Engineered human dicentric chromosomes show centromere plasticity |
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Authors: | Anne?W?Higgins Karen?M?Gustashaw Email author" target="_blank">Huntington?F?WillardEmail author |
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Institution: | (1) Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA;(2) Brigham and Women's Hospital, Boston, MA 02115, USA;(3) Olympus America, Inc., Melville, NY 11747, USA;(4) Institute for Genome Sciences & Policy, Duke University, CIEMAS Bldg, Room 2376, 101 Science Drive, Durham, NC 27708, USA |
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Abstract: | The centromere is essential for the faithful distribution of a cell's genetic material to subsequent generations. Despite
intense scrutiny, the precise genetic and epigenetic basis for centromere function is still unknown. Here, we have used engineered
dicentric human chromosomes to investigate mammalian centromere structure and function. We describe three classes of dicentric
chromosomes isolated in different cell lines: functionally monocentric chromosomes, in which one of the two genetically identical
centromeres is consistently inactivated; functionally dicentric chromosomes, in which both centromeres are consistently active;
and dicentric chromosomes heterogeneous with respect to centromere activity. A study of serial single cell clones from heterogeneous
cell lines revealed that while centromere activity is usually clonal, the centromere state (i.e. functionally monocentric
or dicentric) in some lines can switch within a growing population of cells. Because pulsed field gel analysis indicated that
the DNA at the centromeres of these chromosomes did not change detectably, this switching of the centromere state is most
likely due to epigenetic changes. Inactivation of one of the two active centromeres in a functionally dicentric chromosome
was observed in a percentage of cells after treatment with Trichostatin A, an inhibitor of histone deacetylation. This study
provides evidence that the activity of human centromeres, while largely stable, can be subject to dynamic change, most likely
due to epigenetic modification. |
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Keywords: | centromere dicentric epigenetics histone acetylation pulsed field gel electrophoresis |
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