Monocyte-specific accessibility of a matrix attachment region in the tumor necrosis factor locus.
Regulation of TNF gene expression is cell type- and stimulus-specific. We have previously identified highly conserved noncoding regulatory elements within DNase I-hypersensitive sites (HSS) located 9 kb upstream (HSS-9) and 3 kb downstream (HSS+3) of the TNF gene, which play an important role in the transcriptional regulation of TNF in T cells. They act as enhancers and interact with the TNF promoter and with each other, generating a higher order chromatin structure. Here, we report a novel monocyte-specific AT-rich DNase I-hypersensitive element located 7 kb upstream of the TNF gene (HSS-7), which serves as a matrix attachment region in monocytes. We show that HSS-7 associates with topoisomerase IIα (Top2) in vivo and that induction of endogenous TNF mRNA expression is suppressed by etoposide, a Top2 inhibitor. Moreover, Top2 binds to and cleaves HSS-7 in in vitro analysis. Thus, HSS-7, which is selectively accessible in monocytes, can tether the TNF locus to the nuclear matrix via matrix attachment region formation, potentially promoting TNF gene expression by acting as a Top2 substrate.
Program in Cellular and Molecular Medicine, Children's Hospital Boston, and Immune Disease Institute, Harvard Medical School, Boston, Massachusetts 02115.
Sebastian
S
Biglione
Program in Cellular and Molecular Medicine, Children's Hospital Boston, and Immune Disease Institute, Harvard Medical School, Boston, Massachusetts 02115.
Alla V
AV
Tsytsykova
Program in Cellular and Molecular Medicine, Children's Hospital Boston, and Immune Disease Institute, Harvard Medical School, Boston, Massachusetts 02115. Electronic address: goldfeld@idi.harvard.edu.
Anne E
AE
Goldfeld
D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D003850:Deoxyribonuclease I / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006657:Histones; D006801:Humans; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology*; D000075223:Poly-ADP-Ribose Binding Proteins; D013601:T-Lymphocytes / Q000166:cytology; D014158:Transcription, Genetic
D000951:Antigens, Neoplasm; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D000075223:Poly-ADP-Ribose Binding Proteins; D004247:DNA; D003850:Deoxyribonuclease I; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human