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Nucleic Acids Res June 2, 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.

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 .

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 CK2β. 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.

PubMed ID: 26912830
PMC ID: PMC4889922
Article link: Nucleic Acids Res
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ash2l cbx3 chd4 cnga1 crebbp cxxc1 dll1 dnmt1 dtx1 gusb hdac1 hes1 hes4 hes5.1 hes5.2 hey1 irf4 kdm6a kmt2a kmt2d kmt2e men1 mmut ncoa6 ncor1 ncor2 notch1 ogt rbbp5 setd5 spen tbca tbl1xr1 tbp tubb2b tubb4b wdr5 wdr82

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References [+] :
Ariyoshi, A conserved structural motif reveals the essential transcriptional repression function of Spen proteins and their role in developmental signaling. 2003, Pubmed