Chromatin Dynamics in Intestinal Epithelial Homeostasis: A Paradigm of Cell Fate Determination versus Cell Plasticity

AbstractThe rapid renewal of intestinal epithelium is mediated by a pool of stem cells, located at the bottom of crypts, giving rise to highly proliferative progenitor cells, which in turn differentiate during their migration along the villus. The equilibrium between renewal and differentiation is critical for establishment and maintenance of tissue homeostasis, and is regulated by signaling pathways (Wnt, Notch, Bmp…) and specific transcription factors (TCF4, CDX2…). Such regulation controls intestinal cell identities by modulating the cellular transcriptome. Recently, chromatin modification and dynamics have been identified as major actors linking signaling pathways and transcriptional regulation in the control of intestinal homeostasis. In this review, we synthesize the many facets of chromatin dynamics involved in controlling intestinal cell fate, such as stemness maintenance, progenitor identity, lineage choice and commitment, and terminal differentiation. In addition, we present recent data underlying the fundamental role of chromatin dynamics in intestinal cell plasticity. Indeed, this plasticity, which includes dedifferentiation processes or the response to environmental cues (like microbiota’s presence or food ingestion), is central for the organ’s physiology. Finally, we discuss the role of chromatin dynamics in the appearance and treatment of diseases caused by deficiencies in the aforementioned mechanisms, such as gastrointestinal cancer, inflammatory bowel disease or irritable bowel syndrome.

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Activation of KCNQ (KV7) K+ channels in enteric neurons inhibits epithelial Cl- secretion in mouse distal colon

AJP Cell Physiology ◽

10.1152/ajpcell.00536.2020 ◽

2021 ◽

Author(s):

Andrew J. Nickerson ◽

Trey S. Rottgen ◽

Vazhaikkurichi M. Rajendran

Keyword(s):

Short Circuit ◽

Short Circuit Current ◽

Distal Colon ◽

Therapeutic Benefit ◽

Enteric Neurons ◽

Intestinal Epithelial ◽

Cell Monolayers ◽

Neuronal Populations ◽

Irritable Bowel

KV7 (KCNQ) K+ channels are expressed in many neuronal populations, and play an important role in regulating membrane potential by generating a hyper-polarizing K+ current and decreasing cell excitability. However, the role of KV7 channels in the neural regulation of intestinal epithelial Cl- secretion is not known. Cl- secretion in mouse distal colon was measured as a function of short circuit current (ISC), while pharmacological approaches were used to test the hypothesis that activation of KV7 channels in enteric neurons would inhibit epithelial Cl- secretion. Flupirtine, a non-selective KV7 activator, inhibited basal Cl- secretion in mouse distal colon and abolished or attenuated the effects of drugs that target various components of enteric neurotransmission, including tetrodotoxin (NaV channel blocker), Veratridine (NaV channel activator), Nicotine (nicotinic acetylcholine receptor agonist) and Hexamethonium (nicotinic antagonist). In contrast, flupritine did not block the response to epithelium-targeted agents VIP (endogenous VPAC receptor ligand) or carbachol (non-selective cholinergic agonist). Flupirtine inhibited Cl- secretion in both full-thickness and seromuscular-stripped distal colon (containing the submucosal, but not myenteric plexus), but generated no response in epithelial T84 cell monolayers. KV7.2 and KV7.3 channel proteins were detected by immunofluorescence in whole-mount preparations of the submucosa from mouse distal colon. ICA 110381 (KV7.2/7.3 specific activator) inhibited Cl- secretion comparably to flupirtine. We conclude that KV7 channel activators inhibit neurally-driven Cl- secretion in the colonic epithelium, and may therefore have therapeutic benefit in treating pathologies associated with hyper-excitable enteric nervous system, such as irritable bowel syndrome with diarrhea (IBS-D).

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The Hippo Pathway Effector YAP1 Regulates Intestinal Epithelial Cell Differentiation

Cells ◽

10.3390/cells9081895 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1895 ◽

Cited By ~ 1

Author(s):

Sepideh Fallah ◽

Jean-François Beaulieu

Keyword(s):

