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 Asymmetric histone inheritance regulates stem cell fate in Drosophila midgut

2020 ◽  
Author(s):  
Emily Zion ◽  
Xin Chen
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Biological Significance ◽  
Cell Lineage ◽  
Germline Stem Cells ◽  
Cell Fates ◽  
Stem Cell Fate ◽  
Distinct Cell

AbstractA fundamental question in developmental biology is how distinct cell fates are established and maintained through epigenetic mechanisms in multicellular organisms. Here, we report that preexisting (old) and newly synthesized (new) histones H3 and H4 are asymmetrically inherited by the distinct daughter cells during asymmetric division of Drosophila intestinal stem cells (ISCs). By contrast, in symmetrically dividing ISCs that produce two self-renewed stem cells, old and new H3 and H4 show symmetric inheritance patterns. These results indicate that asymmetric histone inheritance is tightly associated with the distinct daughter cell fates. To further understand the biological significance of this asymmetry, we express a mutant histone that compromises asymmetric histone inheritance pattern. We find increased symmetric ISC division and ISC tumors during aging under this condition. Together, our results demonstrate that asymmetric histone inheritance is important for establishing distinct cell identities in a somatic stem cell lineage, consistent with previous findings in asymmetrically dividing male germline stem cells in Drosophila. Therefore, this work sheds light on the principles of histone inheritance in regulating stem cell fate in vivo.

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.

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 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.

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 Stem Cells, Diet, and Physiology

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 740-740
Author(s):  
Daniela Drummond-Barbosa
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Lineage ◽  
Germline Stem Cell ◽  
Stem Cell Regulation ◽  
Stem Cell Lineage ◽  
Sensor Control ◽  
Nutrient Signaling ◽  
Multicellular Organisms

Abstract Nutrient availability, stresses, and aging affect tissue stem cells in multicellular organisms; yet, the underlying physiological mechanisms in vivo remains largely unexplored. Dr. Drummond-Barbosa pioneered using Drosophila to study the physiology of tissue stem cell regulation. Her laboratory played a major role in delineating how diet, brain insulin-like peptides, and the TOR nutrient sensor control the germline stem cell (GSC) lineage. They also discovered that adipocyte-specific disruption of amino acid transport, other nutrient signaling, and metabolic pathways causes distinct germline phenotypes. They also showed that nuclear receptors act in multiple tissues to affect the GSC lineage through direct and indirect mechanisms. More recently, her group has been exploring how other physiological stresses affect the GSC lineage. Her group’s studies point to extensive communication between the brain, adipocytes, hepatocyte-like cells, and the germline, and underscore the complexity of the physiological network that modulates stem cell lineage behavior.

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 Non-Random Sister Chromatid Segregation in Human Tissue Stem Cells

Symmetry ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1868
Author(s):  
Krishnanchali Panchalingam ◽  
Laura Jacox ◽  
Benjamin D. Cappiello ◽  
James L. Sherley
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Sister Chromatid ◽  
Human Tissue ◽  
Cell Kinetics ◽  
Genetic Fidelity ◽  
Cell Strain ◽  
Hepatic Stem Cell ◽  
Sister Chromatids ◽  
Chromatid Segregation

The loss of genetic fidelity in tissue stem cells is considered a significant cause of human aging and carcinogenesis. Many cellular mechanisms are well accepted for limiting mutations caused by replication errors and DNA damage. However, one mechanism, non-random sister chromatid segregation, remains controversial. This atypical pattern of chromosome segregation is restricted to asymmetrically self-renewing cells. Though first confirmed in murine cells, non-random segregation was originally proposed by Cairns as an important genetic fidelity mechanism in human tissues. We investigated human hepatic stem cells expanded by suppression of asymmetric cell kinetics (SACK) for evidence of non-random sister chromatid segregation. Cell kinetics and time-lapse microscopy analyses established that an ex vivo expanded human hepatic stem cell strain possessed SACK agent-suppressible asymmetric cell kinetics. Complementary DNA strand-labeling experiments revealed that cells in hepatic stem cell cultures segregated sister chromatids non-randomly. The number of cells cosegregating sister chromatids with the oldest “immortal DNA strands” was greater under conditions that increased asymmetric self-renewal kinetics. Detection of this mechanism in a human tissue stem cell strain increases support for Cairns’ proposal that non-random sister chromatid segregation operates in human tissue stem cells to limit carcinogenesis.

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