Genetic and Chemical Screenings Identify HDAC3 as a Key Regulator in Hepatic Differentiation of Human Pluripotent Stem Cells.
Genetic and Chemical Screenings Identify HDAC3 as a Key Regulator in Hepatic Differentiation of Human Pluripotent Stem Cells.
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DOI：
10.1016/j.stemcr.2018.05.001
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发表时间：
2018-07-10
影响因子：
5.9
通讯作者：
Ding Q
中科院分区：
文献类型：
--
作者：
Li S;Li M;Liu X;Yang Y;Wei Y;Chen Y;Qiu Y;Zhou T;Feng Z;Ma D;Fang J;Ying H;Wang H;Musunuru K;Shao Z;Zhao Y;Ding Q
源自人类多能干细胞 (hPSC) 的肝细胞样细胞 (HLC) 为疾病建模和移植提供了有前途的细胞资源。然而，分化的 HLC 表现出不成熟的表型并包含异质群体。因此，更好地理解 HLC 差异将提高未来应用的可能性。在这里，通过利用基于 CRISPR-Cas9 的全基因组筛选技术和具有报告读数的高通量 hPSC 筛选平台，我们鉴定了 HLC 分化的几种潜在遗传调节因子。通过在我们的平台内使用化学筛选方法，我们还确定了可以进一步促进 HLC 分化并保留体外培养的原代肝细胞特征的化合物。值得注意的是，两项筛选均发现组蛋白脱乙酰酶 3 (HDAC3) 是肝分化的关键调节因子。从机制上讲，HDAC3 与肝脏转录因子（例如 HNF4）形成复合物，并在肝脏分化过程中共同调节转录程序。这项研究强调了一种研究和优化 hPSC 分化的广泛有用的方法。全基因组遗传筛查以确定肝分化中的调节因子 HDAC3 调节肝分化 小分子 CI-994 治疗可改善肝分化 研究和优化 hPSC 分化的广泛有用方法 Ding 及其同事开发了一种广泛有用的方法来研究参与人类多能干细胞肝分化的新型调节因子，该方法结合了报告系统构建、全基因组 基于 CRISPR-Cas9 的遗传筛选和靶向化学筛选。研究表明 HDAC3 是肝谱系决定的关键调节因子。
Hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) offer a promising cell resource for disease modeling and transplantation. However, differentiated HLCs exhibit an immature phenotype and comprise a heterogeneous population. Thus, a better understanding of HLC differentiation will improve the likelihood of future application. Here, by taking advantage of CRISPR-Cas9-based genome-wide screening technology and a high-throughput hPSC screening platform with a reporter readout, we identified several potential genetic regulators of HLC differentiation. By using a chemical screening approach within our platform, we also identified compounds that can further promote HLC differentiation and preserve the characteristics of in vitro cultured primary hepatocytes. Remarkably, both screenings identified histone deacetylase 3 (HDAC3) as a key regulator in hepatic differentiation. Mechanistically, HDAC3 formed a complex with liver transcriptional factors, e.g., HNF4, and co-regulated the transcriptional program during hepatic differentiation. This study highlights a broadly useful approach for studying and optimizing hPSC differentiation. Genome-wide genetic screening to identify regulators in hepatic differentiation HDAC3 regulates hepatic differentiation Small molecule CI-994 treatment improves hepatic differentiation A broadly useful approach for studying and the optimization of hPSC differentiation Ding and colleagues developed a broadly useful approach to study novel regulators involved in hepatic differentiation of human pluripotent stem cells, with a combination of reporter system construction, genome-wide CRISPR-Cas9-based genetic screening, and targeted chemical screening. Studies revealed HDAC3 as a key regulator in hepatic lineage determination.
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一个 iCRISPR 平台，用于在人类多能干细胞中进行快速、可多重、可诱导的基因组编辑。
影响因子：
23.9
作者：
Gonzalez, Federico;Zhu, Zengrong;Shi, Zhong-Dong;Lelli, Katherine;Verma, Nipun;Li, Qing V.;Huangfu, Danwei
通讯作者：
Huangfu, Danwei
连续的 EMT-MET 机制驱动人胚胎干细胞向肝细胞分化。
影响因子：
16.6
作者：
Li Q;Hutchins AP;Chen Y;Li S;Shan Y;Liao B;Zheng D;Shi X;Li Y;Chan WY;Pan G;Wei S;Shu X;Pei D
通讯作者：
Pei D
DOI：
10.1083/jcb.126.1.223
发表时间：
1994-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Nagy P;Bisgaard HC;Thorgeirsson SS
通讯作者：
Thorgeirsson SS
影响因子：
50.3
作者：
Bhaskara S;Knutson SK;Jiang G;Chandrasekharan MB;Wilson AJ;Zheng S;Yenamandra A;Locke K;Yuan JL;Bonine-Summers AR;Wells CE;Kaiser JF;Washington MK;Zhao Z;Wagner FF;Sun ZW;Xia F;Holson EB;Khabele D;Hiebert SW
通讯作者：
Hiebert SW
影响因子：
64.5
作者：
Poleshko A;Shah PP;Gupta M;Babu A;Morley MP;Manderfield LJ;Ifkovits JL;Calderon D;Aghajanian H;Sierra-Pagán JE;Sun Z;Wang Q;Li L;Dubois NC;Morrisey EE;Lazar MA;Smith CL;Epstein JA;Jain R
通讯作者：
Jain R