Activating the PARP-1 sensor component of the groucho/ TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway.
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 CaMKIIdelta 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, CaMKIIdelta 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.
Ju
Bong-Gun
BG
Howard Hughes Medical Institute, University of California, San Diego, Department and School of Medicine, La Jolla, CA 92093, USA.
Solum
Derek
D
Song
Eun Joo
EJ
Lee
Kong-Joo
KJ
Rose
David W
DW
Glass
Christopher K
CK
Rosenfeld
Michael G
MG
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D000072056:Transcription Factor HES-1; D015533:Transcriptional Activation
D051792:Basic Helix-Loop-Helix Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D011065:Poly(ADP-ribose) Polymerases; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C489735:Hes1 protein, rat; C091023:gro protein, Drosophila