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Functional Characterization of the De Novo Methyltransferase Dnmt3b

Permanent Link: http://ufdc.ufl.edu/UFE0024911/00001

Material Information

Title: Functional Characterization of the De Novo Methyltransferase Dnmt3b
Physical Description: 1 online resource (214 p.)
Language: english
Creator: Gopalakrishnan, Suhasni
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: cenp, centromere, dna, dnmt3b, epigenetics, methylation, splice
Biochemistry and Molecular Biology (IDP) -- Dissertations, Academic -- UF
Genre: Medical Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: FUNCTIONAL CHARACTERIZATION OF THE DE NOVO DNA METHYLTRANSFERASE DNMT3B DNA methylation is an epigenetic mark that is required for transcriptional repression in mammalian development, imprinting, and in the maintenance of genome stability. Genome-wide methylation patterns are established and maintained by three DNA methyltransferases (DNMTs)-DNMT1, DNMT3A, and DNMT3B. DNMT3B is specifically involved in silencing the satellite repeats at the centromeric and pericentromeric regions. The role of DNMT3B at the centromeric region is also emphasized by mitotic defects arising due to chromosome instability observed in ICF syndrome, a disease caused by germline mutations in DNMT3B. Although the mechanism of DNA methylation is well known, the targeting of DNA methylation and DNMT3B to certain genomic loci remains poorly understood. DNMT3B is also regulated by alternative splicing. Several DNMT3B splice variants are overexpressed in tumor cells and negatively regulate normal DNMT3B mediated DNA methylation. Therefore it is important to understand the significance of DNMT3B splice variants in development and tumorigenesis. In the present study, a yeast two-hybrid screening was performed and several novel DNMT3B protein interactions were identified. Of the several proteins identified, the interaction of DNMT3B with the mammalian chromatin associated factor MCAF and the chromodomain helicase DNA binding protein CHD3 were confirmed, and need further characterization. The interaction between DNMT3B and the constitutive centromeric protein CENP-C was confirmed in mammalian cells. Results from siRNA knock downs, bisulfite genomic sequencing and ChIP, demonstrate that CENP-C recruits DNA methylation and DNMT3B to both centromeric and pericentromeric satellite repeats. CENP-C and DNMT3B influence the histone modifications in satellite repeat regions, including marks characteristic of centromeric chromatin and disruption of this interaction causes elevated transcription of centromeric repeats. Loss of CENP-C or DNMT3B leads to elevated chromosome misalignment and segregation defects during mitosis. Taken together, the interaction between CENP-C and DNMT3B suggests a novel mechanism by which DNA methylation is targeted to discrete regions of the genome and contributes to chromosomal stability. In another study, a novel alternatively spliced form of DNMT3B lacking exon 5 was identified and characterized. This variant was termed DNMT3B3?5 because of its close resemblance with the ubiquitously expressed DNMT3B3 isoform. The novel splice variant lacking exon 5 is highly expressed in pluripotent cells and neural tissues, and is conserved in the mouse and is re-expressed on converting differentiated mEFs into pluripotent iPS cells. DNMT3B3?5 also displays altered expression in human tumor cell lines as well as an altered subcellular localization. Ectopic overexpression of DNMT3B3?5 resulted in repetitive element hypomethylation. Taken together, these results demonstrate that alternative splicing of exon 5 may play an important role in stem cell maintenance or differentiation and exon 5 could influence the functional properties of DNMT3B.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Suhasni Gopalakrishnan.
Thesis: Thesis (Ph.D.)--University of Florida, 2009.
Local: Adviser: Brown, Kevin D.
Local: Co-adviser: Robertson, Keith D.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-02-28

