How DNA methylation patterns are shaped during development - how methylation and demethylation are targeted to specific loci at specific times - is not known. Germ cells establish methylation imprints depending on the sex of the gonad after erasing the male and female -specific marks inherited from the previous generation. Our main hypothesis is that DNA cytosine 5-hydroxymethylation and chromatin composition are important components of the imprint cycle, being involved in the erasure and establishment phases in germ cells and in the maintenance phase in the soma. To demonstrate this, we will analyze DNA methylation, DNA cytosine hydroxymethylation and chromatin globally and at specific imprinted genes in germ cells and somatic cells. To test the role of specific epigenetic modifiers in the cycle of imprinting, we will genetically perturb these functions during the erasure, establishment and maintenance phases of the imprinting cycle. These results collectively will help understand how DNA methylation, DNA hydroxymethylation and chromatin marks collaborate in the epigenetic remodeling of germ cells and in erasing, establishing and maintaining genomic imprints. Correct global epigenetic remodeling and imprint reseting during embryonic-fetal germ cell development is essential for the health of the next generation and for future generations.

Public Health Relevance

We propose to test the role of DNA cytosine hydroxymethylation and chromatin in the erasure, establishment and maintenance of genomic imprints. Experiments using genome-wide mapping methods, novel allele- specific assays and mouse genetic tools will collectively help understand how DNA methylation, DNA hydroxymethylation and chromatin marks collaborate in the global epigenetic remodeling of germ cells and in erasing, establishing and maintaining genomic imprints. Correct global epigenetic remodeling and imprint resetting during embryonic-fetal germ cell development is essential for the health of the next generation and for future generations.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM064378-11
Application #
8653962
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
2002-04-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010
Pfeifer, Gerd P; Szabó, Piroska E (2018) Gene body profiles of 5-hydroxymethylcytosine: potential origin, function and use as a cancer biomarker. Epigenomics 10:1029-1032
Iqbal, Khursheed; Tran, Diana A; Li, Arthur X et al. (2016) High type I error and misrepresentations in search for transgenerational epigenetic inheritance: response to Guerrero-Bosagna. Genome Biol 17:154
Jin, Seung-Gi; Zhang, Zhi-Min; Dunwell, Thomas L et al. (2016) Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration. Cell Rep 14:493-505
Szabó, Piroska E (2016) Response to ""Variable directionality of gene expression changes across generations does not constitute negative evidence of epigenetic inheritance"" Sharma, A. Environmental Epigenetics, 2015, 1-5. Genome Biol 17:105
Szabó, Piroska E (2015) Response to: the nature of evidence for and against epigenetic inheritance. Genome Biol 16:138
Iqbal, Khursheed; Tran, Diana A; Li, Arthur X et al. (2015) Deleterious effects of endocrine disruptors are corrected in the mammalian germline by epigenome reprogramming. Genome Biol 16:59
Tran, Diana A; Bai, Angela Y; Singh, Purnima et al. (2014) Characterization of the imprinting signature of mouse embryo fibroblasts by RNA deep sequencing. Nucleic Acids Res 42:1772-83
Hahn, Maria A; Szabó, Piroska E; Pfeifer, Gerd P (2014) 5-Hydroxymethylcytosine: a stable or transient DNA modification? Genomics 104:314-23
Singh, Purnima; Li, Arthur X; Tran, Diana A et al. (2013) De novo DNA methylation in the male germ line occurs by default but is excluded at sites of H3K4 methylation. Cell Rep 4:205-19
Liao, Ji; He, Yikun; Szabó, Piroska E (2013) The Pou5f1 distal enhancer is sufficient to drive Pou5f1 promoter-EGFP expression in embryonic stem cells. Int J Dev Biol 57:725-9

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