scholarly journals Differential condensation of sister chromatids coordinates with Cdc6 to ensure distinct cell cycle progression inDrosophilamale germline stem cell lineage

2021 ◽  
Author(s):  
Rajesh Ranjan ◽  
Jonathan Snedeker ◽  
Matthew Wooten ◽  
Carolina Chu ◽  
Sabrina Bracero ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Cycle Progression ◽  
Daughter Cell ◽  
Asymmetric Division ◽  
Germline Stem Cell ◽  
Cycle Progression ◽  
Daughter Cells ◽  
Sister Chromatids

AbstractStem cells undergo asymmetric division to produce both a self-renewing stem cell and a differentiating daughter cell. DuringDrosophilamale germline stem cell (GSC) asymmetric division, preexisting old histones H3 and H4 are enriched in the self-renewed stem daughter cell, whereas the newly synthesized H3 and H4 are enriched in the differentiating daughter cell. However, the biological consequences in the two daughter cells resulting from asymmetric histone inheritance remained to be elucidated. In this work, we track both old and new histones throughout GSC cell cycle using high spatial and temporal resolution microscopy. We find several unique features differentiating old versus new histone-enriched sister chromatids, including nucleosome density, chromosomal condensation, and H3 Ser10 phosphorylation. These distinct chromosomal features lead to their differential association with Cdc6, an essential component of the pre-replication complex, which subsequently contributes to asynchronous initiation of DNA replication in the two resulting daughter cells. Disruption of asymmetric histone inheritance abolishes both differential Cdc6 association and asynchronous S-phase entry, demonstrating that asymmetric histone acts upstream of these critical events during cell cycle progression. Furthermore, GSC defects are detected under these conditions, indicating a connection between histone inheritance, cell cycle progression and cell fate decision. Together, these studies reveal that cell cycle remodeling as a crucial biological ‘readout’ of asymmetric histone inheritance, which precedes and could lead to other well-known readouts such as differential gene expression. This work also enhances our understanding of asymmetric histone inheritance and epigenetic regulation in other stem cells or asymmetrically dividing cells in multicellular organisms.

scholarly journals Cell cycle exit and stem cell differentiation are coupled through regulation of mitochondrial activity in the Drosophila testis

2021 ◽  
Author(s):  
Diego Sainz de la Maza ◽  
Silvana Hof-Michel ◽  
Lee Phillimore ◽  
Christian Bökel ◽  
Marc Amoyel
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Cycle Progression ◽  
Stem Cell Differentiation ◽  
Mitochondrial Activity ◽  
Self Renewal ◽  
Cycle Progression ◽  
Cell Identity ◽  
Drosophila Testis

AbstractStem cells maintain tissue homeostasis by proliferating to replace cells lost to damage or natural turnover. Whereas stem and progenitor cells proliferate, fully differentiated cells exit the cell cycle. How cell identity and cell cycle state are coordinated during this process is still poorly understood. The Drosophila testis niche supports germline stem cells and somatic cyst stem cells (CySCs), which are the only proliferating somatic cells in the testis. CySCs give rise to post-mitotic cyst cells and therefore provide a tractable model to ask how stem cell identity is linked to proliferation. We show that the G1/S cyclin, Cyclin E, is required for CySC self-renewal; however, its canonical transcriptional regulator, a complex of the E2f1 and Dp transcription factors is dispensable for self-renewal and cell cycle progression. Nevertheless, we demonstrate that E2f1/Dp activity must be silenced to allow CySCs to differentiate. We show that E2f1/Dp activity inhibits the expression of genes important for mitochondrial activity. Furthermore, promoting mitochondrial activity or biogenesis is sufficient to rescue the differentiation of CySCs with ectopic E2f1/Dp activity but not their exit from the cell cycle. Our findings together indicate that E2f1/Dp coordinates cell cycle progression with stem cell identity by regulating the metabolic state of CySCs.

scholarly journals Establishing cell-intrinsic limitations in cell cycle progression controls graft growth and promotes differentiation of pancreatic endocrine cells

2020 ◽  
Author(s):  
Lina Sui ◽  
Yurong Xin ◽  
Daniela Georgieva ◽  
Giacomo Diedenhofen ◽  
Leena Haataja ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Endocrine Cells ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Growth Potential ◽  
Proliferative Potential ◽  
G1 Arrest ◽  
Cycle Progression

