全基因组结合靶点，并确定相对较少的这些假定的靶基因需要Ets1才能正常表达。有趣的是，与自身免疫性疾病易感性相关的一组基因是由Ets1调节的。鉴定B细胞中Ets1的靶基因将有助于更清楚地了解Ets1如何调节B细胞反应以及它的缺失如何促进自身抗体的分泌。
The transcription factor Ets1 is highly expressed in B lymphocytes. Loss of Ets1 leads to premature B cell differentiation into antibody-secreting cells (ASCs), secretion of autoantibodies, and development of autoimmune disease. Despite the importance of Ets1 in B cell biology, few Ets1 target genes are known in these cells. To obtain a more complete picture of the function of Ets1 in regulating B cell differentiation, we performed Ets1 ChIP-seq in primary mouse B cells to identify >10,000-binding sites, many of which were localized near genes that play important roles in B cell activation and differentiation. Although Ets1 bound to many sites in the genome, it was required for regulation of less than 5% of them as evidenced by gene expression changes in B cells lacking Ets1. The cohort of genes whose expression was altered included numerous genes that have been associated with autoimmune disease susceptibility. We focused our attention on four such Ets1 target genes Ptpn22, Stat4, Egr1, and Prdm1 to assess how they might contribute to Ets1 function in limiting ASC formation. We found that dysregulation of these particular targets cannot explain altered ASC differentiation in the absence of Ets1. We have identified genome-wide binding targets for Ets1 in B cells and determined that a relatively small number of these putative target genes require Ets1 for their normal expression. Interestingly, a cohort of genes associated with autoimmune disease susceptibility is among those that are regulated by Ets1. Identification of the target genes of Ets1 in B cells will help provide a clearer picture of how Ets1 regulates B cell responses and how its loss promotes autoantibody secretion.
影响因子：
15.3
作者：
Valentine, Mary A.;Czernik, Andrew J.;Rachie, Nisa;Hidaka, Hiroyoshi;Fisher, Constance L.;Cambier, John C.;Bomsztyk, Karol
通讯作者：
Bomsztyk, Karol