Noncooperative interactions between transcription factors and clustered DNA binding sites enable graded transcriptional responses to environmental inputs.
A paradigm in transcriptional regulation is that graded increases in transcription factor (TF) concentration are translated into on/off transcriptional responses by cooperative TF binding to adjacent sites. Digital transcriptional responses underlie the definition of anatomical boundaries during development. Here we show that NF-kappaB, a TF controlling inflammation and immunity, is conversely an analog transcriptional regulator that uses clustered binding sites noncooperatively. We observed that increasing concentrations of NF-kappaB are translated into gradual increments in gene transcription. We provide a thermodynamic interpretation of the experimental observations by combining quantitative measurements and a minimal physical model of an NF-kappaB-dependent promoter. We demonstrate that NF-kappaB binds independently to adjacent sites to promote additive RNA Pol II recruitment and graded transcriptional outputs. These findings reveal an alternative mode of operation of clustered TF binding sites, which might function in biological conditions where the transcriptional output is proportional to the strength of an environmental input.
Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, 20139 Milan, Italy.
Luca
L
Giorgetti
Trevor
T
Siggers
Guido
G
Tiana
Greta
G
Caprara
Samuele
S
Notarbartolo
Teresa
T
Corona
Manolis
M
Pasparakis
Paolo
P
Milani
Martha L
ML
Bulyk
Gioacchino
G
Natoli
D001665:Binding Sites; D002460:Cell Line; D004777:Environment; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008957:Models, Genetic; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D012319:RNA Polymerase II / Q000378:metabolism; D013816:Thermodynamics
D016328:NF-kappa B; D012319:RNA Polymerase II