Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks.
Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks.
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DOI：
10.1101/gad.268821.115
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发表时间：
2015-12-01
影响因子：
10.5
通讯作者：
Hemberger M
中科院分区：
文献类型：
--
作者：
Latos PA;Sienerth AR;Murray A;Senner CE;Muto M;Ikawa M;Oxley D;Burge S;Cox BJ;Hemberger M
拉托斯等人。证明ELF5的精确水平对于滋养层干细胞(TSC)室的正常扩张和胚胎存活至关重要。他们的数据将ELF5置于化学计量学敏感的转录网络的中心，在那里它扮演着控制TSC增殖和分化之间平衡的分子开关。ELF5是一种转录因子，在滋养层中起关键作用，在那里它加强滋养层干细胞(TSC)特异性转录回路。然而，ELF5也存在于滋养层细胞的分化中，这些滋养层细胞已经停止表达其他TSC基因，如CDX2和Eome。在本研究中，我们旨在阐明ELF5在TSC自我更新和分化开始之间的界面上的上下文依赖作用。我们证明，ELF5的精确水平对于TSC的正常扩张和胚胎存活至关重要，因为ELF5的过度表达触发了早熟滋养层细胞的分化。通过整合蛋白质相互作用组、转录组和全基因组染色质免疫沉淀数据，我们揭示了这种丰度依赖的功能是通过首选ELF5结合伙伴的改变来调节的；在TSCs中，ELF5与EBES的相互作用将Tfap2c招募到TSC特异性基因的三倍占据位置，推动它们的表达。相反，ELF5和Tfap2c的相互作用随着其蛋白质水平的增加而变得主要。这会触发与含有同源Tfap2c基序的双占位和单占位结合，导致相关的促进分化基因的激活。这些数据将ELF5置于化学计量学敏感的转录网络的中心，在那里它扮演着控制TSC增殖和分化之间平衡的分子开关。
Latos et al. demonstrate that precise levels of Elf5 are critical for normal expansion of the trophoblast stem cell (TSC) compartment and embryonic survival. Their data place Elf5 at the center of a stoichiometry-sensitive transcriptional network, where it acts as a molecular switch governing the balance between TSC proliferation and differentiation. Elf5 is a transcription factor with pivotal roles in the trophoblast compartment, where it reinforces a trophoblast stem cell (TSC)-specific transcriptional circuit. However, Elf5 is also present in differentiating trophoblast cells that have ceased to express other TSC genes such as Cdx2 and Eomes. In the present study, we aimed to elucidate the context-dependent role of Elf5 at the interface between TSC self-renewal and the onset of differentiation. We demonstrate that precise levels of Elf5 are critical for normal expansion of the TSC compartment and embryonic survival, as Elf5 overexpression triggers precocious trophoblast differentiation. Through integration of protein interactome, transcriptome, and genome-wide chromatin immunoprecipitation data, we reveal that this abundance-dependent function is mediated through a shift in preferred Elf5-binding partners; in TSCs, Elf5 interaction with Eomes recruits Tfap2c to triply occupied sites at TSC-specific genes, driving their expression. In contrast, the Elf5 and Tfap2c interaction becomes predominant as their protein levels increase. This triggers binding to double- and single-occupancy sites that harbor the cognate Tfap2c motif, causing activation of the associated differentiation-promoting genes. These data place Elf5 at the center of a stoichiometry-sensitive transcriptional network, where it acts as a molecular switch governing the balance between TSC proliferation and differentiation.