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Epigenetic effects of fetal alcohol exposure on hypothalamic proopiomelanocortin gene
Descriptive
TitleInfo
Title
Epigenetic effects of fetal alcohol exposure on hypothalamic proopiomelanocortin gene
Name
(type = personal)
NamePart
(type = family)
Bekdash
NamePart
(type = given)
Rola Aldana
NamePart
(type = date)
1971-
DisplayForm
Rola Bekdash
Role
RoleTerm
(authority = RULIB)
author
Name
(type = personal)
NamePart
(type = family)
Sarkar
NamePart
(type = given)
Dipak K
DisplayForm
Dipak K Sarkar
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
chair
Name
(type = personal)
NamePart
(type = family)
Kusnecov
NamePart
(type = given)
Alexander W
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Alexander W Kusnecov
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Pietrzykowski
NamePart
(type = given)
Andrzej Z
DisplayForm
Andrzej Z Pietrzykowski
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Pintar
NamePart
(type = given)
John E
DisplayForm
John E Pintar
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Belden
NamePart
(type = given)
William J
DisplayForm
William J Belden
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
outside member
Name
(type = corporate)
NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
(type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm
(authority = RULIB)
school
TypeOfResource
Text
Genre
(authority = marcgt)
theses
OriginInfo
DateCreated
(qualifier = exact)
2012
DateOther
(qualifier = exact);
(type = degree)
2012-01
CopyrightDate
(qualifier = exact)
2012
Place
PlaceTerm
(type = code)
xx
Language
LanguageTerm
(authority = ISO639-2b);
(type = code)
eng
Abstract
(type = abstract)
Hypothalamic POMC neurons, one of the major regulators of the HPA axis, immune functions, and energy homeostasis, are vulnerable to the adverse effects of fetal alcohol exposure (FAE) exhibiting a significant decrease in POMC gene expression and functions in the arcuate area of the hypothalamus of adult offspring. This permanent deficit in gene expression could be caused by epigenetic mechanisms such as histone modifications and DNA methylation induced by alcohol exposure during critical period of development. We found that FAE decreased significantly the protein and mRNA levels of histone-modifying enzymes that methylate H3K4me2,3 (Set7/9), acetylate H3K9 (CBP) or phosphorylate H3S10. These are activation marks that correlate with gene expression. FAE significantly increased the protein levels and gene expression of G9a and Setdb1 that methylate the repressive mark H3K9me2 in β-endorphin-producing POMC neurons of adult offspring. These changes were associated with increased levels of the DNA-methyltranferase Dnmt1 and the methyl-CpG-binding protein 2 MeCP2 but not Dnmt3a. Microarray analysis confirmed that alcohol exposure modulated the gene expression profile of the epigenetic machinery in LCM-captured POMC neurons. ChIP assay revealed a significant reduction in the activation mark H3K4me3 along Exon 3 of POMC gene in alcohol-exposed rats associated with no change in the repressive mark H3K9me2 in Exon 3 and promoter region of POMC gene. We then examined whether gestational choline supplementation, a major methyl donor, could mitigate alcohol adverse effects on POMC neurons. Gestational choline normalized in alcohol-exposed rats the methylation of H3K4 and H3K9 with no significant effect on other histone marks such as acetylated H3K9 or phosphorylated H3S10. Similarly, gestational choline normalized the protein levels and gene expression of histone-modifying and DNA-methylating enzymes in POMC neurons. This data correlated with normalization of POMC gene methylation, POMC gene expression and β-EP peptide production. In conclusion, these studies demonstrate that FAE induces long-lasting epigenetic modifications of POMC gene in the hypothalamus by altering histone marks and methylation state along POMC gene. The hypermethylation state of POMC gene might be a cause for induction of lower β-endorphin activity and its inhibitory regulation of stress axis function in the adult offspring.
Subject
(authority = RUETD)
Topic
Neuroscience
RelatedItem
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TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
(type = RULIB)
ETD
Identifier
ETD_3726
PhysicalDescription
Form
(authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
xiv, 140 p. : ill.
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Note
(type = statement of responsibility)
by Rola Aldana Bekdash
Subject
(authority = ETD-LCSH)
Topic
Fetal alcohol syndrome
Subject
(authority = ETD-LCSH)
Topic
Fetus—Development
Subject
(authority = ETD-LCSH)
Topic
Gene expression
Identifier
(type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000063984
RelatedItem
(type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
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rucore19991600001
Location
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(authority = marcorg);
(displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier
(type = doi)
doi:10.7282/T31835JJ
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
RightsDeclaration
(ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder
(type = personal)
Name
FamilyName
Bekdash
GivenName
Rola
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
(encoding = w3cdtf);
(point = start);
(qualifier = exact)
2011-12-12 17:18:26
AssociatedEntity
Name
Rola Bekdash
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
DateTime
(encoding = w3cdtf);
(point = start);
(qualifier = exact)
2012-01-31
DateTime
(encoding = w3cdtf);
(point = end);
(qualifier = exact)
2012-11-08
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after December 31, 2012.
At the request of the author on November 8, 2012, the restriction has been removed.
At the request of the author on November 8, 2012, the restriction has been removed.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical
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4410368
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4413440
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