AbstractLimitations in cell proliferation are a key barrier to reprogramming differentiated cells to pluripotent stem cells, and conversely, acquiring these limitations may be important to establish the differentiated state. The pancreas, and beta cells in particular have a low proliferative potential, which limits regeneration, but how these limitations are established is largely unknown. Understanding proliferation potential is important for the safty of cell replacement therapy with cell products made from pluripotent stem cell which have unlimited proliferative potential. Here we test a novel hypothesis, that these limitations are established through limitations in S-phase progression. We used a stem cell-based system to expose differentiating stem cells to small molecules that interfere with cell cycle progression either by inducing G1 arrest, impairing S-phase entry, or S-phase completion. Upon release from these molecules, we determined growth potential, differentiation and function of insulin-producing endocrine cells both in vitro and after grafting in vivo. We found that the combination of G1 arrest with a compromised ability to complete DNA replication promoted the differentiation of pancreatic progenitor cells towards insulin-producing cells, improved the stability of the differentiated state, and protected mice from diabetes without the formation of cystic growths. Therefore, a compromised ability to enter S-phase and replicate the genome is a functionally important property of pancreatic endocrine differentiation, and can be exploited to generate insulin-producing organoids with predictable growth potential after transplantation.

scholarly journals Stem cell mitotic drive ensures asymmetric epigenetic inheritance

2018 ◽  
Author(s):  
Rajesh Ranjan ◽  
Jonathan Snedeker ◽  
Xin Chen
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Sister Chromatid ◽  
Germline Stem Cell ◽  
Cell Fates ◽  
Daughter Cells ◽  
Sister Chromatids ◽  
Distinct Cell

SUMMARYThrough the process of symmetric cell division, one mother cell gives rise to two identical daughter cells. Many stem cells utilize asymmetric cell division (ACD) to produce a self-renewed stem cell and a differentiating daughter cell. Since both daughter cells inherit the identical genetic information during ACD, a crucial question concerns how non-genic factors could be inherited differentially to establish distinct cell fates. It has been hypothesized that epigenetic differences at sister centromeres could contribute to biased sister chromatid attachment and segregation. However, direct in vivo evidence has never been shown. Here, we report that a stem cell-specific ‘mitotic drive’ ensures biased sister chromatid attachment and segregation. We have found during stem cell ACD, sister centromeres become asymmetrically enriched with proteins involved in centromere specification and kinetochore function. Furthermore, we show that that temporally asymmetric microtubule activities direct polarized nuclear envelope breakdown, allowing for the preferential recognition and attachment of microtubules to asymmetric sister kinetochores and sister centromeres. This communication occurs in a spatiotemporally regulated manner. Abolishment of either the establishment of asymmetric sister centromeres or the asymmetric microtubule emanation results in randomized sister chromatid segregation, which leads to stem cell loss. Our results demonstrate that the cis-asymmetry at sister centromeres tightly coordinates with the trans-asymmetry from the mitotic machinery to allow for differential attachment and segregation of genetically identical yet epigenetically distinct sister chromatids. Together, these results provide the first direct in vivo mechanisms for partitioning epigenetically distinct sister chromatids in asymmetrically dividing stem cells, which opens a new direction to study how this mechanism could be used in other developmental contexts to achieve distinct cell fates through mitosis.One Sentence SummaryDuring Drosophila male germline stem cell asymmetric division, sister centromeres communicate with spindle microtubules for differential attachment and segregation of sister chromatids.

scholarly journals A switch in cilia-mediated Hedgehog signaling controls muscle stem cell quiescence and cell cycle progression

2019 ◽  
Author(s):  
Sara Betania Cruz-Migoni ◽  
Kamalliawati Mohd Imran ◽  
Aysha Wahid ◽  
Oisharja Rahman ◽  
James Briscoe ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Cycle Progression ◽  
Ex Vivo ◽  
List Type ◽  
Quiescent State ◽  
Self Renewal ◽  
Cycle Progression

