We wish to continue our studies on the """"""""Function of the Subunits of Eukaryotic Chromosomes"""""""" by focusing attention on the relationship between nuclear organization and gene expression at the level of the chromosomal loop. For these studies we have selected the powerful biological system of immunoglobulin genes in the mouse for which we have considerable experience. OUr experimental approach combines biochemical, cell biological, immunological, molecular, and reverse genetic techniques. During the previous funding period of this grant we discovered a family of DNA sequences that organize chromosomal loops in the interphase nucleus which we termed MARs (""""""""Matrix Association Regions""""""""). Significantly, both MAR sequences and their nuclear binding sites are evolutionarily conserved, and MARs containing topoisomerase II sites are located in the immunoglobulin genes next to the enhancer elements. Here we propose to elucidate the functions of MARs, to determine the DNA sequences and proteins that are functionally important, and to localize MAR sequence binding sites within the nucleus. Specifically, we wish to address the four following Specific Aims: (1) To functionally characterize the role of MARs in gene transcription: . position requirements with respect to enhancers . capacity to override chromosomal position effects . ability to serve as boundaries between chromatin domains (2) To delineate the functionally crucial DNA sequences within a MAR (3) To characterize the proteins that bind to Mar sequences (4) To determine the nuclear location of MAR sequence binding sites

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National Institute of General Medical Sciences (NIGMS)
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University of Texas Sw Medical Center Dallas
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Xiang, Yougui; Park, Sung-Kyun; Garrard, William T (2014) A major deletion in the V?-J? intervening region results in hyperelevated transcription of proximal V? genes and a severely restricted repertoire. J Immunol 193:3746-54
Park, Sung-Kyun; Xiang, Yougui; Feng, Xin et al. (2014) Pronounced cohabitation of active immunoglobulin genes from three different chromosomes in transcription factories during maximal antibody synthesis. Genes Dev 28:1159-64
Zhou, Xiaorong; Xiang, Yougui; Ding, Xiaoling et al. (2013) Loss of an Igýý gene enhancer in mature B cells results in rapid gene silencing and partial reversible dedifferentiation. Mol Cell Biol 33:2091-101
Xiang, Yougui; Park, Sung-Kyun; Garrard, William T (2013) Výý gene repertoire and locus contraction are specified by critical DNase I hypersensitive sites within the Výý-Jýý intervening region. J Immunol 190:1819-26
Zhou, Xiaorong; Xiang, Yougui; Ding, Xiaoling et al. (2012) A new hypersensitive site, HS10, and the enhancers, E3' and Ed, differentially regulate Ig? gene expression. J Immunol 188:2722-32
Xiang, Yougui; Zhou, Xiaorong; Hewitt, Susannah L et al. (2011) A multifunctional element in the mouse Ig? locus that specifies repertoire and Ig loci subnuclear location. J Immunol 186:5356-66
Zhou, Xiaorong; Xiang, Yougui; Garrard, William T (2010) The Ig? gene enhancers, E3' and Ed, are essential for triggering transcription. J Immunol 185:7544-52
Liu, Zhe; Ma, Zhenyi; Terada, Lance S et al. (2009) Divergent roles of RelA and c-Rel in establishing chromosomal loops upon activation of the Igkappa gene. J Immunol 183:3819-30
Xiang, Yougui; Garrard, William T (2008) The Downstream Transcriptional Enhancer, Ed, positively regulates mouse Ig kappa gene expression and somatic hypermutation. J Immunol 180:6725-32
Xiao, Fei; Widlak, Piotr; Garrard, William T (2007) Engineered apoptotic nucleases for chromatin research. Nucleic Acids Res 35:e93

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