Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK.
EMBO J. 2014 Jun 2;33(11):1212-26. doi: 10.1002/embj.201386825. Epub 2014 Apr 23.
Despite major advances in the generation of genome-wide binding maps, the mechanisms by which transcription factors (TFs) regulate cell type identity have remained largely obscure. Through comparative analysis of 10 key haematopoietic TFs in both mast cells and blood progenitors, we demonstrate that the largely cell type-specific binding profiles are not opportunistic, but instead contribute to cell type-specific transcriptional control, because (i) mathematical modelling of differential binding of shared TFs can explain differential gene expression, (ii) consensus binding sites are important for cell type-specific binding and (iii) knock-down of blood stem cell regulators in mast cells reveals mast cell-specific genes as direct targets. Finally, we show that the known mast cell regulators Mitf and c-fos likely contribute to the global reorganisation of TF binding profiles. Taken together therefore, our study elucidates how key regulatory TFs contribute to transcriptional programmes in several distinct mammalian cell types.
尽管在生成全基因组结合图谱方面取得了重大进展，但转录因子 (TF) 调节细胞类型身份的机制在很大程度上仍然不清楚。通过对肥大细胞和血液祖细胞中 10 种关键造血 TF 的比较分析，我们证明了这些主要的细胞类型特异性结合谱不是偶然的，而是有助于细胞类型特异性转录控制，因为 (i) 共享 TF 的差异结合的数学建模可以解释差异基因表达，(ii) 共识结合位点对于细胞类型特异性结合很重要，(iii) 在肥大细胞中敲低血液干细胞调节剂会揭示肥大细胞特异性基因作为直接靶标。最后，我们表明已知的肥大细胞调节剂 Mitf 和 c-fos 可能有助于 TF 结合谱的全局重新组织。因此，总的来说，我们的研究阐明了关键调节 TF 如何有助于几种不同哺乳动物细胞类型的转录程序。
