scholarly journals The contribution of lincRNAs at the interface between cell cycle regulation and cell state maintenance

2019 ◽  
Author(s):  
Adriano Biasini ◽  
Adam Alexander Thil Smith ◽  
Baroj Abdulkarim ◽  
Jennifer Yihong Tan ◽  
Maria Ferreira da Silva ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Cell Cycle Progression ◽  
Embryonic Stem ◽  
Differentially Expressed ◽  
Cell Cycle Regulators ◽  
Cycle Progression ◽  
Cell State ◽  
The Impact

ABSTRACTCell cycle progression requires dynamic and tightly-regulated transitions between well-defined cell cycle stages. These transitions are controlled by the interplay of established cell cycle regulators. Changes in the activity of these regulators are thought to underpin differences in cell cycle kinetics between distinct cell types. Here, we investigate whether cell type-specific long intergenic noncoding RNAs (lincRNAs) contribute to embryonic stem cell adaptations, which have been shown to be essential for the maintenance of embryonic stem cell state.We used single cell RNA-sequencing data of mouse embryonic stem cells (mESC) staged as G1, S, or G2/M to identify genes differentially expressed between these phases. We found differentially expressed lincRNAs to be enriched amongst cell cycle regulated genes. These cell cycle associated lincRNAs (CC-lincRNAs) are co-expressed with protein-coding genes with established roles in cell cycle progression. Interestingly, 70% of CC-lincRNAs are differentially expressed between G1 and S, suggesting they may contribute to the maintenance of the short G1 phase that characterizes the embryonic stem cell cycle. Consistent with this hypothesis, the promoters of CC-lincRNAs are enriched in pluripotency transcription factor binding sites, and their transcripts are frequently co-regulated with genes involved in the maintenance of pluripotency. We tested the impact of 2 CC-lincRNA candidates and show that modulation of their expression is associated with impaired cell cycle progression, further underlining the contribution of mESC-specific lincRNAs to cell cycle modulation in these cells.

scholarly journals Helicobacter pylori interferes with an embryonic stem cell micro RNA cluster to block cell cycle progression

Silence ◽  
2011 ◽  
Vol 2 (1) ◽  
pp. 7 ◽  
Author(s):  
Cédric Belair ◽  
Jessica Baud ◽  
Sandrine Chabas ◽  
Cynthia M Sharma ◽  
Jörg Vogel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Helicobacter Pylori ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Cell Cycle Progression ◽  
Embryonic Stem ◽  
Micro Rna ◽  
Cycle Progression ◽  
Block Cell Cycle Progression

HMGA1 Drives Inflammatory Pathways, Cell Cycle Progression, and Embryonic Stem Cell Genes During Leukemic Transformation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1371-1371
Author(s):  
Andrew Schuldenfrei ◽  
Amy Belton ◽  
Jeanne Kowalski ◽  
C. Conover Talbot ◽  
Francescopaolo Di Cello ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Differentially Expressed Genes ◽  
Cell Cycle Progression ◽  
Embryonic Stem ◽  
Differentially Expressed ◽  
Lymphoid Leukemia ◽  
Cycle Progression ◽  
Hmga1 Expression ◽  
Cellular Pathways ◽  
Late Stages

Abstract Abstract 1371 Although the high mobility group AT-hook 1 (HMGA1) gene functions as a potent oncogene in experimental models and high expression of HMGA1 portends a poor prognosis in diverse tumors, its role in leukemogenesis has remained elusive. We showed previously that HMGA1 induces leukemic transformation in cultured cells and causes aggressive lymphoid leukemia in transgenic mice. Inhibiting HMGA1 expression blocks colony formation in human lymphoid leukemia cells in vitro. Moreover, high levels correlate with relapse in childhood acute lymphoblastic leukemia (ALL), suggesting that it plays an important role in ALL. Because HMGA1 functions as a chromatin remodeling protein that modulates gene expression, we hypothesized that it drives leukemogenesis by dysregulating specific genes and pathways. To identify genes and cellular pathways induced by HMGA1 that could be targeted in therapy, we performed global gene expression profile analysis from lymphoid cells from the HMGA1 transgenic mice at different stages in tumorigenesis. All HMGA1 transgenics succumb to lymphoid malignancy with complete penetrance by 8–12 months. Pooled RNA samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) were analyzed for differential expression of >20,000 unique genes by microarray analysis (Affymetrix) using both a parametric and nonparametric approach. A subset of differentially expressed genes was confirmed using quantitative, RT-PCR. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis (IPA; www.ingenuity.com) and Gene Set Enrichment Analysis. To determine if these genes and pathways were relevant in human ALL, we knocked down HMGA1 expression in human ALL cells and assessed expression of a subset of the differentially expressed genes. Early in leukemogenesis (at 2 months), 113 genes were differentially expressed in the HMGA1 transgenics compared to controls. In established leukemia (12 months), 715 genes were differentially expressed. In established tumors, the dysregulated genes are involved in cancer, cell cycle regulation, and cell-mediated immune response by Ingenuity Pathway Analysis. Geneset enrichment showed that embryonic stem cell genes are enriched in the established leukemic cells. At both early and late stages in leukemogenesis, differentially regulated genes are involved in cellular development, hematopoiesis, and hematologic development. Early in leukemogenesis, most of the significantly dysregulated genes are involved in the inflammatory response and included NF-kappaB as a major node. In human ALL cells, knock-down of HMGA1 also resulted in knock-down of genes identified in our transgenic model, suggesting that these HMGA1 regulated genes are also relevant to human ALL. In summary, we found that HMGA1 induces inflammatory pathways early in leukemogenesis and pathways involved in embryonic stem cells, cell cycle progression, and cancer in established tumors. HMGA1 also dysregulates genes involved in cellular development and hematopoiesis at both early and late stages of tumorigenesis. Some of these HMGA1 pathways were also present in human ALL cells. Moreover, these results provide mechanistic insight into HMGA1 function at different stages in leukemogenesis and point to cellular pathways that could serve as therapeutic targets in ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Jie Gao ◽  
Shannon M Buckley ◽  
Luisa Cimmino ◽  
Maria Guillamot ◽  
Alexandros Strikoudis ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Ubiquitin Ligase ◽  
Protein Interactions ◽  
Cell Cycle Progression ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Ubiquitin Ligase Complex

