Cell and chromatin transitions in intestinal stem cell regeneration
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ABSTRACT:
PROVIDER: PRJNA759894 | ENA |
REPOSITORIES: ENA
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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
Project description:The limited regenerative capacity of the human heart is responsible for the high morbidity and mortality world-wide. In contrast, zebrafish possess a robust regenerative capacity. Here, we have characterized the chromatin state transitions during zebrafish heart regeneration and interrogated how gene expression patterns are orchestrated. We found a massive gain of repressive chromatin marks one day after myocardial injury, followed by a large-scale acquisition of active chromatin characteristics on day 4 and a switch to a repressive state on day 14. The correlative analysis predicted known and less well-characterized transcription factors and transcription factor ensembles involved in these transitions and classified them into activators or repressors of specific gene expression programs. Detailed analysis revealed that rapid transcriptional responses involved in extracellular matrix reorganization and TOR signaling involve the engagement of super-enhancers, while H3K4me3 breadth highly correlates with transcriptional activity and the dynamic transcriptional changes at genes involved in proteolysis, cell cycle activity, and cell differentiation. Finally, we detected significant evolutionary conservation between the regulatory regions that drive zebrafish and neonatal mouse regeneration, suggesting that reactivation of transcriptional and epigenetic networks converging on these conserved elements might unlock the regenerative potential of adult human hearts
2024-01-25 | GSE211677 | GEO
Project description:Alterations that perturb differentiation and cell state transitions can lead to defects in development, function and the genesis of cancer. Studying cellular plasticity at high resolution and in real time has proven difficult using existing methods. Here, we use a quantitative approach to gain insights into cell state dynamics of normal mammary epithelial cells (MECs) and validate the model's predictions in vivo. In the absence of Slug/SNAI2, basal mammary progenitor cells transition into a luminal differentiation state, while luminal progenitor cells proliferate and expand; these changes result in abnormal mammary architecture and defects in tissue function. Loss of Slug also disrupts cellular plasticity leading to defects in tissue regeneration and the initiation of cancer. Mechanistically, Slug promotes cellular plasticity by recruiting the chromatin modifier, LSD1 (lysine specific demethylase 1), to promoters of lineage specific genes to represses transcription. Together, these finding demonstrate that Slug is necessary for cellular adaptation during tissue development and regeneration, and that transitioning back into a more primitive stem-like state is a prerequisite for tumor initiation. reference x sample
2014-06-23 | E-GEOD-54713 | biostudies-arrayexpress
Project description:To investigate the chromatin state into an adult stem cell lineage, we generate cell-type specific chromatin state maps in the adult Drosophila intestine and identify principal chromatin state transitions during lineage determination. we profiled the binding sites of five chromatin-associated proteins from which the previously described five major types of chromatin.
2023-10-26 | GSE224965 | GEO
Project description:To investigate the chromatin state into an adult stem cell lineage, we generate cell-type specific chromatin state maps in the adult Drosophila intestine and identify principal chromatin state transitions during lineage determination. we profiled the binding sites of five chromatin-associated proteins from which the previously described five major types of chromatin.
2023-10-26 | GSE224963 | GEO
Project description:To investigate the chromatin state into an adult stem cell lineage, we generate cell-type specific chromatin state maps in the adult Drosophila intestine and identify principal chromatin state transitions during lineage determination. we profiled the binding sites of five chromatin-associated proteins from which the previously described five major types of chromatin.
2023-10-26 | GSE224962 | GEO
Project description:The intestinal epithelial regeneration is driven by intestinal stem cells under homeostatic conditions. Differentiated intestinal epithelial cells, such as Paneth cells, are capable of acquiring multipotency and contributing to regeneration upon loss of intestinal stem cells. Paneth cells also support intestinal stem cell survival and regeneration. We report here that depletion of an RNA-binding protein named polypyrimidine tract binding protein 1 (PTBP1) in mouse intestinal epithelial cells causes intestinal stem cell death and epithelial regeneration failure. Mechanistically, we show that PTBP1 inhibits neuronal-like splicing programs in intestinal crypt cells, which is critical for maintaining intestinal stem cell stemness. This function is achieved at least in part through promoting the non-productive splicing of its paralog PTBP2. Moreover, PTBP1 inhibits the expression of an AKT inhibitor PHLDA3 in Paneth cells and permits AKT activation, which presumably maintains Paneth cell plasticity and function in supporting intestinal stem cell niche. We show that PTBP1 directly binds to a CU-rich region in the 3’ UTR of Phlda3, which we demonstrate to be critical for downregulating the mRNA and protein levels of Phlda3. Our results thus reveal the multifaceted in vivo regulation of intestinal epithelial regeneration by PTBP1 at the post-transcriptional level.
2023-01-18 | GSE185499 | GEO
Project description:The intestine is a barrier tissue whose epithelium has high intrinsic turnover rate; intestinal stem cells, in response to signals from the niche, self-renew and produce progeny that differentiate to fulfill the continuous demand for new epithelial cells that are continuously shed into the lumen. The intestine is innervated by a dense network of peripheral nerves that controls nutrient absorption, intestinal motility, and visceral pain sensation. However, the roles of neurons in regulating epithelial cell homeostasis or regeneration remain as yet undiscovered. Here we investigate the effects of gut-innervating sympathetic neurons on epithelial cell repair following irradiation (IR)-induced gut injury. We observed that sympathetic innervation density in the gut increases post IR, while chemical sympathetic denervation impairs gut regeneration. Combining single cell RNA-sequencing and in vivo experiments, we discovered that sympathetic neurons regulate gut regeneration through modulation of IL22 production in type 3 innate lymphoid cells (ILC3) downstream of 2-adrenergic receptor signaling. These results define a novel neuroimmune axis important for intestinal regeneration.
2023-08-18 | GSE214821 | GEO
Project description:We identify arachidonic acid (AA), as a direct proliferation promoter of intestinal epithelial cells, facilitating small intestinal regeneration. In the transcriptomes, it shows that AA treatment upregulated proliferation-related genes including Wnt signaling target genes, while downregulated differentiation-related genes including enterocyte, goblet cell, Paneth cell, enteroendocrine cell, and tuft cell markers. Additionally, AA could also upregulate stem cell-associated genes which have been highly expressed three days after 12Gy IR injury (e.g. Clu, Lamc2, Anxa1, Areg, and Ly6d). The study shows that AA treatment can be considered a potential therapy for irradiation injury repair and tissue regeneration.
2020-07-27 | GSE146871 | 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.
2023-11-26 | GSE238056 | GEO