Centromere assembly and non-random sister chromatid segregation in stem cells

2020 ◽  
Vol 64 (2) ◽  
pp. 223-232 ◽  
Author(s):  
Ben L. Carty ◽  
Elaine M. Dunleavy
Keyword(s):  
Stem Cells ◽  
Cell Division ◽  
Cell Fate ◽  
Sister Chromatid ◽  
Asymmetric Cell Division ◽  
Protein A ◽  
Germline Stem Cells ◽  
Sister Chromatids ◽  
Centromere Protein A ◽  
Oocyte Meiosis

Abstract Asymmetric cell division (ACD) produces daughter cells with separate distinct cell fates and is critical for the development and regulation of multicellular organisms. Epigenetic mechanisms are key players in cell fate determination. Centromeres, epigenetically specified loci defined by the presence of the histone H3-variant, centromere protein A (CENP-A), are essential for chromosome segregation at cell division. ACDs in stem cells and in oocyte meiosis have been proposed to be reliant on centromere integrity for the regulation of the non-random segregation of chromosomes. It has recently been shown that CENP-A is asymmetrically distributed between the centromeres of sister chromatids in male and female Drosophila germline stem cells (GSCs), with more CENP-A on sister chromatids to be segregated to the GSC. This imbalance in centromere strength correlates with the temporal and asymmetric assembly of the mitotic spindle and potentially orientates the cell to allow for biased sister chromatid retention in stem cells. In this essay, we discuss the recent evidence for asymmetric sister centromeres in stem cells. Thereafter, we discuss mechanistic avenues to establish this sister centromere asymmetry and how it ultimately might influence cell fate.

scholarly journals Cytokine receptor-Eb1 interaction couples cell polarity and fate during asymmetric cell division

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Cuie Chen ◽  
Ryan Cummings ◽  
Aghapi Mordovanakis ◽  
Alan J Hunt ◽  
Michael Mayer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Division ◽  
Cell Fate ◽  
Cell Polarity ◽  
Adult Stem Cells ◽  
Asymmetric Cell Division ◽  
Cytokine Receptor ◽  
Spindle Orientation ◽  
Germline Stem Cells ◽  
Self Renewal

Asymmetric stem cell division is a critical mechanism for balancing self-renewal and differentiation. Adult stem cells often orient their mitotic spindle to place one daughter inside the niche and the other outside of it to achieve asymmetric division. It remains unknown whether and how the niche may direct division orientation. Here we discover a novel and evolutionary conserved mechanism that couples cell polarity to cell fate. We show that the cytokine receptor homolog Dome, acting downstream of the niche-derived ligand Upd, directly binds to the microtubule-binding protein Eb1 to regulate spindle orientation in Drosophila male germline stem cells (GSCs). Dome’s role in spindle orientation is entirely separable from its known function in self-renewal mediated by the JAK-STAT pathway. We propose that integration of two functions (cell polarity and fate) in a single receptor is a key mechanism to ensure an asymmetric outcome following cell division.

scholarly journals Cytokine receptor-Eb1 interaction couples cell polarity and fate during asymmetric cell division

2017 ◽  
Author(s):  
Cuie Chen ◽  
Ryan Cummings ◽  
Aghapi Mordovanakis ◽  
Alan J. Hunt ◽  
Michael Mayer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Division ◽  
Cell Fate ◽  
Cell Polarity ◽  
Adult Stem Cells ◽  
Asymmetric Cell Division ◽  
Cytokine Receptor ◽  
Spindle Orientation ◽  
Germline Stem Cells ◽  
Self Renewal

AbstractAsymmetric stem cell division is a critical mechanism for balancing self-renewal and differentiation. Adult stem cells often orient their mitotic spindle to place one daughter inside the niche and the other outside of it to achieve asymmetric division. It remains unknown whether and how the niche may direct division orientation. Here we discover a novel and evolutionary conserved mechanism that couples cell polarity to cell fate. We show that the cytokine receptor homolog Dome, acting downstream of the niche-derived ligand Upd, directly binds to the microtubule-binding protein Eb1 to regulate spindle orientation in Drosophila male germline stem cells (GSCs). Dome’s role in spindle orientation is entirely separable from its known function in self-renewal mediated by the JAK-STAT pathway. We propose that integration of two functions (cell polarity and fate) in a single receptor is a key mechanism to ensure an asymmetric outcome following cell division.

