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

Pratik N P Singh; Wei Gu; Shariq Madha; Allen W Lynch; Paloma Cejas; Ruiyang He; Swarnabh Bhattacharya; Miguel Muñoz Gomez; Matthew G Oser; Myles Brown; Henry W Long; Clifford A Meyer; Qiao Zhou; Ramesh A Shivdasani

doi:10.1016/j.stem.2024.04.015

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

Cell Stem Cell. 2024 May 7:S1934-5909(24)00142-5. doi: 10.1016/j.stem.2024.04.015. Online ahead of print.

Authors

Affiliations

¹ 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.
² Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ 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.
⁶ 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.
⁷ Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: jqz4001@med.cornell.edu.
⁸ 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.

PMID: 38733993
DOI: 10.1016/j.stem.2024.04.015

Abstract

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.

Keywords: chromatin dynamics; determination of terminal cell fates; hormone producing cells; human enteroendocrine cells; intestinal stem cells; transcription factor oscillation.