MECHANISMS OF GENOMIC IMPRINTING
Principal Investigator: Andrew R Hoffman
Abstract: [unreadable] DESCRIPTION (provided by applicant): While the vast majority of autosomal genes are expressed from both parental alleles, a small subset of genes, most of which are involved with development, growth and behavior, are expressed from only one allele. These genes are said to be imprinted, as it was initially hypothesized that an epigenetic mark was present on one of the alleles to prevent its transcription. Mutations in imprinted genes are responsible for a number of diseases, including Prader-Willi Syndrome and pseudohypoparathyroidism. The goal of this grant is to discover and explain the underlying mechanisms governing the imprinting of genes. Two specific areas are targeted for intense investigation: 1. Deciphering the Histone Code: It has recently been shown that histones may be modified by acetylation, methylation, phosphorylation, and ubiquitination, and that these modifications may regulate gene transcription. These studies will determine if there is a specific or characteristic histone code that signals to the cell's transcriptional machinery that a gene is imprinted and that only one of the alleles should be transcribed. 2. The Epigenome in Cancer and Development: DNA methylation has been shown to be an important component of the imprinting process, as differentially methylated regions are often associated with gene silencing. Using a novel methylated oligonucleotide approach, it will be possible to add methyl groups to a specific region of a gene and thereby induce specific DNA methylation changes to learn how region-specific methylation can alter the imprinting process. The role of methylation patterns in imprinted genes that have lost imprinting in malignant tissues will also be examined. These aspects of the control of genomic imprinting are closely inter-related and inter-dependent phenomena, and advances in one area will provide new insights into the other mechanisms governing transcriptional control. Ultimately, it will be possible to develop a comprehensive chromatin/DNA model of imprinting. [unreadable] [unreadable]
Funding Period: 1986-07-01 - 2009-03-31
more information: NIH RePORT
- IVF results in de novo DNA methylation and histone methylation at an Igf2-H19 imprinting epigenetic switchTao Li
Medical Service, VA Palo Alto Health Care System, CA 94304, USA
Mol Hum Reprod 11:631-40. 2005..We suggest that ART, which includes IVF and various culture media, might cause imprinting errors that involve both aberrant DNA methylation and histone methylation at an epigenetic switch of the Igf2-H19 gene region...
- CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1Jian Qun Ling
Medical Service, Department of Veterans Affairs, Palo Alto Health Care System, and Department of Medicine, Stanford University, Palo Alto, CA 94304, USA
Science 312:269-72. 2006....
- Directing DNA methylation to inhibit gene expressionAndrew R Hoffman
Department of Medicine, Stanford University, Medical Service, VA Palo Alto Health Care System, Miranda Ave, Palo Alto, California 94304, USA
Cell Mol Neurobiol 26:425-38. 2006..5. In principle, using this methodology, it should be possible to design methylated oligonucleotides that can methylate CpG islands and thereby downregulate any gene...
- Correction of aberrant imprinting of IGF2 in human tumors by nuclear transfer-induced epigenetic reprogrammingHui Ling Chen
Medical Service, VA Palo Alto Health Care System, Palo Alto, CA, USA
EMBO J 25:5329-38. 2006....
- Epigenetics of long-range chromatin interactionsJian Qun Ling
VA Palo Alto Health Care System, CA 94304, USA
Pediatr Res 61:11R-16R. 2007..These findings emphasize the importance of studying the geography and architecture of the nucleus as an important factor in the regulation of gene transcription...
- Generation of novel adipocyte monolayer cultures from embryonic stem cellsTheresa L Chen
Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA
Stem Cells Dev 16:371-80. 2007..The adipocytes are functionally active, as evidenced by their response to lipolytic agents, such as forskolin, Bt2-cAMP, and isoproterenol, with more than 20-fold increases in glycerol release...
- A complex deoxyribonucleic acid looping configuration associated with the silencing of the maternal Igf2 alleleXinwen Qiu
Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA
Mol Endocrinol 22:1476-88. 2008..This silencing configuration exists in newborn liver, mouse embryonic fibroblast, and embryonic stem cells and persists during mitosis, conferring a mechanism for epigenetic memory...
- CTCF regulates allelic expression of Igf2 by orchestrating a promoter-polycomb repressive complex 2 intrachromosomal loopTao Li
Medical Service, VA Palo Alto Health Care System, Palo Alto, California 94304, USA
Mol Cell Biol 28:6473-82. 2008....