scholarly journals Centromere function in asymmetric cell division in Drosophila female and male germline stem cells

Open Biology ◽  
2021 ◽  
Vol 11 (11) ◽  
Author(s):  
Antje M. Kochendoerfer ◽  
Federica Modafferi ◽  
Elaine M. Dunleavy
Keyword(s):  
Stem Cells ◽  
Cell Division ◽  
Cell Fate ◽  
Chromosome Segregation ◽  
Asymmetric Cell Division ◽  
Genetic Material ◽  
Asymmetric Distribution ◽  
Germline Stem Cells ◽  
Male Germline ◽  
Male Germline Stem Cells

The centromere is the constricted chromosomal region required for the correct separation of the genetic material at cell division. The kinetochore protein complex assembles at the centromere and captures microtubules emanating from the centrosome to orchestrate chromosome segregation in mitosis and meiosis. Asymmetric cell division (ACD) is a special type of mitosis that generates two daughter cells with different fates. Epigenetic mechanisms operating at the centromere have been proposed to contribute to ACD. Recent studies have shown that an asymmetric distribution of CENP-A—the centromere-specific histone H3 variant—between sister chromatids can bias chromosome segregation in ACD. In stem cells, this leads to non-random sister chromatid segregation, which can affect cell fate. These findings support the ‘silent sister' hypothesis, according to which the mechanisms of ACD are epigenetically regulated through centromeres. Here, we review the recent data implicating centromeres in ACDs and cell fate in Drosophila melanogaster female and male germline stem cells.

scholarly journals Unidirectional fork movement coupled with strand-specific histone incorporation ensures asymmetric histone inheritance

2018 ◽  
Author(s):  
Matthew Wooten ◽  
Jonathan Snedeker ◽  
Zehra Nizami ◽  
Xinxing Yang ◽  
Rajesh Ranjan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Replication ◽  
Cell Fate ◽  
Asymmetric Cell Division ◽  
Cell Types ◽  
Germline Stem Cells ◽  
Histone H4 ◽  
Inheritance Patterns ◽  
Sister Chromatids ◽  
Chromatin Fibers

One Sentence SummaryDNA replication establishes asymmetric epigenomesSummaryOne of the most fundamental questions in developmental biology concerns how cells with identical genomes differentiate into distinct cell types. One important context for understanding cell fate specification is asymmetric cell division, where the two daughter cells establish different cell fates following a single division. Many stem cells undergo asymmetric division to produce both a self-renewing stem cell and a differentiating daughter cell1–5. Here we show that histone H4 is inherited asymmetrically in asymmetrically dividing Drosophila male germline stem cells, similar to H36. In contrast, both H2A and H2B are inherited symmetrically. By combining superresolution microscopy with the chromatin fiber method, we are able to study histone inheritance patterns on newly replicated chromatin fibers. Using this technique, we find asymmetric inheritance patterns for old and new H3, but symmetric inheritance patterns for old and new H2A on replicating sister chromatids. Furthermore, co-localization studies on isolated chromatin fibers and proximity ligation assays on intact nuclei reveal that old H3 are preferentially incorporated by the leading strand while newly synthesized H3 are enriched on the lagging strand. Finally, using a sequential nucleoside analog incorporation assay, we detect a high incidence of unidirectional DNA replication on germline-derived chromatin fibers and DNA fibers. The unidirectional fork movement coupled with the strand preference of histone incorporation could explain how old and new H3 are asymmetrically incorporated by replicating sister chromatids. In summary, our work demonstrates that the intrinsic asymmetries in DNA replication may help construct sister chromatids enriched with distinct populations of histones. Therefore, these results suggest unappreciated roles for DNA replication in asymmetrically dividing cells in multicellular organisms.

