scholarly journals Cellular plasticity at the nexus of development and disease

Development ◽  
2021 ◽  
Vol 148 (3) ◽  
pp. dev197392
Author(s):  
Lillian B. Spatz ◽  
Ramon U. Jin ◽  
Jason C. Mills
Keyword(s):  
Global Health ◽  
Initial Step ◽  
Cell Plasticity ◽  
Cell Identity ◽  
Fields Of Study ◽  
Poster Sessions ◽  
Epigenomic Regulation ◽  
Cellular Identity ◽  
Developmental Contexts ◽  
Identity Changes

ABSTRACTIn October 2020, the Keystone Symposia Global Health Series hosted a Keystone eSymposia entitled ‘Tissue Plasticity: Preservation and Alteration of Cellular Identity’. The event synthesized groundbreaking research from unusually diverse fields of study, presented in various formats, including live and virtual talks, panel discussions and interactive e-poster sessions. The meeting focused on cell identity changes and plasticity in multiple tissues, species and developmental contexts, both in homeostasis and during injury. Here, we review the key themes of the meeting: (1) cell-extrinsic drivers of plasticity; (2) epigenomic regulation of cell plasticity; and (3) conserved mechanisms governing plasticity. A salient take-home conclusion was that there may be conserved mechanisms used by cells to execute plasticity, with autodegradative activity (autophagy and lysosomes) playing a crucial initial step in diverse organs and organisms.

scholarly journals Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

2021 ◽  
Author(s):  
Chien-Wen Chen ◽  
Bo-Jhih Guan ◽  
Mohammed R Alzahrani ◽  
Zhaofeng Gao ◽  
Long Gao ◽  
...  
Keyword(s):  
Er Stress ◽  
Stress Responses ◽  
Cell Function ◽  
Cell Plasticity ◽  
Β Cells ◽  
Β Cell ◽  
Cell Identity ◽  
Β Cell Function ◽  
Novel Biomarkers ◽  
High Degree

Pancreatic β-cells undergo high levels of endoplasmic reticulum (ER) stress due to their role in insulin secretion. Hence, they require sustainable and efficient adaptive stress responses to cope with the stress. Whether duration and episodes of chronic ER stress directly compromises β-cell identity is largely unknown. We show that under reversible, chronic ER stress, β-cells undergo a distinct transcriptional and translational reprogramming. During reprogramming, expression of master regulators of β-cell function and identity and proinsulin processing is impaired. Upon recovery from stress, β-cells regain their identity, highlighting a high-degree of adaptive β-cell plasticity. Remarkably, when stress episodes exceed a certain threshold, β-cell identity is gradually lost. Single cell RNA-seq analysis of islets from type 1 diabetes (T1D) patients, identifies the severe deregulation of the chronic stress-adaptation program, and reveals novel biomarkers for progression of T1D. Our results suggest β-cell adaptive exhaustion (βEAR) is a significant component of the pathogenesis of T1D.

scholarly journals Revealing the Key Regulators of Cell Identity in the Human Adult Pancreas

2020 ◽  
Author(s):  
Lotte Vanheer ◽  
Andrea Alex Schiavo ◽  
Matthias Van Haele ◽  
Tine Haesen ◽  
Adrian Janiszewski ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Types ◽  
List Type ◽  
Cell Identity ◽  
Pancreatic Cell ◽  
Human Adult ◽  
Gene Regulatory ◽  
Cellular Identity

SUMMARYCellular identity during development is under the control of transcription factors that form gene regulatory networks. However, the transcription factors and gene regulatory networks underlying cellular identity in the human adult pancreas remain largely unexplored. Here, we integrate multiple single-cell RNA sequencing datasets of the human adult pancreas, totaling 7393 cells, and comprehensively reconstruct gene regulatory networks. We show that a network of 142 transcription factors forms distinct regulatory modules that characterize pancreatic cell types. We present evidence that our approach identifies key regulators of cell identity in the human adult pancreas. We predict that HEYL and JUND are active in acinar and alpha cells, respectively, and show that these proteins are present in the human adult pancreas as well as in human induced pluripotent stem cell-derived pancreatic cells. The comprehensive gene regulatory network atlas can be explored interactively online. We anticipate our analysis to be the starting point for a more sophisticated dissection of how transcription factors regulate cell identity in the human adult pancreas. Furthermore, given that transcription factors are major regulators of embryo development and are often perturbed in diseases, a comprehensive understanding of how transcription factors work will be relevant in development and disease biology.HIGHLIGHTS-Reconstruction of gene regulatory networks for human adult pancreatic cell types-An interactive resource to explore and visualize gene expression and regulatory states-Predicting putative transcription factors driving pancreatic cell identity-HEYL and JUND as candidate regulators of acinar and alpha cell identity, respectively

scholarly journals FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma

2021 ◽  
Author(s):  
Grace Orstad ◽  
Alex Jones ◽  
Brian Lohman ◽  
Katherine L Gillis ◽  
Eric L Snyder
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Target Genes ◽  
Marker Genes ◽  
Alveolar Type ◽  
Significant Heterogeneity ◽  
Type I ◽  
Cell Identity ◽  
Genetically Engineered Mouse Model ◽  
Cellular Identity

