TP53 promotes lineage commitment of human embryonic stem cells through ciliogenesis and sonic hedgehog signaling.
TP53 promotes lineage commitment of human embryonic stem cells through ciliogenesis and sonic hedgehog signaling.
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DOI：
10.1016/j.celrep.2022.110395
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发表时间：
2022-02-15
期刊：
影响因子：
8.8
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Sivakumar S;Qi S;Cheng N;Sathe AA;Kanchwala M;Kumar A;Evers BM;Xing C;Yu H
非整倍体、分化缺陷和肿瘤抑制因子TP 53的失活均在肿瘤发生过程中频繁发生。在这里，我们通过灭活人类胚胎干细胞（hESC）中的TP 53来探索这些癌症特征之间的潜在联系。TP 53 −/− hESC表现出增殖率增加、有丝分裂错误和低度结构非整倍性;在小鼠中产生分化不良的未成熟畸胎瘤;并且在体外不能分化为神经祖细胞（NPC）。全基因组CRISPR筛选揭示了hESC分化为NPC的纤毛发生和音刺猬（Shh）途径的要求。TP 53基因缺失导致神经节纤毛发生异常。除了通过CDKN 1A抑制细胞增殖外，TP 53还激活BBS 9的转录，BBS 9编码适当Shh信号传导和NPC形成所需的纤毛发生调节剂。TP 53的这种发育调节的转录程序促进纤毛发生，抑制Shh信号传导，并使hESC向神经谱系转化。Sivakumar等人表明，肿瘤抑制因子TP 53促进人胚胎干细胞（hESC）分化为成熟畸胎瘤。他们进一步确定了TP 53的发育调节转录程序，该程序促进纤毛发生，抑制Shh信号传导，并将hESC提交给神经谱系。他们的发现暗示了TP 53在肿瘤抑制中的分化促进功能。
Aneuploidy, defective differentiation, and inactivation of the tumor suppressor TP53 all occur frequently during tumorigenesis. Here, we probe the potential links among these cancer traits by inactivating TP53 in human embryonic stem cells (hESCs). TP53−/− hESCs exhibit increased proliferation rates, mitotic errors, and low-grade structural aneuploidy; produce poorly differentiated immature teratomas in mice; and fail to differentiate into neural progenitor cells (NPCs) in vitro. Genome-wide CRISPR screen reveals requirements of ciliogenesis and sonic hedgehog (Shh) pathways for hESC differentiation into NPCs. TP53 deletion causes abnormal ciliogenesis in neural rosettes. In addition to restraining cell proliferation through CDKN1A, TP53 activates the transcription of BBS9, which encodes a ciliogenesis regulator required for proper Shh signaling and NPC formation. This developmentally regulated transcriptional program of TP53 promotes ciliogenesis, restrains Shh signaling, and commits hESCs to neural lineages. Sivakumar et al. show that the tumor suppressor TP53 promotes human embryonic stem cell (hESC) differentiation into mature teratomas. They further identify a developmentally regulated transcriptional program of TP53 that promotes ciliogenesis, restrains Shh signaling, and commits hESCs to neural lineages. Their findings implicate the differentiation-promoting function of TP53 in tumor suppression.
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