NF-κB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages

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Science  18 Jun 2021:
Vol. 372, Issue 6548, pp. 1349-1353
DOI: 10.1126/science.abc0269

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Timing cues epigenomic reprogramming

Different temporal dynamics of activation of the transcription factor nuclear factor κB (NF-κB) can influence the inflammatory response of activated macrophages. Cheng et al. report a mechanism by which oscillatory and sustained NF-κB signaling may produce distinct transcriptional responses (see the Perspective by Nandagopal et al.). Oscillatory activation of NF-κB activated poised enhancers to transcribe inflammatory genes in mouse macrophages. However, sustained activation of NF-κB produced in cells activated by other stimuli acted on the epigenome. These stimuli relieved chromatin silencing at enhancers and enabled regulation of additional genes.

Science, abc0269, this issue p. 1349; see also abj2040, p. 1263


The epigenome of macrophages can be reprogrammed by extracellular cues, but the extent to which different stimuli achieve this is unclear. Nuclear factor κB (NF-κB) is a transcription factor that is activated by all pathogen-associated stimuli and can reprogram the epigenome by activating latent enhancers. However, we show that NF-κB does so only in response to a subset of stimuli. This stimulus specificity depends on the temporal dynamics of NF-κB activity, in particular whether it is oscillatory or non-oscillatory. Non-oscillatory NF-κB opens chromatin by sustained disruption of nucleosomal histone–DNA interactions, enabling activation of latent enhancers that modulate expression of immune response genes. Thus, temporal dynamics can determine a transcription factor’s capacity to reprogram the epigenome in a stimulus-specific manner.

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