Little is known on post-transcriptional regulation of adult and embryonic stem cell maintenance and differentiation. Here we characterize the role of Ddb1, a component of the CUL4-DDB1 ubiquitin ligase complex. Ddb1 is highly expressed in multipotent hematopoietic progenitors and its deletion leads to abrogation of both adult and fetal hematopoiesis, targeting specifically transiently amplifying progenitor subsets. However, Ddb1 deletion in non-dividing lymphocytes has no discernible phenotypes. Ddb1 silencing activates Trp53 pathway and leads to significant effects on cell cycle progression and rapid apoptosis. The abrogation of hematopoietic progenitor cells can be partially rescued by simultaneous deletion of Trp53. Conversely, depletion of DDB1 in embryonic stem cell (ESC) leads to differentiation albeit negative effects on cell cycle and apoptosis. Mass spectrometry reveals differing protein interactions between DDB1 and distinct DCAFs, the substrate recognizing components of the E3 complex, between cell types. Our studies identify CUL4-DDB1 complex as a novel post-translational regulator of stem and progenitor maintenance and differentiation.

scholarly journals G1-phase progression in pluripotent stem cells

2021 ◽  
Author(s):  
Menno ter Huurne ◽  
Hendrik G. Stunnenberg
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Cycle Progression ◽  
Embryonic Stem ◽  
Cell Number ◽  
Molecular Networks ◽  
Cell Cycle Regulators ◽  
Cycle Progression ◽  
Expression Of Genes ◽  
Promote Cell Cycle Progression

AbstractDuring early embryonic development both the rapid increase in cell number and the expression of genes that control developmental decisions are tightly regulated. Accumulating evidence has indicated that these two seemingly independent processes are mechanistically intertwined. The picture that emerges from studies on the cell cycle of embryonic stem cells is one in which proteins that promote cell cycle progression prevent differentiation and vice versa. Here, we review which transcription factors and signalling pathways play a role in both maintenance of pluripotency as well as cell cycle progression. We will not only describe the mechanism behind their function but also discuss the role of these regulators in different states of mouse pluripotency. Finally, we elaborate on how canonical cell cycle regulators impact on the molecular networks that control the maintenance of pluripotency and lineage specification.

Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes

2003 ◽  
Vol 285 (6) ◽  
pp. H2355-H2363 ◽  
Author(s):  
Mirit Snir ◽  
Izhak Kehat ◽  
Amira Gepstein ◽  
Raymond Coleman ◽  
Joseph Itskovitz-Eldor ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Late Stage ◽  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Es Cell ◽  
Cardiomyocyte Proliferation ◽  
Ki 67

Assessment of early ultrastructural development and cell-cycle regulation in human cardiac tissue is significantly hampered by the lack of a suitable in vitro model. Here we describe the possible utilization of human embryonic stem cell (ES) lines for investigation of these processes. With the use of the embryoid body (EB) differentiation system, human ES cell-derived cardiomyocytes at different developmental stages were isolated and their histomorphometric, ultrastructural, and proliferative properties were characterized. Histomorphometric analysis revealed an increase in cell length, area, and length-to-width ratio in late-stage EBs (>35 days) compared with early (10–21 days) and intermediate (21–35 days) stages. This was coupled with a progressive ultrastructural development from an irregular myofibrillar distribution to an organized sarcomeric pattern. Cardiomyocyte proliferation, assessed by double labeling with cardiac-specific antibodies and either [3H]thymidine incorporation or Ki-67 immunolabeling, demonstrated a gradual withdrawal from cell cycle. Hence, the percentage of positively stained nuclei in early-stage cardiomyocytes ([3H]thymidine: 60 ± 10%, Ki-67: 54 ± 23%) decreased to 36 ± 7% and 9 ± 16% in intermediate-stage EBs and to <1% in late-stage cardiomyocytes. In conclusion, a reproducible temporal pattern of early cardiomyocyte proliferation, cell-cycle withdrawal, and ultrastructural maturation was noted in this model. Establishment of this unique in vitro surrogate system may allow to examine the molecular mechanisms underlying these processes and to assess interventions aiming to modify these properties. Moreover, the detailed characterization of the ES cell-derived cardiomyocyte may be crucial for the development of future cell replacement strategies aiming to regenerate functional myocardium.