Asymmetric organelle inheritance predicts human blood stem cell fate

Blood ◽  
2021 ◽  
Author(s):  
Dirk Loeffler ◽  
Florin Schneiter ◽  
Weijia Wang ◽  
Arne Wehling ◽  
Tobias Kull ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Cell Fate ◽  
Human Blood ◽  
Asymmetric Cell Division ◽  
Cell Fates ◽  
Hematopoietic Stem ◽  
Stem Cell Fate ◽  
Blood Stem Cells

Understanding human hematopoietic stem cell fate control is important for their improved therapeutic manipulation. Asymmetric cell division, the asymmetric inheritance of factors during division instructing future daughter cell fates, was recently described in mouse blood stem cells. In human blood stem cells, the possible existence of asymmetric cell division remained unclear due to technical challenges in its direct observation. Here, we use long-term quantitative single-cell imaging to show that lysosomes and active mitochondria are asymmetrically inherited in human blood stem cells and that their inheritance is a coordinated, non-random process. Furthermore, multiple additional organelles, including autophagosomes, mitophagosomes, autolysosomes and recycling endosomes show preferential asymmetric co-segregation with lysosomes. Importantly, asymmetric lysosomal inheritance predicts future asymmetric daughter cell cycle length, differentiation and stem cell marker expression, while asymmetric inheritance of active mitochondria correlates with daughter metabolic activity. Hence, human hematopoietic stem cell fates are regulated by asymmetric cell division, with both mechanistic evolutionary conservation and differences to the mouse system.

scholarly journals CENP-C regulates centromere assembly, asymmetry and epigenetic age in Drosophila germline stem cells

2020 ◽  
Author(s):  
Ben L Carty ◽  
Anna A Dattoli ◽  
Elaine M Dunleavy
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Germ Line ◽  
Asymmetric Distribution ◽  
Germline Stem Cells ◽  
Daughter Cells ◽  
Sister Chromatids ◽  
Asymmetric Divisions ◽  
Centromere Assembly

AbstractGermline stem cells divide asymmetrically to produce one new daughter stem cell and one daughter cell that will subsequently undergo meiosis and differentiate to generate the mature gamete. The silent sister hypothesis proposes that in asymmetric divisions, the selective inheritance of sister chromatids carrying specific epigenetic marks between stem and daughter cells impacts cell fate. To facilitate this selective inheritance, the hypothesis specifically proposes that the centromeric region of each sister chromatid is distinct. In Drosophila germ line stem cells (GSCs), it has recently been shown that the centromeric histone CENP-A (called CID in flies) - the epigenetic determinant of centromere identity - is asymmetrically distributed between sister chromatids. In these cells, CID deposition occurs in G2 phase such that sister chromatids destined to end up in the stem cell harbour more CENP-A, assemble more kinetochore proteins and capture more spindle microtubules. These results suggest a potential mechanism of ‘mitotic drive’ that might bias chromosome segregation. Here we report that the inner kinetochore protein CENP-C, is required for the assembly of CID in G2 phase in GSCs. Moreover, CENP-C is required to maintain a normal asymmetric distribution of CID between stem and daughter cells. In addition, we find that CID is lost from centromeres in aged GSCs and that a reduction in CENP-C accelerates this loss. Finally, we show that CENP-C depletion in GSCs disrupts the balance of stem and daughter cells in the ovary, shifting GSCs toward a self-renewal tendency. Ultimately, we provide evidence that centromere assembly and maintenance via CENP-C is required to sustain asymmetric divisions in female Drosophila GSCs.

scholarly journals CENP-C functions in centromere assembly, the maintenance of CENP-A asymmetry and epigenetic age in Drosophila germline stem cells

PLoS Genetics ◽  
2021 ◽  
Vol 17 (5) ◽  
pp. e1009247
Author(s):  
Ben L. Carty ◽  
Anna A. Dattoli ◽  
Elaine M. Dunleavy
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Germ Line ◽  
Asymmetric Distribution ◽  
Germline Stem Cells ◽  
Daughter Cells ◽  
Sister Chromatids ◽  
Asymmetric Divisions ◽  
Centromere Assembly

Germline stem cells divide asymmetrically to produce one new daughter stem cell and one daughter cell that will subsequently undergo meiosis and differentiate to generate the mature gamete. The silent sister hypothesis proposes that in asymmetric divisions, the selective inheritance of sister chromatids carrying specific epigenetic marks between stem and daughter cells impacts cell fate. To facilitate this selective inheritance, the hypothesis specifically proposes that the centromeric region of each sister chromatid is distinct. In Drosophila germ line stem cells (GSCs), it has recently been shown that the centromeric histone CENP-A (called CID in flies)—the epigenetic determinant of centromere identity—is asymmetrically distributed between sister chromatids. In these cells, CID deposition occurs in G2 phase such that sister chromatids destined to end up in the stem cell harbour more CENP-A, assemble more kinetochore proteins and capture more spindle microtubules. These results suggest a potential mechanism of ‘mitotic drive’ that might bias chromosome segregation. Here we report that the inner kinetochore protein CENP-C, is required for the assembly of CID in G2 phase in GSCs. Moreover, CENP-C is required to maintain a normal asymmetric distribution of CID between stem and daughter cells. In addition, we find that CID is lost from centromeres in aged GSCs and that a reduction in CENP-C accelerates this loss. Finally, we show that CENP-C depletion in GSCs disrupts the balance of stem and daughter cells in the ovary, shifting GSCs toward a self-renewal tendency. Ultimately, we provide evidence that centromere assembly and maintenance via CENP-C is required to sustain asymmetric divisions in female Drosophila GSCs.

scholarly journals The polarity protein Baz forms a platform for the centrosome orientation during asymmetric stem cell division in the Drosophila male germline

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Mayu Inaba ◽  
Zsolt G Venkei ◽  
Yukiko M Yamashita
Keyword(s):  
Stem Cells ◽  
Cell Division ◽  
Cell Polarity ◽  
Asymmetric Cell Division ◽  
Underlying Mechanism ◽  
Germline Stem Cells ◽  
Cell Fates ◽  
Male Germline ◽  
Distinct Cell ◽  
Tightly Coupled

Many stem cells divide asymmetrically in order to balance self-renewal with differentiation. The essence of asymmetric cell division (ACD) is the polarization of cells and subsequent division, leading to unequal compartmentalization of cellular/extracellular components that confer distinct cell fates to daughter cells. Because precocious cell division before establishing cell polarity would lead to failure in ACD, these two processes must be tightly coupled; however, the underlying mechanism is poorly understood. In Drosophila male germline stem cells, ACD is prepared by stereotypical centrosome positioning. The centrosome orientation checkpoint (COC) further serves to ensure ACD by preventing mitosis upon centrosome misorientation. In this study, we show that Bazooka (Baz) provides a platform for the correct centrosome orientation and that Baz-centrosome association is the key event that is monitored by the COC. Our work provides a foundation for understanding how the correct cell polarity may be recognized by the cell to ensure productive ACD.

scholarly journals Asymmetric assembly of centromeres epigenetically regulates stem cell fate

2020 ◽  
Vol 219 (4) ◽  
Author(s):  
Anna Ada Dattoli ◽  
Ben L. Carty ◽  
Antje M. Kochendoerfer ◽  
Conall Morgan ◽  
Annie E. Walshe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Cell Fate ◽  
Germline Stem Cells ◽  
Differentiated Cells ◽  
Oocyte Meiosis ◽  
Assembly Factor ◽  
Stem Cell Division ◽  
Female Germline ◽  
Centromere Assembly

Centromeres are epigenetically defined by CENP-A–containing chromatin and are essential for cell division. Previous studies suggest asymmetric inheritance of centromeric proteins upon stem cell division; however, the mechanism and implications of selective chromosome segregation remain unexplored. We show that Drosophila female germline stem cells (GSCs) and neuroblasts assemble centromeres after replication and before segregation. Specifically, CENP-A deposition is promoted by CYCLIN A, while excessive CENP-A deposition is prevented by CYCLIN B, through the HASPIN kinase. Furthermore, chromosomes inherited by GSCs incorporate more CENP-A, making stronger kinetochores that capture more spindle microtubules and bias segregation. Importantly, symmetric incorporation of CENP-A on sister chromatids via HASPIN knockdown or overexpression of CENP-A, either alone or together with its assembly factor CAL1, drives stem cell self-renewal. Finally, continued CENP-A assembly in differentiated cells is nonessential for egg development. Our work shows that centromere assembly epigenetically drives GSC maintenance and occurs before oocyte meiosis.

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