Combinatorial recruitment of CREB, C/EBPβ and c-Jun determines activation of promoters upon keratinocyte differentiation.
BACKGROUND
Transcription factors CREB, C/EBPβ and Jun regulate genes involved in keratinocyte proliferation and differentiation. We questioned if specific combinations of CREB, C/EBPβ and c-Jun bound to promoters correlate with RNA polymerase II binding, mRNA transcript levels and methylation of promoters in proliferating and differentiating keratinocytes.


RESULTS
Induction of mRNA and RNA polymerase II by differentiation is highest when promoters are bound by C/EBP β alone, C/EBPβ together with c-Jun, or by CREB, C/EBPβ and c-Jun, although in this case CREB binds with low affinity. In contrast, RNA polymerase II binding and mRNA levels change the least upon differentiation when promoters are bound by CREB either alone or in combination with C/EBPβ or c-Jun. Notably, promoters bound by CREB have relatively high levels of RNA polymerase II binding irrespective of differentiation. Inhibition of C/EBPβ or c-Jun preferentially represses mRNA when gene promoters are bound by corresponding transcription factors and not CREB. Methylated promoters have relatively low CREB binding and, accordingly, those which are bound by C/EBPβ are induced by differentiation irrespective of CREB. Composite "Half and Half" consensus motifs and co localizing consensus DNA binding motifs are overrepresented in promoters bound by the combination of corresponding transcription factors.


CONCLUSIONS
Correlational and functional data describes combinatorial mechanisms regulating the activation of promoters. Colocalization of C/EBPβ and c-Jun on promoters without strong CREB binding determines high probability of activation upon keratinocyte differentiation.
Department of Pathology and Lab Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Julian M
JM
Rozenberg
Paramita
P
Bhattacharya
Raghunath
R
Chatterjee
Kimberly
K
Glass
Charles
C
Vinson
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000502:physiology*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*
D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016755:Proto-Oncogene Proteins c-jun