Shared requirement for MYC upstream super-enhancer region in tissue regeneration and cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE244298 | GEO | 2025/03/30
REPOSITORIES: GEO
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Project description:Tissue regeneration after injury involves the dedifferentiation of somatic cells, a natural adaptive reprogramming that leads to the emergence of injury-responsive cells with fetal-like characteristics. However, there is no direct evidence that adaptive reprogramming involves a shared molecular mechanism with direct cellular reprogramming. Here, we induced dedifferentiation of intestinal epithelial cells using OSKM (Oct4, Sox2, Klf4, and c-Myc) in vivo. The OSKM-induced forced dedifferentiation showed similar molecular features of intestinal regeneration, including a transition from homeostatic cell types to injury-responsive-like cell types. These injury-responsive-like cells, sharing gene signatures of revival stem cells and atrophy-induced villus epithelial cells, actively assisted tissue regeneration following damage. In contrast to normal intestinal regeneration involving Ptgs2 induction, the OSKM promotes autonomous production of prostaglandin E2 via epithelial Ptgs1 expression. These results indicate prostaglandin synthesis is a common mechanism for intestinal regeneration, but involves a different enzyme when partial reprogramming is applied to the intestinal epithelium.
2023-11-26 | GSE238056 | GEO
Project description:Tissue regeneration after injury involves the dedifferentiation of somatic cells, a natural adaptive reprogramming that leads to the emergence of injury-responsive cells with fetal-like characteristics. However, there is no direct evidence that adaptive reprogramming involves a shared molecular mechanism with direct cellular reprogramming. Here, we induced dedifferentiation of intestinal epithelial cells using OSKM (Oct4, Sox2, Klf4, and c-Myc) in vivo. The OSKM-induced forced dedifferentiation showed similar molecular features of intestinal regeneration, including a transition from homeostatic cell types to injury-responsive-like cell types. These injury-responsive-like cells, sharing gene signatures of revival stem cells and atrophy-induced villus epithelial cells, actively assisted tissue regeneration following damage. In contrast to normal intestinal regeneration involving Ptgs2 induction, the OSKM promotes autonomous production of prostaglandin E2 via epithelial Ptgs1 expression. These results indicate prostaglandin synthesis is a common mechanism for intestinal regeneration, but involves a different enzyme when partial reprogramming is applied to the intestinal epithelium.
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Project description:Tissue regeneration after injury is thought to involve the dedifferentiation of somatic cells, which is often understood as evidence for natural adaptative reprogramming in vivo. In the intestinal epithelium, acute tissue damage triggers the rapid emergence of injury-responsive cells with fetal-like characteristics, a sign of dedifferentiation. However, there is no direct evidence that tissue regeneration involves a shared molecular mechanism with direct cellular reprogramming. It is also not known whether dedifferentiation shares a single (de)differentiation pathway or consists of multiple parallel routes between adult and fetal states. Here, we induced dedifferentiation of intestinal epithelial cells by forced partial reprogramming in vivo using the “Yamanaka factors” (Oct4, Sox2, Klf4 and c-Myc: OSKM). The induced dedifferentiation showed shared molecular features of intestinal regeneration, with rapid transition from homeostatic intestinal cell types to injury-responsive-like cells sharing a common gene signature of revival stem cells and atrophy-induced villus epithelial cells. When applied to intestinal organoids, induced dedifferentiation allowed the organoids to adopt fetal characteristics ex vivo, suggesting a direct effect on the intestinal epithelium. In vivo, induced dedifferentiation promoted regeneration from acute tissue injury caused by ionizing radiation (IR) via the formation of injury-responsive-like cells. Taken together, in the intestinal epithelium, in vivo reprogramming shares the same molecular pathway as damage-induced tissue regeneration and facilitates the repair process.
2023-11-26 | GSE237173 | GEO
Project description:Tissue regeneration after injury is thought to involve the dedifferentiation of somatic cells, which is often understood as evidence for natural adaptative reprogramming in vivo. In the intestinal epithelium, acute tissue damage triggers the rapid emergence of injury-responsive cells with fetal-like characteristics, a sign of dedifferentiation. However, there is no direct evidence that tissue regeneration involves a shared molecular mechanism with direct cellular reprogramming. It is also not known whether dedifferentiation shares a single (de)differentiation pathway or consists of multiple parallel routes between adult and fetal states. Here, we induced dedifferentiation of intestinal epithelial cells by forced partial reprogramming in vivo using the “Yamanaka factors” (Oct4, Sox2, Klf4 and c-Myc: OSKM). The induced dedifferentiation showed shared molecular features of intestinal regeneration, with rapid transition from homeostatic intestinal cell types to injury-responsive-like cells sharing a common gene signature of revival stem cells and atrophy-induced villus epithelial cells. When applied to intestinal organoids, induced dedifferentiation allowed the organoids to adopt fetal characteristics ex vivo, suggesting a direct effect on the intestinal epithelium. In vivo, induced dedifferentiation promoted regeneration from acute tissue injury caused by ionizing radiation (IR) via the formation of injury-responsive-like cells. Taken together, in the intestinal epithelium, in vivo reprogramming shares the same molecular pathway as damage-induced tissue regeneration and facilitates the repair process.
