Abstract
Switching specific patterns of gene repression and activation in response to precise temporal/spatial signals is critical for normal development. Here we report a pathway in which induction of CaMKIIδ triggers an unexpected switch in the function of the HES1 transcription factor from a TLE-dependent repressor to an activator required for neuronal differentiation. These events are based on activation of the poly(ADP-ribose) polymerase1 (PARP-1) sensor component of the groucho/TLE-corepressor complex mediating dismissal of the corepressor complex from HES1-regulated promoters. In parallel, CaMKIIδ mediates a required phosphorylation of HES1 to permit neurogenic gene activation, revealing the ability of a specific signaling pathway to modulate both the derepression and the subsequent coactivator recruitment events required for transcriptional activation of a neurogenic program. The identification of PARP-1 as a regulated promoter-specific exchange factor required for activation of specific neurogenic gene programs is likely to be prototypic of similar molecular mechanisms.
| Original language | English |
|---|---|
| Pages (from-to) | 815-829 |
| Number of pages | 15 |
| Journal | Cell |
| Volume | 119 |
| Issue number | 6 |
| DOIs | |
| State | Published - 17 Dec 2004 |
Bibliographical note
Funding Information:We are very grateful to C. Nelson for excellent technical assistance; I. Bassets for gel filtration; V. Lunyak, P. Briata, L. Erkman, and V. Perissi for critical reading of the manuscript; and X. Zhu, R. McEvilly, and the other members of the Rosenfeld lab for discussions and valuable advice during the course of this study. We also thank Dr. R. Tsien for valuable discussion; R. Kageyama, D. Maiguel, and S.L. Oei for plasmids; J. Hightower and M. Fisher for figure and manuscript preparation; and M. Gonzalez (Santa Cruz Biotechnology) for advice on reagents. M.G.R. is an investigator with the Howard Hughes Medical Institute and B.J. is supported by USAMRMC (DAMD17-01-1-0184). T hese studies were supported by grants from Sander Programs for Asthma Research to M.G.R. and NIH to C.K.G, D.W.R., and M.G.R.