生物
增强子
肝细胞核因子4
细胞生物学
染色质
福克斯A1
爪蟾
转录因子
诱导多能干细胞
核受体
甲状腺激素受体
基因表达
染色质重塑
基因表达调控
肝细胞
分子生物学
作者
Haiting Ma,Esmée de Zwaan,Yang Eric Guo,Paloma Cejas,Prathapan Thiru,Martijn van de Bunt,Jacob F Jeppesen,Sudeepa Syamala,Alessandra Dall'Agnese,Brian J Abraham,Dongdong Fu,Carrie Garrett-Engele,Tong Ihn Lee,Henry W Long,Linda G Griffith,Richard A Young,Rudolf Jaenisch
标识
DOI:10.1016/j.stem.2022.03.015
摘要
To understand the mechanisms regulating the in vitro maturation of hPSC-derived hepatocytes, we developed a 3D differentiation system and compared gene regulatory elements in human primary hepatocytes with those in hPSC-hepatocytes that were differentiated in 2D or 3D conditions by RNA-seq, ATAC-seq, and H3K27Ac ChIP-seq. Regulome comparisons showed a reduced enrichment of thyroid receptor THRB motifs in accessible chromatin and active enhancers without a reduced transcription of THRB. The addition of thyroid hormone T3 increased the binding of THRB to the CYP3A4 proximal enhancer, restored the super-enhancer status and gene expression of NFIC, and reduced the expression of AFP. The resultant hPSC-hepatocytes showed gene expression, epigenetic status, and super-enhancer landscape closer to primary hepatocytes and activated regulatory regions including non-coding SNPs associated with liver-related diseases. Transplanting the hPSC-hepatocytes resulted in the engraftment of human hepatocytes into the mouse liver without disrupting normal liver histology. This work implicates the environmental factor-nuclear receptor axis in regulating the maturation of hPSC-hepatocytes.
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