Genomic imprinting is closely associated with human genetic disorders due to its functional hemizygosity. The Peg3 domain on human chromosome 19q13.4/proximal mouse chromosome 7 is also associated with several imprinting-related genetic disorders, including frequent loss of human PEG3 expression in the patients of glioma, breast and ovarian cancers. Thus, the long-term objective of this project is to understand the mechanisms controlling the imprinting of the Peg3 domain. In the previous funding cycle, we predicted that the Peg3 domain is likely controlled by one potential ICR (Imprinting Control Region), the Peg3-DMR (Differentially Methylated Region). We subsequently demonstrated that deletion of the Peg3-DMR has a global impact on the transcription of the Peg3 domain. Paternal and maternal transmission of this targeted deletion also resulted in decreased and increased growth rates of the mouse, respectively, an imprinting phenotype associated with proximal mouse chromosome 7. We also discovered that this potential ICR has a very unusual tandem array of YY1 binding sites, and that reducing the in vivo levels of YY1 protein during oogenesis resulted in target-specific DNA hypomethylation on the Peg3-DMR. Based on these observations, we hypothesize 1) that the imprinting of the Peg3 domain is controlled by the Peg3-DMR and 2) that this control requires YY1 as a main trans factor for targeting de novo DNA methylation during oogenesis. In the current proposal, we will test these hypotheses with the following three aims.
Aim1 will further characterize the ICR roles played by the Peg3-DMR using the mutant mice lacking the Peg3-DMR.
Aim2 will dissect the exact contributions of YY1 to the observed ICR roles of the Peg3-DMR by generating another KO allele with mutated YY1 sites.
Aim3 will investigate potential mechanisms by which YY1 establishes and maintains the allele-specific DNA methylation of the Peg3-DMR. The results from these experiments will provide valuable insights regarding previously unnoticed roles for YY1 in genomic imprinting as well as human genetic disorders linked to the Peg3 domain.

Public Health Relevance

A small number of mammalian genes (less than 200) are not functionally equal between the two parental alleles due to an unusual dosage control mechanism, genomic imprinting. The current proposal is aiming to characterize regulatory mechanisms of genomic imprinting.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066225-10
Application #
8534144
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
2004-02-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$286,318
Indirect Cost
$92,860
Name
Louisiana State University A&M Col Baton Rouge
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
075050765
City
Baton Rouge
State
LA
Country
United States
Zip Code
70803
Kim, Hana; Ekram, Muhammad B; Bakshi, Arundhati et al. (2015) AEBP2 as a transcriptional activator and its role in cell migration. Genomics 105:108-15
Faisal, Mohammad; Kim, Hana; Kim, Joomyeong (2014) Sexual differences of imprinted genes' expression levels. Gene 533:434-8
Frey, Wesley D; Kim, Joomyeong (2014) APeg3: regulation of Peg3 through an evolutionarily conserved ncRNA. Gene 540:251-7
Ye, An; He, Hongzhi; Kim, Joomyeong (2014) Paternally expressed Peg3 controls maternally expressed Zim1 as a trans factor. PLoS One 9:e108596
Bakshi, Arundhati; Kim, Joomyeong (2014) Retrotransposon-based profiling of mammalian epigenomes: DNA methylation of IAP LTRs in embryonic stem, somatic and cancer cells. Genomics 104:538-44
Ekram, Muhammad B; Kim, Joomyeong (2014) High-throughput targeted repeat element bisulfite sequencing (HT-TREBS): genome-wide DNA methylation analysis of IAP LTR retrotransposon. PLoS One 9:e101683
Thiaville, Michelle M; Huang, Jennifer M; Kim, Hana et al. (2013) DNA-binding motif and target genes of the imprinted transcription factor PEG3. Gene 512:314-20
Thiaville, Michelle M; Kim, Hana; Frey, Wesley D et al. (2013) Identification of an evolutionarily conserved cis-regulatory element controlling the Peg3 imprinted domain. PLoS One 8:e75417
Ekram, Muhammad B; Kang, Keunsoo; Kim, Hana et al. (2012) Retrotransposons as a major source of epigenetic variations in the mammalian genome. Epigenetics 7:370-82
Kim, Joomyeong; Ekram, Muhammad B; Kim, Hana et al. (2012) Imprinting control region (ICR) of the Peg3 domain. Hum Mol Genet 21:2677-87

Showing the most recent 10 out of 34 publications