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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Nucleic+Acids+Res
2016 ; 44
(10
): 4703-20
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A phospho-dependent mechanism involving NCoR and KMT2D controls a permissive
chromatin state at Notch target genes
#MMPMID26912830
Oswald F
; Rodriguez P
; Giaimo BD
; Antonello ZA
; Mira L
; Mittler G
; Thiel VN
; Collins KJ
; Tabaja N
; Cizelsky W
; Rothe M
; Kühl SJ
; Kühl M
; Ferrante F
; Hein K
; Kovall RA
; Dominguez M
; Borggrefe T
Nucleic Acids Res
2016[Jun]; 44
(10
): 4703-20
PMID26912830
show ga
The transcriptional shift from repression to activation of target genes is
crucial for the fidelity of Notch responses through incompletely understood
mechanisms that likely involve chromatin-based control. To activate silenced
genes, repressive chromatin marks are removed and active marks must be acquired.
Histone H3 lysine-4 (H3K4) demethylases are key chromatin modifiers that
establish the repressive chromatin state at Notch target genes. However, the
counteracting histone methyltransferase required for the active chromatin state
remained elusive. Here, we show that the RBP-J interacting factor SHARP is not
only able to interact with the NCoR corepressor complex, but also with the H3K4
methyltransferase KMT2D coactivator complex. KMT2D and NCoR compete for the
C-terminal SPOC-domain of SHARP. We reveal that the SPOC-domain exclusively binds
to phosphorylated NCoR. The balance between NCoR and KMT2D binding is shifted
upon mutating the phosphorylation sites of NCoR or upon inhibition of the NCoR
kinase CK2?. Furthermore, we show that the homologs of SHARP and KMT2D in
Drosophila also physically interact and control Notch-mediated functions in vivo
Together, our findings reveal how signaling can fine-tune a committed chromatin
state by phosphorylation of a pivotal chromatin-modifier.