SummaryTissue homeostasis requires a tight control of stem cells to maintain quiescence in normal conditions, and ensure a balance between progenitor cell production and the need to preserve a stem cell pool in repair conditions. Using ex-vivo and in-vivo genetic approaches, we provide evidence that primary cilium-mediated repressive Hedgehog (Hh) signalling is required to maintain skeletal muscle stem cells (MuSCs) in a quiescent state. De-repression and further activation of Hh signalling initiates MuSC entry and progression through the cell cycle, and controls self-renewal to ensure efficient repair of injured muscles. We propose a model whereby disassembly of primary cilia upon MuSC activation induces a switch in Hh signalling from a repressive to active state that controls exit from quiescence. Positive Hh response in bi-potential muscle progenitor cells regulates also cell cycle progression and drives MuSC self-renewal. These findings identify Hh signalling as a major regulator of MuSC activity.HighlightsCilia-containing quiescent MuSCs are Hh signalling suppressedMuSC activation coincides with a switch to active Hh signallingSmo mutation delays cell cycle entry and progression, and causes impaired self-renewalPtch1 mutation promotes exit from quiescence, rapid cell cycle and increased self-renewalGraphical abstract

PTTG has a Dual Role of Promotion-Inhibition in the Development of Pituitary Adenomas

2019 ◽  
Vol 26 (11) ◽  
pp. 800-818
Author(s):  
Zujian Xiong ◽  
Xuejun Li ◽  
Qi Yang
Keyword(s):  
Cell Cycle ◽  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Cell Cycle Progression ◽  
Key Factors ◽  
Cycle Progression ◽  
Sister Chromatids ◽  
Regulation Of Cell Cycle ◽  
Late Stages

Pituitary Tumor Transforming Gene (PTTG) of human is known as a checkpoint gene in the middle and late stages of mitosis, and is also a proto-oncogene that promotes cell cycle progression. In the nucleus, PTTG works as securin in controlling the mid-term segregation of sister chromatids. Overexpression of PTTG, entering the nucleus with the help of PBF in pituitary adenomas, participates in the regulation of cell cycle, interferes with DNA repair, induces genetic instability, transactivates FGF-2 and VEGF and promotes angiogenesis and tumor invasion. Simultaneously, overexpression of PTTG induces tumor cell senescence through the DNA damage pathway, making pituitary adenoma possessing the potential self-limiting ability. To elucidate the mechanism of PTTG in the regulation of pituitary adenomas, we focus on both the positive and negative function of PTTG and find out key factors interacted with PTTG in pituitary adenomas. Furthermore, we discuss other possible mechanisms correlate with PTTG in pituitary adenoma initiation and development and the potential value of PTTG in clinical treatment.

scholarly journals Characterization of histone inheritance patterns in the Drosophila female germline

2020 ◽  
Author(s):  
Elizabeth W. Kahney ◽  
Lydia Sohn ◽  
Kayla Viets-Layng ◽  
Robert Johnston ◽  
Xin Chen
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Single Gene ◽  
Asymmetric Division ◽  
Germline Stem Cell ◽  
Inheritance Patterns ◽  
Daughter Cells ◽  
Dividing Cells ◽  
Female Germline

ABSTRACTStem cells have the unique ability to undergo asymmetric division which produces two daughter cells that are genetically identical, but commit to different cell fates. The loss of this balanced asymmetric outcome can lead to many diseases, including cancer and tissue dystrophy. Understanding this tightly regulated process is crucial in developing methods to treat these abnormalities. Here, we report that produced from a Drosophila female germline stem cell asymmetric division, the two daughter cells differentially inherit histones at key genes related to either maintaining the stem cell state or promoting differentiation, but not at constitutively active or silenced genes. We combined histone labeling with DNA Oligopaints to distinguish old versus new histone distribution and visualize their inheritance patterns at single-gene resolution in asymmetrically dividing cells in vivo. This strategy can be widely applied to other biological contexts involving cell fate establishment during development or tissue homeostasis in multicellular organisms.

scholarly journals Expression of Cell Cycle–Related Genes With Cytokine-Induced Cell Cycle Progression of Primitive Hematopoietic Stem Cells

2010 ◽  
Vol 19 (4) ◽  
pp. 453-460 ◽  
Author(s):  
Peter J. Quesenberry ◽  
Gerri J. Dooner ◽  
Michael Del Tatto ◽  
Gerald A. Colvin ◽  
Kevin Johnson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Hematopoietic Stem

scholarly journals Skp2 contributes to cell cycle progression in trophoblast stem cells and to placental development

2020 ◽  
Vol 25 (6) ◽  
pp. 427-438 ◽  
Author(s):  
Yuhei Yamauchi ◽  
Akihiro Nita ◽  
Masaaki Nishiyama ◽  
Yoshiharu Muto ◽  
Hideyuki Shimizu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Cycle Progression ◽  
Placental Development ◽  
Cycle Progression ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem

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.

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