Change in cancer cell identity is well characterized as a mechanism of cancer progression and acquired resistance to targeted therapies. Lung adenocarcinoma (LUAD) exhibits significant heterogeneity in cell identity and differentiation state; these characteristics correlate directly with prognosis, response to available therapies, and acquisition of drug resistance. In previous work, we have shown that FoxA1 and FoxA2 (FoxA1/2) activate a gastric differentiation program in NKX2-1-negative LUAD. Here we investigate the role of FoxA1/2 in NKX2-1-positive LUAD. We find that FoxA1/2 are consistently expressed in NKX2-1-positive human LUAD. Foxa1/2 deletion severely impairs proliferation and significantly prolongs overall survival in a genetically engineered mouse model of KRAS-driven LUAD. FoxA1/2 activate expression of a mixed-lineage transcriptional program characterized by co-expression of pulmonary (Alveolar Type II) and gastrointestinal marker genes. Loss of FoxA1/2 causes a lineage switch, activating gene expression programs associated with Alveolar Type I cells and maturing squamous epithelial cells. Inhibition of NKX2-1 partially rescues the antiproliferative impact of FoxA1/2 loss, showing that NKX2-1 retains some degree of activity in FoxA1/2-null cells, despite its inability to activate canonical target genes. In summary, this study identifies FoxA1/2 expression as a novel vulnerability in NKX2-1-positive LUAD and shows that FoxA1/2 actively regulate cellular identity in this disease.

scholarly journals Nuclear organization and regulation of the differentiated state

2021 ◽  
Author(s):  
Eliya Bitman-Lotan ◽  
Amir Orian
Keyword(s):  
Nuclear Organization ◽  
Biophysical Properties ◽  
Cell Identity ◽  
Nuclear Lamins ◽  
Related Disease ◽  
Age Related ◽  
Silent Genes ◽  
Nuclear Environment ◽  
Cellular Identity ◽  
Relevant Gene

AbstractRegulation of the differentiated identity requires active and continued supervision. Inability to maintain the differentiated state is a hallmark of aging and aging-related disease. To maintain cellular identity, a network of nuclear regulators is devoted to silencing previous and non-relevant gene programs. This network involves transcription factors, epigenetic regulators, and the localization of silent genes to heterochromatin. Together, identity supervisors mold and maintain the unique nuclear environment of the differentiated cell. This review describes recent discoveries regarding mechanisms and regulators that supervise the differentiated identity and protect from de-differentiation, tumorigenesis, and attenuate forced somatic cell reprograming. The review focuses on mechanisms involved in H3K9me3-decorated heterochromatin and the importance of nuclear lamins in cell identity. We outline how the biophysical properties of these factors are involved in self-compartmentalization of heterochromatin and cell identity. Finally, we discuss the relevance of these regulators to aging and age-related disease.

scholarly journals Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals

2019 ◽  
Author(s):  
Jae-Hyun Yang ◽  
Patrick T. Griffin ◽  
Daniel L. Vera ◽  
John K. Apostolides ◽  
Motoshi Hayano ◽  
...  
Keyword(s):  
Yeast Cells ◽  
Epigenetic Landscape ◽  
Dna Breaks ◽  
Cell Identity ◽  
Epigenetic Information ◽  
Living Things ◽  
Yeast Aging ◽  
Tissue Changes ◽  
Cellular Identity ◽  
Over Time

