Two immunoglobulin kappa (Ig kappa) gene transcriptional control elements have been identified and characterized in considerable detail. One element, the Ig kappa promoter, is found upstream of all Ig kappa variable region genes. The other element, the kappa enhancer, lies in the intron that separates the joining from the constant region exons. The activity of the kappa enhancer controls kappa gene transcription at early stages of lymphoid development (i.e. the pre B cell stage). At this developmental stage the activity of the kappa enhancer is continually required for kappa gene transcription. At later stages of lymphoid development however, the properties of the kappa promoter and enhancer elements are insufficient to explain Ig kappa transcriptional control. At later stages of development Ig kappa transcription can continue in the absence of kappa enhancer activity. Therefore, there is a developmentally controlled transcriptional mechanism capable of maintaining kappa transcription in the absence of kappa enhancer activity. The mechanism of action and the DNA sequences responsible for this enhancer-independent transcription of Ig kappa genes are completely unknown. The long term goals of the research described in this proposal are to identify the DNA sequence requirements for enhancer-independent transcription and to understand the mechanism of action of this transcriptional control mechanism. Several parallel approaches to these problems will be utilized. One approach for identifying DNA sequences required for enhancer-independent transcription will take advantage of certain properties of somatic cell hybrids we have prepared. Other studies will focus on identifying specific chromatin differences between cell lines transcribing their kappa genes but differing in their ability to support enhancer-independent transcription. Mechanistically, the role of stably inherited chromatin alterations and the nuclear factors responsible for these alterations will be studied. Additionally, we will attempt to determine whether the mechanism of enhancer-independent transcription requires prior kappa enhancer activity, or whether it can activate transcription de novo. Finally, we will pursue studies relating to position- independent and copy number-dependent transcription of transfected Ig kappa genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM042415-02
Application #
3300932
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1989-07-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Atchison, Michael L (2014) Function of YY1 in Long-Distance DNA Interactions. Front Immunol 5:45
Hodawadekar, Suchita; Yu, Duonan; Cozma, Diana et al. (2007) B-Lymphoma cells with epigenetic silencing of Pax5 trans-differentiate into macrophages, but not other hematopoietic lineages. Exp Cell Res 313:331-40
Hodawadekar, Suchita; Wei, Fang; Yu, Duonan et al. (2006) Epigenetic histone modifications do not control Igkappa locus contraction and intranuclear localization in cells with dual B cell-macrophage potential. J Immunol 177:6165-71
Wilkinson, Frank H; Park, Kyoungsook; Atchison, Michael L (2006) Polycomb recruitment to DNA in vivo by the YY1 REPO domain. Proc Natl Acad Sci U S A 103:19296-301
McDevit, Daniel C; Perkins, Leslie; Atchison, Michael L et al. (2005) The Ig kappa 3' enhancer is activated by gradients of chromatin accessibility and protein association. J Immunol 174:2834-42
Srinivasan, Lakshmi; Pan, Xuan; Atchison, Michael L (2005) Transient requirements of YY1 expression for PcG transcriptional repression and phenotypic rescue. J Cell Biochem 96:689-99
Bai, Yuchen; Srinivasan, Lakshmi; Perkins, Leslie et al. (2005) Protein acetylation regulates both PU.1 transactivation and Ig kappa 3' enhancer activity. J Immunol 175:5160-9
Joo, Myungsoo; Park, Gye Young; Wright, Jeffrey G et al. (2004) Transcriptional regulation of the cyclooxygenase-2 gene in macrophages by PU.1. J Biol Chem 279:6658-65
Srinivasan, Lakshmi; Atchison, Michael L (2004) YY1 DNA binding and PcG recruitment requires CtBP. Genes Dev 18:2596-601
Nagulapalli, Sujatha; Goheer, Aisha; Pitt, Leslie et al. (2002) Mechanism of e47-Pip interaction on DNA resulting in transcriptional synergy and activation of immunoglobulin germ line sterile transcripts. Mol Cell Biol 22:7337-50

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