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Epigenetic defects in stem cells def...

Montgomery, Nathan D.

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Epigenetic defects in stem cells deficient in polycomb group function.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Epigenetic defects in stem cells deficient in polycomb group function./
Author:	Montgomery, Nathan D.
Description:	178 p.
Notes:	Adviser: Terry Magnuson.
Contained By:	Dissertation Abstracts International68-04B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3262661

Epigenetic defects in stem cells deficient in polycomb group function.
Montgomery, Nathan D.

Epigenetic defects in stem cells deficient in polycomb group function. - 178 p.

Adviser: Terry Magnuson.

Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2007.

During development, the expression states of many genes must be maintained through cell divisions in order to ensure lineage-, time-, and dose-appropriate patterns of gene expression. This transcriptional memory is independent of permanent DNA sequences changes and instead involves reversible epigenetic mechanisms. Polycomb Group (PcG) proteins represent a conserved family of developmental regulators that mediate heritable transcriptional silencing by covalently modifying histone proteins. Here, we demonstrate that mutations in the PcG gene Embryonic ectoderm development (Eed) produce a variety of epigenetic defects in mouse embryos and stem cells. EED is a noncatalytic subunit of Polycomb Repressive Complex 2, a 600 kDa complex containing a number of proteins, including the histone H3-lysine 27 (H3K27) methyltransferase EZH2. Consistent with the role of PcG genes in transcriptional memory, Eed mutant embryos and trophoblast stem cells have defects in genomic imprinting, a process by which an allele's expression is dependent upon the gender of the parent from which it was inherited. To determine whether these gene expression defects revealed a required role for EED in PRC2 function, we characterized the status of H3K27 methylation in Eed mutant stem cells. H3K7 can be mono-, di-, or trimethylated (H3K27me1, H3K27me2, H3K27me3, respectively), but it has been unclear which of these marks are mediated by PRC2. Here, we demonstrate that EED is required for all three methylation states. Additionally, although EED is present as four distinct isoforms in mammalian cells, these isoforms are not necessary for H3K27 methylation. Instead, EED's core WD-40 motifs and histone binding domain alone are sufficient to mediate histone methylation. Finally, although the histone methylation defects in Eed mutant stem cells appear to be global, the imprinted expression defects are restricted to DNA hypomethylated, extraembryonic tissues and to genes that are imprinted normally in DNA methyltransferase 1 (Dnmt1) mutant placentas. Together, these results suggest that histone methylation and DNA methylation may have non-overlapping roles in imprinted gene regulation.Subjects--Topical Terms:

1017730
Biology, Genetics.

Epigenetic defects in stem cells deficient in polycomb group function.
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035 $a (UMI)AAI3262661
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100 1 $a Montgomery, Nathan D. $3 1271699
245 1 0 $a Epigenetic defects in stem cells deficient in polycomb group function.
300 $a 178 p.
500 $a Adviser: Terry Magnuson.
500 $a Source: Dissertation Abstracts International, Volume: 68-04, Section: B, page: 2053.
502 $a Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2007.
520 $a During development, the expression states of many genes must be maintained through cell divisions in order to ensure lineage-, time-, and dose-appropriate patterns of gene expression. This transcriptional memory is independent of permanent DNA sequences changes and instead involves reversible epigenetic mechanisms. Polycomb Group (PcG) proteins represent a conserved family of developmental regulators that mediate heritable transcriptional silencing by covalently modifying histone proteins. Here, we demonstrate that mutations in the PcG gene Embryonic ectoderm development (Eed) produce a variety of epigenetic defects in mouse embryos and stem cells. EED is a noncatalytic subunit of Polycomb Repressive Complex 2, a 600 kDa complex containing a number of proteins, including the histone H3-lysine 27 (H3K27) methyltransferase EZH2. Consistent with the role of PcG genes in transcriptional memory, Eed mutant embryos and trophoblast stem cells have defects in genomic imprinting, a process by which an allele's expression is dependent upon the gender of the parent from which it was inherited. To determine whether these gene expression defects revealed a required role for EED in PRC2 function, we characterized the status of H3K27 methylation in Eed mutant stem cells. H3K7 can be mono-, di-, or trimethylated (H3K27me1, H3K27me2, H3K27me3, respectively), but it has been unclear which of these marks are mediated by PRC2. Here, we demonstrate that EED is required for all three methylation states. Additionally, although EED is present as four distinct isoforms in mammalian cells, these isoforms are not necessary for H3K27 methylation. Instead, EED's core WD-40 motifs and histone binding domain alone are sufficient to mediate histone methylation. Finally, although the histone methylation defects in Eed mutant stem cells appear to be global, the imprinted expression defects are restricted to DNA hypomethylated, extraembryonic tissues and to genes that are imprinted normally in DNA methyltransferase 1 (Dnmt1) mutant placentas. Together, these results suggest that histone methylation and DNA methylation may have non-overlapping roles in imprinted gene regulation.
590 $a School code: 0153.
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Biology, Molecular. $3 1017719
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710 2 0 $a The University of North Carolina at Chapel Hill. $b Genetics & Molecular Biology. $3 1271700
773 0 $t Dissertation Abstracts International $g 68-04B.
790 $a 0153
790 1 0 $a Magnuson, Terry, $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3262661