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Pioneer transcription factor FoxA is positioned on hypersensitive nucleosomes at active enhancers

机译:先锋转录因子FoxA位于活性增强子的超敏核小体上

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The Nucleosome organization at gene regulatorysequences, such as at enhancers and promoters, is essentialfor understanding how genes are regulated. We haveaddressed how local nucleosome positioning and sensitivityare regulated in a tissue-specific manner focusing onpioneer transcription factor FoxA. FoxA can open a localdomain of compacted chromatin in vitro, in the absenceof ATP-dependent remodeling enzymes. Although micrococcalnuclease (MNase)-based genome-wide nucleosomemaps have been developed extensively, many studies aresubject to an overdigestion bias that may fail to mapMNase-hypersensitive nucleosomes. We mapped thehypersensitive nucleosomes in mouse liver on genomicscale by carefully titrating the MNase digestion level. Wefound the hypersensitive nucleosomes were specificallylocated at active enhancers and promoters, and correlatedwith DNase l-hypersensitive sites. Furthermore, majorityof FoxA2 binding events overlapped with the hypersensitivenucleosomes at active enhancers. We identified anamphipathic helix structure in C-terminal domain ofFoxA that was required for the chromatin opening andthe activation of target genes. We suggest that the pioneertranscription factor FoxA can organize nucleosome structuresthat are essential for gene activation.
机译:基因调控序列(如增强子和启动子)上的核小体组织对于理解基因的调控至关重要。我们已经解决了如何集中于先锋转录因子FoxA的组织特异性方式调节局部核小体的定位和敏感性。 FoxA可以在没有ATP依赖的重塑酶的情况下在体外打开紧密染色质的局部结构域。尽管已经广泛开发了基于微球菌核酸酶(MNase)的全基因组核小体图,但许多研究仍存在消化不良的偏见,可能无法绘制MNase超敏核小体的图。通过仔细滴定MNase消化水平,我们在基因组规模上绘制了小鼠肝脏中的超敏核小体。我们发现超敏核小体特异性地定位在活性增强子和启动子上,并与DNasel超敏位点相关。此外,大多数FoxA2结合事件与超敏核小体在活性增强子上重叠。我们确定了FoxA的C末端域中的两亲性螺旋结构,这是染色质打开和激活目标基因所必需的。我们建议,先锋转录因子FoxA可以组织对基因激活至关重要的核小体结构。

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