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

Autor:	Singh PNP; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Gu W; Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Madha S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Lynch AW; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Cejas P; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA., He R; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Bhattacharya S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Muñoz Gomez M; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Oser MG; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Brown M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Long HW; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Meyer CA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Zhou Q; Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: jqz4001@med.cornell.edu., Shivdasani RA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: ramesh_shivdasani@dfci.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell stem cell [Cell Stem Cell] 2024 Jul 05; Vol. 31 (7), pp. 1038-1057.e11. Date of Electronic Publication: 2024 May 10.
DOI:	10.1016/j.stem.2024.04.015
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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