Stem Cells ◽

Cell Differentiation ◽

Epithelial Cells ◽

Cell Line ◽

Intestinal Epithelial Cells ◽

Hippo Pathway ◽

Intestinal Cell ◽

Intestinal Epithelial ◽

The Hippo Pathway

The human intestine is covered by epithelium, which is continuously replaced by new cells provided by stem cells located at the bottom of the glands. The maintenance of intestinal stem cells is supported by a niche which is composed of several signaling proteins including the Hippo pathway effectors YAP1/TAZ. The role of YAP1/TAZ in cell proliferation and regeneration is well documented but their involvement on the differentiation of intestinal epithelial cells is unclear. In the present study, the role of YAP1/TAZ on the differentiation of intestinal epithelial cells was investigated using the HT29 cell line, the only multipotent intestinal cell line available, with a combination of knockdown approaches. The expression of intestinal differentiation cell markers was tested by qPCR, Western blot, indirect immunofluorescence and electron microscopy analyses. The results show that TAZ is not expressed while the abolition of YAP1 expression led to a sharp increase in goblet and absorptive cell differentiation and reduction of some stem cell markers. Further studies using double knockdown experiments revealed that most of these effects resulting from YAP1 abolition are mediated by CDX2, a key intestinal cell transcription factor. In conclusion, our results indicate that YAP1/TAZ negatively regulate the differentiation of intestinal epithelial cells through the inhibition of CDX2 expression.

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PGE2promotes Ca2+-mediated epithelial barrier disruption through EP1and EP4receptors in Caco-2 cell monolayers

AJP Cell Physiology ◽

10.1152/ajpcell.00397.2009 ◽

2010 ◽

Vol 299 (2) ◽

pp. C324-C334 ◽

Cited By ~ 41

Author(s):

M. José Rodríguez-Lagunas ◽

Raquel Martín-Venegas ◽

Juan José Moreno ◽

Ruth Ferrer

Keyword(s):

Signaling Pathways ◽

Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Epithelial Barrier Function ◽

Cell Monolayers ◽

Intracellular Ca ◽

Inflammatory Processes ◽

Zona Occludens

We recently demonstrated that PGE2induces the disruption of the intestinal epithelial barrier function. In the present study, our objectives were to study the role of PGE2receptors (EP1–EP4) and the signaling pathways involved in this event. Paracellular permeability (PP) was assessed in differentiated Caco-2 cell cultures from d-mannitol fluxes and transepithelial electrical resistance (TER) in the presence of different PGE2receptor agonists (carbacyclin, sulprostone, butaprost, ONO-AE1-259, ONO-AE-248, GR63799, and ONO-AE1-329) and antagonists (ONO-8711, SC-19220, AH-6809, ONO-AE3-240, ONO-AE3-208, and AH-23848). The results indicate that EP1and EP4but not EP2and EP3might be involved in PP regulation. These effects were mediated through PLC-inositol trisphosphate (IP3)-Ca2+and cAMP-PKA signaling pathways, respectively. We also observed an increase in intracellular Ca2+concentration ([Ca2+]i) strengthened by cAMP formation indicating a cross talk interaction of these two pathways. Moreover, the participation of a conventional PKC isoform was shown. The results also indicate that the increase in PP may be correlated with the redistribution of occludin, zona occludens 1 (ZO-1), and the perijunctional actin ring together with an increase in myosin light chain kinase activity. Although the disruption of epithelial barrier function observed in inflammatory bowel disease (IBD) patients has been traditionally attributed to cytokines, the present study focused on the role of PGE2in PP regulation, as mucosal levels of this eicosanoid are also increased in these inflammatory processes.

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T2065 Curcumin Suppresses Intestinal Epithelial Response to Clostridium difficile Infection: Role of Cell Signaling Pathways

Gastroenterology ◽

10.1016/s0016-5085(09)62911-5 ◽

2009 ◽

Vol 136 (5) ◽

pp. A-631

Author(s):

Nandakumar Srinivasan ◽

Dharmalingam Subramaniam ◽

Aarthi Varman ◽

Rama P. Ramanujam ◽

Courtney W. Houchen ◽

...

Keyword(s):

Clostridium Difficile ◽

Cell Signaling ◽

Signaling Pathways ◽

Clostridium Difficile Infection ◽

Intestinal Epithelial ◽

Cell Signaling Pathways

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Androgen action in cell fate and communication during prostate development at single-cell resolution

Development ◽

10.1242/dev.196048 ◽

2020 ◽

pp. dev.196048

Author(s):

Dong-Hoon Lee ◽

Adam W. Olson ◽

Jinhui Wang ◽

Won Kyung Kim ◽

Jiaqi Mi ◽

...

Keyword(s):

Single Cell ◽

Signaling Pathways ◽

Cell Fate ◽

Molecular Mechanisms ◽

Bud Formation ◽

Master Regulators ◽

Prostate Development ◽

Dynamic Cell ◽

Cell Signaling Networks

Androgens/androgen receptor (AR) mediated signaling pathways are essential for prostate development, morphogenesis, and regeneration. Specifically, stromal AR-signaling has been shown to be essential for prostatic initiation. However, the molecular mechanisms underlying AR-initiated mesenchymal-epithelial interactions in prostate development remain unclear. Here, using a newly generated mouse model, we directly addressed the fate and role of genetically marked AR-expressing cells during embryonic prostate development. Androgen signaling-initiated signaling pathways were identified in mesenchymal niche populations at single cell transcriptomic resolution. The dynamic cell-signaling networks regulated by stromal AR were characterized in regulating prostatic epithelial bud formation. Pseudotime analyses further revealed the differentiation trajectory and fate of AR-expressing cells in both prostatic mesenchymal and epithelial cell populations. Specifically, the cellular properties of Zeb1-expressing progenitors were assessed. Selective deletion of AR signaling in a subpopulation mesenchymal rather than epithelial cells dysregulates the expression of the master regulators and significantly impairs prostatic bud formation. These data provide novel, high-resolution evidence demonstrating the important role of mesenchymal androgen signaling as cellular niches controlling prostate early development by initiating dynamic mesenchyme-epithelia cell interactions.

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LncRNAs Regulatory Networks in Cellular Senescence

International Journal of Molecular Sciences ◽

10.3390/ijms20112615 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2615 ◽

Cited By ~ 13

Author(s):

Pavan Kumar Puvvula

Keyword(s):

Signaling Pathways ◽

Cell Fate ◽

Regulatory Networks ◽

Translation Regulation ◽

Reading Frame ◽

Downstream Signaling ◽

Cellular Processes ◽

Fate Decision ◽

Functional Mechanisms

Long noncoding RNAs (lncRNAs) are a class of transcripts longer than 200 nucleotides with no open reading frame. They play a key role in the regulation of cellular processes such as genome integrity, chromatin organization, gene expression, translation regulation, and signal transduction. Recent studies indicated that lncRNAs are not only dysregulated in different types of diseases but also function as direct effectors or mediators for many pathological symptoms. This review focuses on the current findings of the lncRNAs and their dysregulated signaling pathways in senescence. Different functional mechanisms of lncRNAs and their downstream signaling pathways are integrated to provide a bird’s-eye view of lncRNA networks in senescence. This review not only highlights the role of lncRNAs in cell fate decision but also discusses how several feedback loops are interconnected to execute persistent senescence response. Finally, the significance of lncRNAs in senescence-associated diseases and their therapeutic and diagnostic potentials are highlighted.

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Glycogen Synthase Kinase-3 Is Required for EfficientDictyosteliumChemotaxis

Molecular Biology of the Cell ◽

10.1091/mbc.e09-10-0891 ◽

2010 ◽

Vol 21 (15) ◽

pp. 2788-2796 ◽

Cited By ~ 16

Author(s):

Regina Teo ◽

Kimberley J. Lewis ◽

Josephine E. Forde ◽

W. Jonathan Ryves ◽

Jonathan V. Reddy ◽

...

Keyword(s):

Cell Signaling ◽

Signaling Pathways ◽

Cell Fate ◽

Glycogen Synthase ◽

Cell Aggregation ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Cell Fate Determination ◽

Cell Signaling Pathways

Glycogen synthase kinase-3 (GSK3) is a highly conserved protein kinase that is involved in several important cell signaling pathways and is associated with a range of medical conditions. Previous studies indicated a major role of the Dictyostelium homologue of GSK3 (gskA) in cell fate determination during morphogenesis of the fruiting body; however, transcriptomic and proteomic studies have suggested that GSK3 regulates gene expression much earlier during Dictyostelium development. To investigate a potential earlier role of GskA, we examined the effects of loss of gskA on cell aggregation. We find that cells lacking gskA exhibit poor chemotaxis toward cAMP and folate. Mutants fail to activate two important regulatory signaling pathways, mediated by phosphatidylinositol 3,4,5-trisphosphate (PIP3) and target of rapamycin complex 2 (TORC2), which in combination are required for chemotaxis and cAMP signaling. These results indicate that GskA is required during early stages of Dictyostelium development, in which it is necessary for both chemotaxis and cell signaling.

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Autophagy Impairment through Lysosome Dysfunction by Brucine Induces Immunogenic Cell Death (ICD)

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500962 ◽

2020 ◽

Vol 48 (08) ◽

pp. 1915-1940

Author(s):

Nestor Ishimwe ◽

Pengfei Wei ◽

Meimei Wang ◽

Hao Zhang ◽

Liansheng Wang ◽

...