SUMMARYAll living things experience entropy, manifested as a loss of inherited genetic and epigenetic information over time. As budding yeast cells age, epigenetic changes result in a loss of cell identity and sterility, both hallmarks of yeast aging. In mammals, epigenetic information is also lost over time, but what causes it to be lost and whether it is a cause or a consequence of aging is not known. Here we show that the transient induction of genomic instability, in the form of a low number of non-mutagenic DNA breaks, accelerates many of the chromatin and tissue changes seen during aging, including the erosion of the epigenetic landscape, a loss of cellular identity, advancement of the DNA methylation clock and cellular senescence. These data support a model in which a loss of epigenetic information is a cause of aging in mammals.One Sentence SummaryThe act of repairing DNA breaks induces chromatin reorganization and a loss of cell identity that may contribute to mammalian aging

scholarly journals Transdifferentiation In Neuroscience: Lights And Shadows

2020 ◽  
Vol 6 (6) ◽  
pp. 1-5
Author(s):  
Cristiana Mollinari ◽  
Keyword(s):  
Cell Identity ◽  
Cellular Identity ◽  
Adult Cells

Adult cells are believed to maintain their differentiated status under stable homeostatic conditions, while cellular identity can become plastic when homeostasis is perturbed such as during an injury and inflammation [1]. Indeed, it is now evident that cell identity is more flexible and plastic than previously thought

scholarly journals Keeping your options open: insights from Dppa2/4 into how epigenetic priming factors promote cell plasticity

2020 ◽  
Vol 48 (6) ◽  
pp. 2891-2902
Author(s):  
Mélanie A. Eckersley-Maslin
Keyword(s):  
Cell Fate ◽  
Regulatory Elements ◽  
Cell Plasticity ◽  
Cell Identity ◽  
Transcriptional Changes ◽  
A Cell ◽  
The Stability ◽  
External Stimuli ◽  
Epigenetic Plasticity

The concept of cellular plasticity is particularly apt in early embryonic development, where there is a tug-of-war between the stability and flexibility of cell identity. This balance is controlled in part through epigenetic mechanisms. Epigenetic plasticity dictates how malleable cells are to change by adjusting the potential to initiate new transcriptional programmes. The higher the plasticity of a cell, the more readily it can adapt and change its identity in response to external stimuli such as differentiation cues. Epigenetic plasticity is regulated in part through the action of epigenetic priming factors which establish this permissive epigenetic landscape at genomic regulatory elements to enable future transcriptional changes. Recent studies on the DNA binding proteins Developmental Pluripotency Associated 2 and 4 (Dppa2/4) support their roles as epigenetic priming factors in facilitating cell fate transitions. Here, using Dppa2/4 as a case study, the concept of epigenetic plasticity and molecular mechanism of epigenetic priming factors will be explored. Understanding how epigenetic priming factors function is key not only to improve our understanding of the tight control of development, but also to give insights into how this goes awry in diseases of cell identity, such as cancer.

scholarly journals Beta cell identity changes with mild hyperglycemia: Implications for function, growth, and vulnerability

2020 ◽  
Vol 35 ◽  
pp. 100959 ◽  
Author(s):  
Aref G. Ebrahimi ◽  
Jennifer Hollister-Lock ◽  
Brooke A. Sullivan ◽  
Ryohei Tsuchida ◽  
Susan Bonner-Weir ◽  
...  
Keyword(s):  
Beta Cell ◽  
Cell Identity ◽  
Mild Hyperglycemia ◽  
Identity Changes

scholarly journals miR302 regulates SNAI1 expression to control mesangial cell plasticity

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Letizia De Chiara ◽  
Darrell Andrews ◽  
Ariane Watson ◽  
Giorgio Oliviero ◽  
Gerard Cagney ◽  
...  
Keyword(s):  
Cell Fate ◽  
De Novo ◽  
Mesangial Cells ◽  
Cell Plasticity ◽  
Cell Fate Decisions ◽  
Epigenetic State ◽  
Epigenetic Modifiers ◽  
Enhanced Expression ◽  
Cellular Identity

Abstract Cell fate decisions are controlled by the interplay of transcription factors and epigenetic modifiers, which together determine cellular identity. Here we elaborate on the role of miR302 in the regulation of cell plasticity. Overexpression of miR302 effected silencing of the TGFβ type II receptor and facilitated plasticity in a manner distinct from pluripotency, characterized by increased expression of Snail. miR302 overexpressing mesangial cells also exhibited enhanced expression of EZH2 coincident with Snail upregulation. esiRNA silencing of each component suggest that Smad3 and EZH2 are part of a complex that regulates plasticity and that miR302 regulates EZH2 and Snail independently. Subsequent manipulation of miR302 overexpressing cells demonstrated the potential of using this approach for reprogramming as evidenced by de novo expression of the tight junction components ZO-1 and E-cadherin and the formation of ZO-1 containing tight junctions. Understanding the processes through which dynamic epigenetic silencing is controlled in adults cells will allow us to address the epigenetic state of acquired disease and whether original states, regenerative in nature, can be restored with therapy.

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