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The Epigenetic Regulator PHF16 Redresses Homeostasis During Intestinal Injury Repair [RNA-seq]

ABSTRACT: The intestinal stem cells (ISCs) are highly vulnerable to DNA damage, being in a constant state of proliferation1. Reserve crypt stem cells restore homeostatic intestinal epithelium following damage-induced ablation of ISCs2-5. Here, we report that the epigenetic regulator PHD finger protein 16 (PHF16) redresses revival stem cell (revSC) activity after damage repair. Phf16-/Y mice showed defects in exit from the regenerative state of revSCs and failed in intestinal crypt regeneration, while they still induced revSCs in response to tissue damage, as observed using single-cell RNA-sequencing. RNA-sequencing and ATAC-sequencing analyses of Phf16-/Y intestinal organoids revealed that PHF16 controls intestinal epithelial differentiation by promoting HBO1-mediated histone H3K14 acetylation, while PHF16 also counteracts YAP/TAZ activity by ubiquitination of CDC73, faithfully reverting damage-induced revSCs to homeostatic gut epithelial cells. Together, our findings demonstrate the importance of timely suppression of regenerative activity by PHF16 for the restoration of gut homeostasis after acute tissue injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE230580 | GEO | 2025/07/06

REPOSITORIES: GEO

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The Epigenetic Regulator PHF16 Redresses Homeostasis During Intestinal Injury Repair

Project description:The intestinal stem cells (ISCs) are highly vulnerable to DNA damage, being in a constant state of proliferation1. Reserve crypt stem cells restore homeostatic intestinal epithelium following damage-induced ablation of ISCs2-5. Here, we report that the epigenetic regulator PHD finger protein 16 (PHF16) redresses revival stem cell (revSC) activity after damage repair. Phf16-/Y mice showed defects in exit from the regenerative state of revSCs and failed in intestinal crypt regeneration, while they still induced revSCs in response to tissue damage, as observed using single-cell RNA-sequencing. RNA-sequencing and ATAC-sequencing analyses of Phf16-/Y intestinal organoids revealed that PHF16 controls intestinal epithelial differentiation by promoting HBO1-mediated histone H3K14 acetylation, while PHF16 also counteracts YAP/TAZ activity by ubiquitination of CDC73, faithfully reverting damage-induced revSCs to homeostatic gut epithelial cells. Together, our findings demonstrate the importance of timely suppression of regenerative activity by PHF16 for the restoration of gut homeostasis after acute tissue injury.

2025-07-06 | GSE207746 | GEO

Chromatin Remodelling in Damaged Intestinal Crypts Orchestrates Redundant TGFβ and Hippo Signalling to Drive Regeneration

Project description:Regenerative cell state dynamics are under-characterized. Intestinal damage prompts reprogramming into revival stem cells (revSCs) that reconstitute Lgr5+ intestinal stem cells (ISCs). Here, single nuclear multiomics of crypts regenerating from irradiation shows revSC epigenetic profiles overlap with ISCs and differentiated lineages. RevSC genes themselves are accessible throughout homeostatic epithelia, while damage-induced crypt remodelling converges on the Hippo and TGFβ pathway that is transiently activated in the crypt and directly induces functional revSCs. Combinatorial analysis of gene expression suggests multiple sources of revSCs, and we show TGFb can reprogram Enterocytes, Goblet, and Paneth cells into revSCs, further demonstrating individual revSCs form organoids. Despite this, loss of TGFβ signalling yielded mild regenerative defects, whereas interference in both Hippo and TGFβ led to rapid intestinal collapse with no detectable revSCs or ISCs. Regenerative signalling is thus poised for activation by a compensatory system of crypt-localized, transient morphogen cues that support robust intestinal regeneration.

2024-08-19 | GSE230766 | GEO

Helminth-induced reprogramming of the stem cell niche inhibits type 2 immunity [scRNA-seq]

Project description:Enteric helminths form intimate physical connections with the intestinal epithelium, yet their ability to directly alter epithelial stem cell fate has not been resolved. Here we demonstrate that infection of mice with the symbiotic parasite Heligmosomoides polygyrus bakeri (Hpb), reprograms the intestinal epithelium into a fetal-like state marked by the emergence of Clusterin-expressing revival stem cells (revSCs). Organoid-based studies using parasite-derived excretory/secretory products reveal that Hpb-mediated revSC generation occurs independent of host-derived immune signals and inhibits type 2 cytokine-driven differentiation of secretory epithelial lineages that promote their expulsion. Reciprocally, type 2 cytokine signals limit revSC differentiation and, consequently, Hpb fitness indicating that helminths compete with their host for control of the intestinal stem cell niche to promote continuation of their life cycle.

