Dataset Information

Proliferation and differentiation of intestinal stem cells depends on the zinc finger transcription factor BCL11/Chronophage

ABSTRACT: The molecular programs that drive proliferation and differentiation of intestinal stem cells (ISCs) are essential for organismal fitness. Notch signalling regulates the binary fate decision of ISCs, favouring enterocyte commitment when Notch activity is high and enteroendocrine cell (EE) fate when activity is low. However, the gene regulatory mechanisms that underlie this process on an organ scale remain poorly understood. Here, we find that the expression of the C2H2-type zinc-finger transcription factor Chronophage (Cph), homologous to mammalian BCL11, increases specifically along the ISC-to-EE lineage when Notch is inactivated. We show that the expression of Cph is regulated by the Achaete-Scute Complex (AS-C) gene, scute, which directly binds to multiple sites within the Cph locus to promote its expression. Our genetic and single-cell RNA sequencing experiments demonstrate that Cph maintains the ISC and EE populations and is necessary to remodel the transcriptome of progenitor cells with low Notch activity. By identifying and functionally validating Cph target genes, we uncover a novel role for sugar free frosting (sff) in directing proliferative and lineage commitment steps of ISCs. Our findings provide mechanistic insight into how Cph maintains intestinal epithelial homeostasis, and together with our evolutionary analysis of Cph/BCL11, suggests that it may represent a general mechanism used by adult somatic stem cells in other tissues to balance proliferation and differentiation.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE280439 | GEO | 2024/10/28

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background & Aims: Hierarchical organization of intestine relies on their stem cells by self-renew and producing committed progenitors. Although signals like Wnt are known to animate the continued renewal by maintaining intestinal stem cells (ISCs) activity, molecular mechanisms especially E3 ubiquitin ligases that modulate ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (Cul4b) in regulating ISC functions. Methods: We generated mice with intestinal epithelial-specific disruption of Cul4b (pVillin-cre; Cul4bfn/Y), inducible disruption of Cul4b (Lgr5-creERT2; Cul4bfn/Y, CAG-creERT2; Cul4bfn/Y) and their control (Cul4bfn/Y). Intestinal tissues were analyzed by histology, immunofluorescence, RNA sequencing and mass spectrum. Intestinal organoids deprived from mice with pVillin-Cre; Cul4bfn/Y, Lgr5-Cre; Cul4bfn/Y, Tg-Cul4b and their controls were used in assays to measure intestinal self-renewal, proliferation and differentiation. Wnt signaling and intestinal markers were analyzed by immunofluorescence and immunoblot assays. Differential proteins upon Cul4b ablation or Cul4b-interacting proteins were identified by mass spectrometry. Results: Cul4b specifically located at ISCs zone. Block of Cul4b impaired intestinal homeostasis maintenance by reduced self-renewal and proliferation. Transcriptome analysis revealed that Cul4b-null intestine lose ISC characterization and showed disturbed ISC niche. Mechanistically, reactivated Wnt pathway could recover intestinal dysfunction of Cul4b knockout mice. Analysis of differential total and ubiquitylated proteins uncovered the novel targeting substrate of Cullin-Ring ubiquitin ligase 4b (CRL4b), immunity-related GTPase family M member 1 (Irgm1) in intestine. Decreased Irgm1 rescued abnormally interferon signaling, overemphasized autophagy and downstream phosphate proteins in Cul4b knockout mice. Conclusion: We conclude that Cul4b is essential for ISC self-renewal and Paneth cell function by targeting Irgm1 and modulating Wnt signaling. Our results demonstrate that Cul4b is a novel ISC stemness and niche regulator.

Dataset Information

Proliferation and differentiation of intestinal stem cells depends on the zinc finger transcription factor BCL11/Chronophage

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets