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.

scholarly journals CENP-A drives asymmetric cell division and maintains stem identity

2019 ◽  
Author(s):  
Anna A. Dattoli ◽  
Ben L. Carty ◽  
Antje M. Kochendoerfer ◽  
Annie E. Walshe ◽  
Elaine M. Dunleavy
Keyword(s):  
Stem Cell ◽  
Asymmetric Cell Division ◽  
Germline Stem Cells ◽  
Cell Identity ◽  
Over Expression ◽  
Identity Maintenance ◽  
Oocyte Meiosis ◽  
Assembly Factor ◽  
Female Germline ◽  
Centromere Assembly

SUMMARYCentromeres, chromosomal loci essential for genome integrity, are epigenetically defined by CENP-A-containing chromatin. Recent studies suggest that parental CENP-A is asymmetrically distributed upon stem cell asymmetric division. However, a direct link between centromeres and stem cell identity has not been demonstrated. We show that Drosophila female germline stem cells (GSCs) and neuroblasts assemble centromeres between G2-phase and prophase, requiring CYCLIN A. Intriguingly, chromosomes that will be inherited by GSCs incorporate more CENP-A and capture more spindle fibers at pro-metaphase. Furthermore, over-expression of CAL1 (Drosophila CENP-A assembly factor) causes GSC-like tumours, while over-expression of both CENP-A and CAL1 promotes stem cell self-renewal. Finally, once centromeres have been assembled in GSCs, continued CENP-A assembly is not required in differentiating cells outside of the niche and CAL1 becomes dispensable. According to our results CENP-A regulates stem cell identity/maintenance. Moreover, crucial centromere assembly occurs in the niche prior to oocyte meiosis.

scholarly journals Klp10A, a stem cell centrosome-enriched kinesin, balances asymmetries in Drosophila male germline stem cell division

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Cuie Chen ◽  
Mayu Inaba ◽  
Zsolt G Venkei ◽  
Yukiko M Yamashita
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Cell Fate ◽  
Germline Stem Cell ◽  
Germline Stem Cells ◽  
Male Germline ◽  
Mother And Daughter ◽  
Stem Cell Divisions ◽  
Stem Cell Division ◽  
Male Germline Stem Cells

Asymmetric stem cell division is often accompanied by stereotypical inheritance of the mother and daughter centrosomes. However, it remains unknown whether and how stem cell centrosomes are uniquely regulated and how this regulation may contribute to stem cell fate. Here we identify Klp10A, a microtubule-depolymerizing kinesin of the kinesin-13 family, as the first protein enriched in the stem cell centrosome in Drosophila male germline stem cells (GSCs). Depletion of klp10A results in abnormal elongation of the mother centrosomes in GSCs, suggesting the existence of a stem cell-specific centrosome regulation program. Concomitant with mother centrosome elongation, GSCs form asymmetric spindle, wherein the elongated mother centrosome organizes considerably larger half spindle than the other. This leads to asymmetric cell size, yielding a smaller differentiating daughter cell. We propose that klp10A functions to counteract undesirable asymmetries that may result as a by-product of achieving asymmetries essential for successful stem cell divisions.

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 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 Stem cell regulation: Implications when differentiated cells regulate symmetric stem cell division

2015 ◽  
Vol 380 ◽  
pp. 203-219 ◽  
Author(s):  
Marte Rørvik Høyem ◽  
Frode Måløy ◽  
Per Jakobsen ◽  
Bjørn Olav Brandsdal
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Cell Regulation ◽  
Stem Cell Regulation ◽  
Differentiated Cells ◽  
Stem Cell Division

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 Mad dephosphorylation at the nuclear pore is essential for asymmetric stem cell division

2021 ◽  
Vol 118 (13) ◽  
pp. e2006786118
Author(s):  
Justin Sardi ◽  
Muhammed Burak Bener ◽  
Taylor Simao ◽  
Abigail E. Descoteaux ◽  
Boris M. Slepchenko ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Daughter Cell ◽  
High Sensitivity ◽  
Bmp Signaling ◽  
Nuclear Pore ◽  
Germline Stem Cells ◽  
Stem Cell Division ◽  
Asymmetric Partitioning

Stem cells divide asymmetrically to generate a stem cell and a differentiating daughter cell. Yet, it remains poorly understood how a stem cell and a differentiating daughter cell can receive distinct levels of niche signal and thus acquire different cell fates (self-renewal versus differentiation), despite being adjacent to each other and thus seemingly exposed to similar levels of niche signaling. In the Drosophila ovary, germline stem cells (GSCs) are maintained by short range bone morphogenetic protein (BMP) signaling; the BMP ligands activate a receptor that phosphorylates the downstream molecule mothers against decapentaplegic (Mad). Phosphorylated Mad (pMad) accumulates in the GSC nucleus and activates the stem cell transcription program. Here, we demonstrate that pMad is highly concentrated in the nucleus of the GSC, while it quickly decreases in the nucleus of the differentiating daughter cell, the precystoblast (preCB), before the completion of cytokinesis. We show that a known Mad phosphatase, Dullard (Dd), is required for the asymmetric partitioning of pMad. Our mathematical modeling recapitulates the high sensitivity of the ratio of pMad levels to the Mad phosphatase activity and explains how the asymmetry arises in a shared cytoplasm. Together, these studies reveal a mechanism for breaking the symmetry of daughter cells during asymmetric stem cell division.

scholarly journals Mad dephosphorylation at the nuclear envelope is essential for asymmetric stem cell division

2019 ◽  
Author(s):  
Justin Sardi ◽  
Muhammed Burak Bener ◽  
Taylor Simao ◽  
Abigail E. Descoteaux ◽  
Boris M. Slepchenko ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Short Range ◽  
Bmp Signaling ◽  
Nuclear Pore ◽  
Germline Stem Cells ◽  
Daughter Cells ◽  
Stem Cell Division ◽  
Cell Niche

SummaryStem cell niche signals act over a short range so that only stem cells but not the differentiating daughter cells receive the self-renewal signals. Drosophila female germline stem cells (GSCs) are maintained by short range BMP signaling; BMP ligands Dpp/Gbb activate receptor Tkv to phosphorylate Mad (phosphor-Mad or pMad) which accumulates in the GSC nucleus and activates the stem cell transcription program. pMad is highly concentrated in the nucleus of the GSC, but is immediately downregulated in the nucleus of the pre-cystoblast (preCB), a differentiating daughter cell, that is displaced away from the niche. Here we show that this asymmetry in the intensity of pMad is formed even before the completion of cytokinesis. A delay in establishing the pMad asymmetry leads to germline tumors through conversion of differentiating cells into a stem cell-like state. We show that a Mad phosphatase Dullard (Dd) interacts with Mad at the nuclear pore, where it may dephosphorylate Mad. A mathematical model explains how an asymmetry can be established in a common cytoplasm. It also demonstrates that the ratio of pMad concentrations in GSC/preCB is highly sensitive to Mad dephosphorylation rate. Our study reveals a previously unappreciated mechanism for breaking symmetry between daughter cells during asymmetric stem cell division.

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