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Project description:Tissue stem cells govern tissue regeneration and wound-repair. Tumors often hijack these normal cellular programs and exploit them for malignancy. Here, we identify such a phenomenon in skin, where stem cells of the epidermis and hair follicle remain faithfully restricted to fueling their own tissue during homeostasis. They lose lineage fidelity during tumorigenesis. Moreover, breakdown of stem cell lineage confinement – granting privileges associated with both fates – is not only a hallmark, but also obligatory for malignancy. Intriguingly, we find that lineage plasticity is also critical in wound-repair, where it functions transiently to redirect fates. Probing mechanism, we show that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers are activated and override the normal enhancers that govern lineage-specificity. In cancer, stress-responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate new oncogenic enhancers that distinguish cancers from wounds.
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Project description:Lgr5+ intestinal stem cells (ISCs) play crucial roles in maintenance of the intestinal epithelium renewal and regeneration after injury. The mechanism underlying the interplay between Wnt and BMP signaling is not fully understood. Here we report that Bcl11b, which is downregulated by BMP signaling, enhances Wnt signaling to maintain Lgr5+ ISCs and promote the regeneration of the intestinal epithelium following damage. Conditional inactivation of the Bcl11b gene leads to a significant decrease of Lgr5+ ISCs in both mouse intestinal crypts and cultured organoids. Mechanistically, BMP suppresses the expression of Bcl11b, which can positively regulate Wnt target genes by inhibiting the function of the Nucleosome Remodeling and Deacetylase (NuRD) complex and facilitating the β-catenin-TCF4 interaction. Bcl11b can also promote intestinal epithelium repair after injuries elicited by both irradiation and DSS-induced inflammation. Furthermore, Bcl11b deletion prevents proliferation and tumorigenesis of colorectal cancer cells. Together, our findings suggest that BMP balances Wnt signaling via Bcl11b to delicately regulate the homeostasis and regeneration of the intestinal epithelium.
2024-10-15 | GSE255138 | GEO
Project description:Regeneration requires the coordination of stem cells, their progeny and distant differentiated tissues. Here, we present a comprehensive atlas of whole-body regeneration in Schmidtea mediterranea and identify wound-induced cell states. An analysis of 299,998 single-cell transcriptomes captured from regeneration-competent and regeneration-incompetent fragments identified transient regeneration-activated cell states (TRACS) in the muscle, epidermis and intestine. TRACS were independent of stem cell division with distinct spatiotemporal distributions, and RNAi depletion of TRACS-enriched genes produced regeneration defects. Muscle expression of notum, follistatin, evi/wls, glypican-1 and junctophilin-1 was required for tissue polarity. Epidermal expression of agat-1/2/3, cyp3142a1, zfhx3 and atp1a1 was important for stem cell proliferation. Finally, expression of spectrinβ and atp12a in intestinal basal cells, and lrrk2, cathepsinB, myosin1e, polybromo-1 and talin-1 in intestinal enterocytes regulated stem cell proliferation and tissue remodelling, respectively. Our results identify cell types and molecules that are important for regeneration, indicating that regenerative ability can emerge from coordinated transcriptional plasticity across all three germ layers.
2021-06-11 | GSE146685 | GEO
Project description:The role of the immune system in regulating tissue stem cells remains poorly understood, as does the relationship between immune-mediated tissue damage and regeneration. Graft vs. host disease (GVHD) occurring after allogeneic bone marrow transplantation (allo-BMT) involves immune-mediated damage to the intestinal epithelium and its stem cell compartment. To assess impacts of T-cell-driven injury on distinct epithelial constituents, we performed single cell RNA sequencing on intestinal crypts following experimental BMT. Intestinal stem cells (ISCs) from GVHD mice exhibited global transcriptomic changes associated with a substantial Interferon-γ response and upregulation of STAT1. To determine its role in crypt function, STAT1 was deleted within murine intestinal epithelium. Following allo-BMT, STAT1 deficiency resulted in reduced epithelial proliferation and impaired ISC recovery. Similarly, epithelial Interferon-γ receptor deletion also attenuated proliferation and ISC recovery post-transplant. Investigating the mechanistic basis underlying this epithelial response, ISC STAT1 expression in GVHD was found to correlate with upregulation of ISC c-Myc. Furthermore, activated T cells stimulated Interferon-γ- dependent epithelial regeneration in co-cultured organoids, and Interferon-γ directly induced STAT1-dependent c-Myc expression and ISC proliferation. These findings illustrate immunologic regulation of a core tissue stem cell program after damage and support a role for Interferon-γ as a direct contributor to epithelial regeneration.
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