scholarly journals Babam2 Regulates Cell Cycle Progression and Pluripotency in Mouse Embryonic Stem Cells as Revealed by Induced DNA Damage

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 397
Author(s):  
Cheuk Yiu Tenny Chung ◽  
Paulisally Hau Yi Lo ◽  
Kenneth Ka Ho Lee
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Gamma Irradiation ◽  
Cellular Senescence ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Embryonic Stem ◽  
Cycle Progression ◽  
Cycle Regulation

BRISC and BRCA1-A complex member 2 (Babam2) plays an essential role in promoting cell cycle progression and preventing cellular senescence. Babam2-deficient fibroblasts show proliferation defect and premature senescence compared with their wild-type (WT) counterpart. Pluripotent mouse embryonic stem cells (mESCs) are known to have unlimited cell proliferation and self-renewal capability without entering cellular senescence. Therefore, studying the role of Babam2 in ESCs would enable us to understand the mechanism of Babam2 in cellular aging, cell cycle regulation, and pluripotency in ESCs. For this study, we generated Babam2 knockout (Babam2−/−) mESCs to investigate the function of Babam2 in mESCs. We demonstrated that the loss of Babam2 in mESCs leads to abnormal G1 phase retention in response to DNA damage induced by gamma irradiation or doxorubicin treatments. Key cell cycle regulators, CDC25A and CDK2, were found to be degraded in Babam2−/− mESCs following gamma irradiation. In addition, Babam2−/− mESCs expressed p53 strongly and significantly longer than in control mESCs, where p53 inhibited Nanog expression and G1/S cell cycle progression. The combined effects significantly reduced developmental pluripotency in Babam2−/− mESCs. In summary, Babam2 maintains cell cycle regulation and pluripotency in mESCs in response to induced DNA damage.

scholarly journals Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression, Stem Cell Maintenance, and Human Disease

2016 ◽  
Vol 36 (14) ◽  
pp. 1900-1907 ◽  
Author(s):  
Fu Huang ◽  
Susan M. Abmayr ◽  
Jerry L. Workman
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Cell Cycle Progression ◽  
Histone Acetyltransferase ◽  
Regulatory Mechanisms ◽  
Cycle Progression ◽  
Stem Cell Maintenance ◽  
Lysine Acetyltransferase ◽  
Cycle Regulation ◽  
Cell Maintenance

The lysine acetyltransferase 6 (KAT6) histone acetyltransferase (HAT) complexes are highly conserved from yeast to higher organisms. They acetylate histone H3 and other nonhistone substrates and are involved in cell cycle regulation and stem cell maintenance. In addition, the human KAT6 HATs are recurrently mutated in leukemia and solid tumors. Therefore, it is important to understand the mechanisms underlying the regulation of KAT6 HATs and their roles in cell cycle progression. In this minireview, we summarize the identification and analysis of the KAT6 complexes and discuss the regulatory mechanisms governing their enzymatic activities and substrate specificities. We further focus on the roles of KAT6 HATs in regulating cell proliferation and stem cell maintenance and review recent insights that aid in understanding their involvement in human diseases.

scholarly journals Identification of differentially expressed non-coding RNAs in embryonic stem cell neural differentiation

2012 ◽  
Vol 40 (13) ◽  
pp. 6001-6015 ◽  
Author(s):  
Konstantinia Skreka ◽  
Simon Schafferer ◽  
Irina-Roxanna Nat ◽  
Marek Zywicki ◽  
Ahmad Salti ◽  
...  
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Neural Differentiation ◽  
Embryonic Stem ◽  
Differentially Expressed ◽  
Non Coding Rnas

scholarly journals The adult stem cell marker Musashi-1 modulates endometrial carcinoma cell cycle progression and apoptosisviaNotch-1 and p21WAF1/CIP1

2011 ◽  
Vol 129 (8) ◽  
pp. 2042-2049 ◽  
Author(s):  
Martin Götte ◽  
Burkhard Greve ◽  
Reinhard Kelsch ◽  
Heike Müller-Uthoff ◽  
Kristin Weiss ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Endometrial Carcinoma ◽  
Cell Cycle Progression ◽  
Carcinoma Cell ◽  
Adult Stem Cell ◽  
Stem Cell Marker ◽  
Cell Marker ◽  
Cycle Progression ◽  
Endometrial Carcinoma Cell

scholarly journals A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development

2017 ◽  
Vol 27 (6) ◽  
pp. 905-913 ◽  
Author(s):  
Kristina Ames ◽  
Dayse S. Da Cunha ◽  
Brenda Gonzalez ◽  
Marina Konta ◽  
Feng Lin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Cell Cycle Progression ◽  
Germline Development ◽  
Cycle Progression ◽  
Stem Cell Proliferation
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