TY - JOUR
T1 - A transcriptional coregulator, SPIN-DOC, attenuates the coactivator activity of Spindlin1
AU - Bae, Narkhyun
AU - Gao, Min
AU - Li, Xu
AU - Premkumar, Tolkappiyan
AU - Sbardella, Gianluca
AU - Chen, Junjie
AU - Bedford, X. Mark T.
N1 - Funding Information:
2 Supported by grants from the Italian Ministero dell’Istruzione, dell’Universita e della Ricerca (MIUR), Progetti di Ricerca di Interesse Nazionale (PRIN 20152TE5PK), Università di Salerno (Italy), and European Cooperation in Science and Technology (COST Action CM1406).
Funding Information:
3 Supported by National Institutes of Health Grant CA216911.
Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/12/22
Y1 - 2017/12/22
N2 - Spindlin1 (SPIN1) is a transcriptional coactivator with critical functions in embryonic development and emerging roles in cancer. SPIN1 harbors three Tudor domains, two of which engage the tail of histone H3 by reading the H3-Lys-4 trimethylation and H3-Arg-8 asymmetric dimethylation marks. To gain mechanistic insight into how SPIN1 functions as a transcriptional coactivator, here we purified its interacting proteins. We identified an uncharacterized protein (C11orf84), which we renamed SPIN1 docking protein (SPIN-DOC), that directly binds SPIN1 and strongly disrupts its histone methylation reading ability, causing it to disassociate from chromatin. The Spindlin family of coactivators has five related members (SPIN1, 2A, 2B, 3, and 4), and we found that all of them bind SPIN-DOC. It has been reported previously that SPIN1 regulates gene expression in the Wnt signaling pathway by directly interacting with transcription factor 4 (TCF4).Weobserved here that SPIN-DOC associates with TCF4 in a SPIN1-dependent manner and dampens SPIN1 coactivator activity in TOPflash reporter assays. Furthermore, knockdown and overexpression experiments indicated that SPIN-DOC represses the expression of a number of SPIN1- regulated genes, including those encoding ribosomalRNAand the cytokine IL1B. In conclusion, we have identified SPIN-DOC as a transcriptional repressor that binds SPIN1 and masks its ability to engage the H3-Lys-4 trimethylation activation mark.
AB - Spindlin1 (SPIN1) is a transcriptional coactivator with critical functions in embryonic development and emerging roles in cancer. SPIN1 harbors three Tudor domains, two of which engage the tail of histone H3 by reading the H3-Lys-4 trimethylation and H3-Arg-8 asymmetric dimethylation marks. To gain mechanistic insight into how SPIN1 functions as a transcriptional coactivator, here we purified its interacting proteins. We identified an uncharacterized protein (C11orf84), which we renamed SPIN1 docking protein (SPIN-DOC), that directly binds SPIN1 and strongly disrupts its histone methylation reading ability, causing it to disassociate from chromatin. The Spindlin family of coactivators has five related members (SPIN1, 2A, 2B, 3, and 4), and we found that all of them bind SPIN-DOC. It has been reported previously that SPIN1 regulates gene expression in the Wnt signaling pathway by directly interacting with transcription factor 4 (TCF4).Weobserved here that SPIN-DOC associates with TCF4 in a SPIN1-dependent manner and dampens SPIN1 coactivator activity in TOPflash reporter assays. Furthermore, knockdown and overexpression experiments indicated that SPIN-DOC represses the expression of a number of SPIN1- regulated genes, including those encoding ribosomalRNAand the cytokine IL1B. In conclusion, we have identified SPIN-DOC as a transcriptional repressor that binds SPIN1 and masks its ability to engage the H3-Lys-4 trimethylation activation mark.
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U2 - 10.1074/jbc.M117.814913
DO - 10.1074/jbc.M117.814913
M3 - Article
C2 - 29061846
AN - SCOPUS:85039439820
SN - 0021-9258
VL - 292
SP - 20808
EP - 20817
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 51
ER -