Structural Features of Transcription Factors Associating with Nucleosome Binding
Structural Features of Transcription Factors Associating with Nucleosome Binding
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DOI：
10.1016/j.molcel.2019.06.009
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发表时间：
2019-09-05
期刊：
影响因子：
16
通讯作者：
Zaret, Kenneth S.
中科院分区：
文献类型：
--
作者：
Garcia, Meilin Fernandez;Moore, Cedric D.;Zaret, Kenneth S.
改变命运的转录因子（TF）扫描染色质，在细胞分化和重编程过程中启动新的遗传程序。然而，允许TF靶向核小体DNA的蛋白质结构域仍然未被探索。我们筛选了不同的转录因子结合到核小体含有基序富集序列的先锋因子在体内的目标。FOXA 1、OCT 4、ASCL 1/E12 α、PU 1、CEBP α和ZELDA显示出一系列与其细胞重编程潜力相关的核小体结合亲和力。我们进一步在蛋白质微阵列上针对不同的核小体序列筛选了593个全长人TF，然后在溶液中进行确认，以区分结合核小体的因子，如神经元AP-2 α/β/γ，与仅结合游离DNA的因子。DNA结合结构域的结构比较显示，有效的核小体粘合剂使用短锚定a螺旋结合DNA，而弱核小体粘合剂使用非结构化区域和/或β折叠。因此，DNA相互作用的特定模式允许核小体扫描，赋予转录因子先锋活性。
Fate-changing transcription factors (TFs) scan chromatin to initiate new genetic programs during cell differentiation and reprogramming. Yet the protein structure domains that allow TFs to target nucleosomal DNA remain unexplored. We screened diverse TFs for binding to nucleosomes containing motif-enriched sequences targeted by pioneer factors in vivo. FOXA1, OCT4, ASCL1/E12 alpha, PU1, CEBP alpha, and ZELDA display a range of nucleosome binding affinities that correlate with their cell reprogramming potential. We further screened 593 full-length human TFs on protein microarrays against different nucleosome sequences, followed by confirmation in solution, to distinguish among factors that bound nucleosomes, such as the neuronal AP-2 alpha/beta/gamma, versus factors that only bound free DNA. Structural comparisons of DNA binding domains revealed that efficient nucleosome binders use short anchoring a helices to bind DNA, whereas weak nucleosome binders use unstructured regions and/or beta sheets. Thus, specific modes of DNA interaction allow nucleosome scanning that confers pioneer activity to transcription factors.