2022-07-14 | GSE199226 | GEO

Helminth-induced reprogramming of the stem cell niche inhibits type 2 immunity [Bulk RNA-seq]

2022-07-14 | GSE199218 | GEO

Reg4+ Deep Crypt Secretory cells function as epithelial niche for Lgr5+ stem cells in colon

Project description:Lgr5+ stem cells reside at crypt bottoms of the small and large intestine. Small intestinal Paneth cells supply Wnt3, EGF and Notch signals to neighboring Lgr5+ stem cells. While the colon lacks Paneth cells, Deep Crypt Secretory (DCS) cells are intermingled with Lgr5+ stem cells at crypt bottoms. Here, we report Reg4 as a marker of DCS cells. To investigate a niche function, we eliminated DCS cells using the diphtheria-toxin receptor gene knocked into the murine Reg4 locus. Ablation of DCS cells results in loss of stem cells from colonic crypts and disrupts gut homeostasis and colon mini-gut formation. In agreement, sorted Reg4+ DCS cells promote organoid formation of single Lgr5+ colon stem cells. Stem cells are forced to generate DCS cells in vitro by combined Notch inhibition and Wnt activation. We conclude that Reg4+ DCS cells serve as Paneth cell equivalents in the colon crypt niche.

2016-10-05 | GSE63256 | GEO

Profiling of RNA Pol II occupancy in adult Drosophila terminal tracheal cell using TaDa (Targeted DamID) in context of homeostasis or damaged intestine

Project description:Cell-type specific transcriptional profiling is key to understanding cell fate specification, function and adaptation. This is particularly advantageous for studying specific cell types from complex tissues. In this study, we have used ‘TaDa’ (Targeted DamID), a technique that enables profiling of rare cell populations or cells difficult to isolate by conventional methods. Furthermore, TaDa profiling occurs in vivo and isn’t subject to artefacts arising from disruption of the tissues and cell sorting. Here, we profile the genome-wide binding of RNA polymerase II (Pol II) in terminal tracheal cells (TTCs) that are tightly associated with intestinal tissue from adult Drosophila. We compare terminal tracheal transcriptome from control to regenerative intestine in adult fly. Our data reveal new tracheal intrinsic mechanisms that are essential, in this gut-trachea communication, for regulating intestinal stem cell proliferative activity in context of damage. Our study represents the first analysis of terminal tracheal cell transcriptional profiling in context of homeostasis and regenerative adult intestine and provide new insight into the regulatory programs that underlie the complex interactions between gut-neighbourhood.

2020-12-21 | GSE163570 | GEO

Adiponectin regulated by IAA in Paneth cells controls renewal and differentiation of gut stem cells to maintain homeostasis of epithelial cells (small intestinal epithelium)

Project description:Crypt cells (mainly stem and transit amplifying (TA) cells) in Adipfl/flpVilli-CreT (gut epithelial cell adiponectin conditioned knockout) mice exhibited stronger ability of renewal and differentiation. ScRNA-seq found that there had much more enrichment intestinal stem and TA cells in Adipfl/flpVilli-CreT mice. The renewal and development of gut epithelial cells in irradiated or DSS (dextran sulfate sodium) treated Adipfl/flpVilli-CreT mice was faster than control Adipfl/flp mice. In vitro culture gut organoid of Adipfl/flpVilli-CreT mice exhibited faster growth than those from Adipfl/flp mice.

2024-06-21 | GSE270099 | GEO

Single-Cell Transcriptomes of the Regenerating Intestine Reveal a Revival Stem Cell [part 2]

Project description:The weekly turnover of the intestinal epithelium is driven by multipotent, Lgr5+, crypt base columnar cells (CBCs). In response to injury, however, Lgr5+ cells are lost but then re-emerge and are required for successful recovery. How these resurgent Lgr5+ stem cells arise is unclear. We transcriptionally profiled single cells from regenerating intestinal epithelia and identified a unique cell type we term the revival stem cell (rSC). rSCs are mutually exclusive to CBCs and are distinguished by elevated expression of cell survival and DNA repair genes. In homeostasis, rSCs are extremely rare, but nevertheless give rise to all the major cell types of the intestine including crypt-villus axes. After damage rSCs display a 20-fold, Yap-dependent, transient expansion, reconstitute the Lgr5+ CBC compartment and are required to regenerate a functional intestine. These studies define a unique stem cell phenotype that is mobilized by damage to reconstitute the intestinal epithelium.

2019-02-28 | GSE123515 | GEO

Single-Cell Transcriptomes of the Regenerating Intestine Reveal a Revival Stem Cell [part 1]

2019-02-28 | GSE117783 | GEO

Cell and chromatin transitions in intestinal stem cell regeneration

Project description:The progeny of intestinal stem cells (ISCs) dedifferentiate in response to ISC attrition. The precise cell sources, transitional states, and chromatin remodeling behind this activity remain unclear. In the skin, stem cell recovery after injury preserves an epigenetic memory of the damage response; whether similar memories arise and persist in regenerated ISCs is not known. We address these questions by examining gene activity and open chromatin at the resolution of single Neurog3-labeled mouse intestinal crypt cells, hence deconstructing forward and reverse differentiation of the intestinal secretory (Sec) lineage. We show that goblet, Paneth, and enteroendocrine cells arise by multilineage priming in common precursors, followed by selective access at thousands of cell-restricted cis-elements. Selective ablation of the ISC compartment elicits speedy reversal of chromatin and transcriptional features in large fractions of precursor and mature crypt Sec cells without obligate cell cycle re-entry. ISC programs decay and reappear along a cellular continuum lacking discernible discrete interim states. In the absence of gross tissue damage, Sec cells simply reverse their forward trajectories, without invoking developmental or other extrinsic programs, and starting chromatin identities are effectively erased. These findings identify strikingly plastic molecular frameworks in assembly and regeneration of a self-renewing tissue.

2022-06-07 | GSE183299 | GEO

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