【科技前瞻】MSB：研究发现调控干细胞的分化命运的转录因子

生物_医药_科研 2019-10-16

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近日，研究人员发现蛋白质浓度的时间波动或能决定胚胎干细胞所转变的细胞类型。研究者对SOX2和OCT4的重要转录因子进行研究，发现这两种转录因子在胚胎干细胞中会随着时间发生改变，其对于胚胎干细胞的自我更新及分化为特定细胞类型非常重要。相关研究结果发表在Molecular Systems Biology杂志上。

该研究进行了复杂的基因工程操作，在一条胚胎干细胞线上制造了5个敲入的“报告”基因，以便可在活体细胞中随着时间延续来随时监测SOX2和OCT4的波动情况，同时阐明这些波动如何影响胚胎干细胞的命运。研究者发现，上述任意一种转录因子水平的小变化都会影响细胞的命运，但仅在细胞生长的G1阶段，增加SOX2的水平似乎会将胚胎干细胞推向神经元型细胞分化方向，而提高OCT4的水平则会强烈地将细胞转向分化为神经元细胞和非神经元细胞，较高的OCT4水平会增加分化因子对细胞染色质的可及性。研究者表示，由于转录因子浓度的波动在很大程度上由基因表达级联的内在随机性所驱动，这或许为我们改变细胞命运从而达到治疗目的的能力设定了基本的限制，后期研究人员将确定这些波动是否能够被部分所抑制，从而减缓其对控制胚胎干细胞命运的影响。

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Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions.

SOX2 and OCT4 are pioneer transcription factors playing a key role in embryonic stem (ES) cell self‐renewal and differentiation. How temporal fluctuations in their expression levels bias lineage commitment is unknown. Here, we generated knock‐in reporter fusion ES cell lines allowing to monitor endogenous SOX2 and OCT4 protein fluctuations in living cells and to determine their impact on mesendodermal and neuroectodermal commitment. We found that small differences in SOX2 and OCT4 levels impact cell fate commitment in G1 but not in S phase. Elevated SOX2 levels modestly increased neuroectodermal commitment and decreased mesendodermal commitment upon directed differentiation. In contrast, elevated OCT4 levels strongly biased ES cells towards both neuroectodermal and mesendodermal fates in undirected differentiation. Using ATAC‐seq on ES cells gated for different endogenous SOX2 and OCT4 levels, we found that high OCT4 levels increased chromatin accessibility at differentiation‐associated enhancers. This suggests that small endogenous fluctuations of pioneer transcription factors can bias cell fate decisions by concentration‐dependent priming of differentiation‐associated enhancers.