Control of inducible gene expression by signal-dependent transcriptional elongation

By D. Hargreaves, T. Horng, R. Medzhitov. Cell, 2009

662 citations recorded by the source corpus.

Most inducible transcriptional programs consist of primary and secondary response genes (PRGs and SRGs) which differ in their kinetics of expression and in their requirements for new protein synthesis and chromatin remodeling. Here we show that many PRGs, in contrast to SRGs, have pre-assembled RNA polymerase II (Pol II) and positive histone modifications at their promoters in the basal state. Pol II at PRGs generates low levels of full-length unspliced transcripts, but fails to make mature, protein-coding transcripts in the absence of stimulation. Induction of PRGs is controlled at the level of transcriptional elongation and mRNA processing, through the signal-dependent recruitment of P-TEFb. P-TEFb is in turn recruited by the bromodomain-containing protein Brd4, which detects H4K5/8/12Ac inducibly acquired at PRG promoters. Finally, the permissive structure of PRGs both stipulates their unique regulation in the basal state by co-repressor complexes and enables their rapid induction in multiple cell types.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/009b40af618e1723032797f8895758e741843c72

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Citations in the corpus

Suppression of inflammation by a synthetic histone mimic (2010, neutral): “In contrast to Il6, the naI-BET gene Tnf showed higher accumulation of BRD2, BRD3 and to a lesser extent BRD4, around the transcriptional start site (TSS) following I-BET treatment (Fig.”
NF-κB Signaling in Macrophages: Dynamics, Crosstalk, and Signal Integration (2019, background): “These genes are poised for transcriptional elongation before stimulation, but cannot be expressed as coding RNAs until they are bound sequentially by NF-κB, Brd4, and finally p-TEFb, releasing RNA polymerase II from its paused state (62).”
Feedback regulation of EGFR signalling: decision making by early and delayed loops (2011, background): “Surprisingly, it was shown that in resting cells, pre-initiation Pol II generates low levels of unspliced and unstable mRNAs, which enables robust, stimulus-dependent transcriptio”
Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells (2010, background): “This observation is particularly interesting in light of the recent finding that many TLR4 target genes are occupied by 'stalled' RNA polymerase II under basal conditions, and that signal-dependent recruitment of PTEFb leads to the rapid activation of transcription, in part by converting stalled RNA”
Distinct roles of GCN5/PCAF‐mediated H3K9ac and CBP/p300‐mediated H3K18/27ac in nuclear receptor transactivation (2011, background): “If both H3K18ac and H3K27ac are required, the likely candidates for effector proteins would include the double bromodomain-containing non-histone proteins (Hargreaves et al, 2009).”
Microbial genes, brain & behaviour – epigenetic regulation of the gut–brain axis (2014, background): “At the same time this modification serves as a recognition signal for bromodomain-containing proteins, which in turn recruit factors of the transcriptional machinery to the now accessible genomic site (Chen et al. 2010; Hargreaves et al. 2009; LeRoy et al. 2008).”
Charting histone modifications and the functional organization of mammalian genomes (2011, background): “Indeed, recent studies in macrophages and ES cells have documented roles for specific transcription factors in regulating steps downstream of initiatio”