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Distinct and Shared Transcriptomes Are Regulated by Microphthalmia-Associated Transcription Factor Isoforms in Mast Cells

机译:不同的和共享的转录组受肥大细胞中的小眼科相关转录因子同工型调节。

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摘要

The Microphthalmia-associated transcription factor (Mitf) is an essential basic helix-loop-helix leucine zipper transcription factor for mast cell development. Mice deficient in Mitf harbor a severe mast cell deficiency, and Mitf-mutant mast cells cultured ex vivo display a number of functional defects. Therefore, an understanding of the genetic program regulated by Mitf may provide important insights into mast cell differentiation. Multiple, distinct isoforms of Mitf have been identified in a variety of cell types; we found that Mitf-a, Mitf-e, and Mitf-mc were the major isoforms expressed in mast cells. To determine the physiologic function of Mitf in mast cells, we restored expression of these isoforms in primary mast cells from Mitf/mice. We found that these isoforms restored granular morphology and integrin-mediated migration. By microarray analysis, proteases, signaling molecules, cell surface receptor, and transporters comprised the largest groups of genes up-regulated by all isoforms. Furthermore, we found that isoforms also regulated distinct genes sets, suggesting separable biological activities. This work defines the transcriptome regulated by Mitf in mast cells and supports its role as master regulator of mast cell differentiation. Expression of multiple isoforms of this transcription factor may provide for redundancy of biological activities while also allowing diversity of function.
机译:小眼症相关转录因子(Mitf)是肥大细胞发育所必需的基本螺旋-环-螺旋亮氨酸拉链转录因子。缺乏Mitf的小鼠存在严重的肥大细胞缺乏症,离体培养的Mitf突变肥大细胞表现出许多功能缺陷。因此,了解由Mitf调控的遗传程序可能会提供有关肥大细胞分化的重要见解。已经在多种细胞类型中鉴定出多种不同的Mitf同工型。我们发现Mitf-a,Mitf-e和Mitf-mc是肥大细胞表达的主要同工型。为了确定Mitf在肥大细胞中的生理功能,我们从Mitf - / -小鼠中恢复了这些同工型在原代肥大细胞中的表达。我们发现这些同工型恢复了颗粒形态和整联蛋白介导的迁移。通过微阵列分析,蛋白酶,信号分子,细胞表面受体和转运蛋白构成了所有同种型上调的最大基因组。此外,我们发现同工型还调节不同的基因集,表明可分离的生物学活性。这项工作定义了Mitf在肥大细胞中调节的转录组,并支持其作为肥大细胞分化的主要调节剂。该转录因子的多种同工型的表达可以提供生物活性的冗余,同时还允许功能的多样性。

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