Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation

被引:3
作者
Singh, Pratik N. P. [1 ,2 ]
Gu, Wei [3 ,7 ]
Madha, Shariq [1 ]
Lynch, Allen W. [2 ]
Cejas, Paloma [2 ]
He, Ruiyang [2 ]
Bhattacharya, Swarnabh [1 ,2 ]
Gomez, Miguel Munoz [2 ]
Oser, Matthew G. [1 ,4 ,5 ]
Brown, Myles [1 ,2 ,4 ,5 ]
Long, Henry W. [2 ]
Meyer, Clifford A. [2 ]
Zhou, Qiao [3 ]
Shivdasani, Ramesh A. [1 ,2 ,4 ,5 ,6 ]
机构
[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA
[2] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA
[3] Weill Cornell Med, Dept Med, Div Regenerat Med, New York, NY 10065 USA
[4] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[5] Harvard Med Sch, Boston, MA 02115 USA
[6] Harvard Stem Cell Inst, Cambridge, MA 02138 USA
[7] BeiGene Res & Dev Co Ltd, Shanghai 200131, Peoples R China
关键词
NEUROENDOCRINE DIFFERENTIATION; GENE-EXPRESSION; NEURONAL CELLS; FATE CHOICE; CHROMATIN; LINEAGE; ASCL1; NEUROGENIN-3; DISTINCT; SPECIFICATION;
D O I
10.1016/j.stem.2024.04.015
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Enteroendocrine cells (EECs) secrete serotonin (enterochromaffin [EC] cells) or specific peptide hormones (non-EC cells) that serve vital metabolic functions. The basis for terminal EEC diversity remains obscure. By forcing activity of the transcription factor (TF) NEUROG3 in 2D cultures of human intestinal stem cells, we replicated physiologic EEC differentiation and examined transcriptional and cis-regulatory dynamics that culminate in discrete cell types. Abundant EEC precursors expressed stage-specific genes and TFs. Before expressing pre-terminal NEUROD1, post-mitotic precursors oscillated between transcriptionally distinct ASCL1 + and HES6 hi cell states. Loss of either factor accelerated EEC differentiation substantially and disrupted EEC individuality; ASCL1 or NEUROD1 deficiency had opposing consequences on EC and non-EC cell features. These TFs mainly bind cis-elements that are accessible in undifferentiated stem cells, and they tailor subsequent expression of TF combinations that underlie discrete EEC identities. Thus, early TF oscillations retard EEC maturation to enable accurate diversity within a medically important cell lineage.
引用
收藏
页码:1038 / 1057.e11
页数:32
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