TNF-induced oscillations in combinatorial transcription factor binding.
We have shown in two accompanying papers that TNF induces oscillations in (1) approximately 13% of the genome, and (2) the activation of MAP kinase and NF-kappaB signaling pathways. Here we aim to bridge oscillations in signal transduction activation to oscillations in genetic output. Specifically, we sought to study how these oscillations can combine in a ligand-specific manner at the level of the promoter to initiate gene transcription. We utilize the late onset gene CD38 as a model gene since it has previously been shown that TNF, but not the related cytokine RANK-L, induces its expression. We find that TNF-induced oscillations in p65 and p50 recruitment to the CD38 promoter correlated with recruitment of MAPK-induced AP-1 recruitment, as analyzed by quantitative ChIP analysis. Through re-ChIP analysis we show that a unique transcriptional complex is seen on the promoter at 3h post-TNF addition, corresponding to the onset of CD38 transcription, which is not seen in the basal state. Moreover, we show that RANK-L was unable to combinatorially recruit AP-1 and NF-kappaB transcription factors to the CD38 promoter, despite inducing the activation of both signaling pathways. These results, in sum with the two accompanying papers, constitute a new paradigm through which cells dynamically orchestrate signaling molecules to coordinate time-resolved gene transcription by the formation of novel time-specific transcriptional complexes.
Sun
Li
L
Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, PO Box 1055, Endocrinology, New York, NY 10029, USA.
Yang
Guozhe
G
Zaidi
Mone
M
Iqbal
Jameel
J
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology / Q000502:physiology; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D052002:NF-kappa B p50 Subunit; D053245:RANK Ligand; C498144:Rela protein, mouse; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D020929:Mitogen-Activated Protein Kinase Kinases; D051997:ADP-ribosyl Cyclase 1