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0024911:00001

Permanent Link: http://ufdc.ufl.edu/UFE0024911/00001

Material Information

Title: Functional Characterization of the De Novo Methyltransferase Dnmt3b
Physical Description: 1 online resource (214 p.)
Language: english
Creator: Gopalakrishnan, Suhasni
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: cenp, centromere, dna, dnmt3b, epigenetics, methylation, splice
Biochemistry and Molecular Biology (IDP) -- Dissertations, Academic -- UF
Genre: Medical Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: FUNCTIONAL CHARACTERIZATION OF THE DE NOVO DNA METHYLTRANSFERASE DNMT3B DNA methylation is an epigenetic mark that is required for transcriptional repression in mammalian development, imprinting, and in the maintenance of genome stability. Genome-wide methylation patterns are established and maintained by three DNA methyltransferases (DNMTs)-DNMT1, DNMT3A, and DNMT3B. DNMT3B is specifically involved in silencing the satellite repeats at the centromeric and pericentromeric regions. The role of DNMT3B at the centromeric region is also emphasized by mitotic defects arising due to chromosome instability observed in ICF syndrome, a disease caused by germline mutations in DNMT3B. Although the mechanism of DNA methylation is well known, the targeting of DNA methylation and DNMT3B to certain genomic loci remains poorly understood. DNMT3B is also regulated by alternative splicing. Several DNMT3B splice variants are overexpressed in tumor cells and negatively regulate normal DNMT3B mediated DNA methylation. Therefore it is important to understand the significance of DNMT3B splice variants in development and tumorigenesis. In the present study, a yeast two-hybrid screening was performed and several novel DNMT3B protein interactions were identified. Of the several proteins identified, the interaction of DNMT3B with the mammalian chromatin associated factor MCAF and the chromodomain helicase DNA binding protein CHD3 were confirmed, and need further characterization. The interaction between DNMT3B and the constitutive centromeric protein CENP-C was confirmed in mammalian cells. Results from siRNA knock downs, bisulfite genomic sequencing and ChIP, demonstrate that CENP-C recruits DNA methylation and DNMT3B to both centromeric and pericentromeric satellite repeats. CENP-C and DNMT3B influence the histone modifications in satellite repeat regions, including marks characteristic of centromeric chromatin and disruption of this interaction causes elevated transcription of centromeric repeats. Loss of CENP-C or DNMT3B leads to elevated chromosome misalignment and segregation defects during mitosis. Taken together, the interaction between CENP-C and DNMT3B suggests a novel mechanism by which DNA methylation is targeted to discrete regions of the genome and contributes to chromosomal stability. In another study, a novel alternatively spliced form of DNMT3B lacking exon 5 was identified and characterized. This variant was termed DNMT3B3?5 because of its close resemblance with the ubiquitously expressed DNMT3B3 isoform. The novel splice variant lacking exon 5 is highly expressed in pluripotent cells and neural tissues, and is conserved in the mouse and is re-expressed on converting differentiated mEFs into pluripotent iPS cells. DNMT3B3?5 also displays altered expression in human tumor cell lines as well as an altered subcellular localization. Ectopic overexpression of DNMT3B3?5 resulted in repetitive element hypomethylation. Taken together, these results demonstrate that alternative splicing of exon 5 may play an important role in stem cell maintenance or differentiation and exon 5 could influence the functional properties of DNMT3B.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Suhasni Gopalakrishnan.
Thesis: Thesis (Ph.D.)--University of Florida, 2009.
Local: Adviser: Brown, Kevin D.
Local: Co-adviser: Robertson, Keith D.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-02-28

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0024911:00001


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PAGE 29

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PAGE 30

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PAGE 31

! 3>! "ET@JP!>d>V!!&AP!KBKKBHEBD!/$)! KPNA5HBNEFD!KBSAEDPJ5V!!2AFXD!BJP!NAP!CSAPKBNES! JPGJPCPDNBNEFDC!LFJ!PBSA!FL!NAP!LEUP! IDFXD!/$)!KPNA5HNJBDCLPJBCPC!a/$0&bQ! /$0&>!aKBEDNPDBDSP!KPNA5HNJBDCLPJ BCPbQ!/$0&;Q!/$0&3)!BDO!/$0&34!a 23# (+*+ !KPNA5HNJBDCLPJBCPCb!BDO!/$0&3*V!!%BNBH5NES!CENP!7%!a7JFHEDPd%5CNPEDPb!BDO! KFNELC!7MM7Y!GJFHEDPd!NJ5GNFGABDdNJ5GNFGAB DdGJFHEDP!BDO!)&,h!p!CEKEHBJ!NF!7HBDN! AFKPFdOFKBED!a7+/b!BJP!CAFXD!ED!GBNNPJDPO !WFRPCV!!&AP!7MM7!BDO!)&,h!OFKBED! BJP!LF@DO!ED!KBD5!SAJFKBNED!JPKFOPHEDT!GJ FNPEDC!BDO!BJP!NAF@TAN!NF!GHB5!BD! EKGFJNBDN!JFHP!ED!NAPEJ!JPT@HBNEFDV!!/$0 &3*!EC!B!JPT@HBNFJ5!/$)!KPNA5HNJBDCLPJBCP! XENA!JFHPC!ED!EKGJEDNEDTV!

PAGE 32

! &BWHP!>d>V!7JFNPEDdGJFNPED!EDNPJBSN EFDC!FL!/$)!KPNA5HNJBDCLPJBCPC! DNMT Protein Function DNMT1 PCNA Targeting to DNA replication foci HDAC1/2 Histone deacetylation Rb, E2F1, HDAC1 Transcriptional repression of promoters of E2F1 regulated genes SUV39H1, G9a, HP1 Histone H3K9 methylation hSNF2H Chromatin remodeling DNMT3A, DNMT3B Increase enzyme activity EZH2 Histone H3K27 methylation DNMT3A HDAC1/2 Histone deacetylation SUV39H1,HP1 Histone H3K9 methylation, chromatin condensation SUMO1, PIAS1 Sumoylation and transcriptional repression DNMT1, DNMT3B Increase enzyme activity PU.1 Hematopoietic specific transcription factor EZH2 Histone H3K27 methylation DNMT3L Stimulate methyltrans ferase activity, imprinting SETDB1 histone H3K9 methylation, transcription repression 3;!

PAGE 33

! &BWHP!>d>V!7JFNPEDdGJFNPED!EDNPJBSNEFDC! FL!/$)!KPNA5HNJBDCL PJBCPC!aSFDNED@POb! DNMT Protein Function DNMT3B HDAC1/2 Histone deacetylation SUV39H1,HP1 Histone H3K9 methylation, chromatin condensation hSNF2H Chromatin remodeling hCAP-C (SMC4), KIF4A, SIN3 A, hCAP-E (SMC2), hSNF2H, HDAC1 Chromatin condensation PU.1, mSIN3A, HDAC1, MECP2 Repress PU.1 transactivation EZH2 Histone H3K27 methylation DNMT3L Stimulate methyltrans ferase activity, imprinting SUMO1 Sumoylation DNMT3L HDAC1/2 Histone deacetylation DNMT3A, DNMT3B Enhance methyltransferase activity 33!

PAGE 34

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PAGE 36

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PAGE 37

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