Keyword(s):

Cell Death ◽

Signaling Pathways ◽

Cell Fate ◽

Intracellular Signaling ◽

High Mobility ◽

Feedback Regulation ◽

Immunogenic Cell Death ◽

Ct26 Tumor ◽

Autophagy Inhibition

Autophagy is an important tightly controlled cellular process that regulates cellular homeostasis and is involved in deciding cell fate such as cell survival and death. The role of autophagy in many intracellular signaling pathways explains its interaction with other different types of cell death, including apoptosis and immunogenic cell death (ICD). The reports showed the complex and intriguing relationship existing between autophagy and immune system signaling pathways. However, the role of autophagy in ICD remains to be clearly elucidated. In this study, we demonstrated that Brucine, a clinically-used small molecule in traditional Chinese medicine, elicited autophagy inhibition. Brucine also triggered cell stress and induced features of ICD, including calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release in MDA-MB-231 and CT26 cancer cells. Brucine impaired autolysosomal degradation and exerted a feedback regulation of ERK1/2-mTOR-p70S6K signaling cascade. Brucine-elicited ICD was confirmed by the rejection of CT26 tumor cells, implanted in the mice after vaccination with Brucine-treated CT26 cells. The impaired autophagy contributed to Brucine-induced ICD, as knock-down of Atg5 significantly reduced Brucine-elicited CRT exposure and HMGB1 release. Our results revealed Brucine as a novel autophagy regulator, ICD inducer and hitherto undocumented role of autophagy in ICD. Thus, these results imply the importance of Brucine in cancer immunotherapy. Therefore, Brucine may be used as an ICD inducer and improve its application in cancer treatment with minimized toxicity.

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Tracing the Origins of Glioblastoma by Investigating the Role of Gliogenic and Related Neurogenic Genes/Signaling Pathways in GBM Development: A Systematic Review

10.21203/rs.3.rs-1208118/v1 ◽

2022 ◽

Author(s):

Ovais Shafi ◽

Ghazia Siddiqui

Keyword(s):

Gene Expression ◽

Signaling Pathways ◽

Cell Fate ◽

Tumor Development ◽

Specific Cell ◽

Neurogenic Genes ◽

Myc Gene ◽

Aggressive Tumors ◽

Stat Pathway

Abstract Background: Glioblastoma is one of the most aggressive tumors. The etiology and the factors determining its onset are not yet entirely known. This study investigates the origins of GBM and for this purpose it focuses primarily on developmental gliogenic processes. It also focuses on impact of the related neurogenic developmental processes in glioblastoma oncogenesis. It also addresses why glial cells are at more risk of tumor development compared to neurons.Methods:Databases including PubMed, MEDLINE and Google Scholar were searched for published articles without any date restrictions, involving glioblastoma, gliogenesis, neurogenesis, stemness, neural stem cells, gliogenic signaling and pathways, neurogenic signaling and pathways, astrocytogenic genes.Results:The origin of GBM is dependent on dysregulation in multiple genes and pathways that accumulatively converge the cells towards oncogenesis. There are multiple layers of steps in glioblastoma oncogenesis including the failure of cell fate specific genes to keep the cells differentiated in their specific cell type such as p300, BMP, HOPX, NRSF/REST and others. There are genes and signaling pathways that are involved in differentiation and also contribute to GBM such as FGFR3, JAK-STAT, hey1 and others. The genes that contribute to differentiation processes but also contribute to stemness in GBM include notch, Sox9, Sox4, c-myc gene overrides p300 and then GFAP, leading to upregulation of nestin, SHH, NF-κB and others. GBM mutations pathologically impact the cell circuitry such as the interaction between Sox2 and JAK-STAT pathway, resulting in GBM development and progression. Conclusion: Glioblastoma originates when the gene expression of key gliogenic genes and signaling pathways become dysregulated. This study identifies key gliogenic genes having the ability to control oncogenesis in glioblastoma cells, including p300, BMP, PAX6, HOPX, NRSF/REST, LIF, TGF beta. It also identifies key neurogenic genes having the ability to control oncogenesis including PAX6, neurogenins including Ngn1, NeuroD1, NeuroD4, Numb, NKX6-1 Ebf, Myt1, ASCL1 and others. This study also postulates how aging contributes to the onset of glioblastoma by dysregulating the gene expression of NF-κB, REST/NRSF, ERK, AKT, EGFR and others.

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