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Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation.

ABSTRACT: Constitutive activation of Wnt/?-catenin inhibits oligodendrocyte myelination. Tcf7l2/Tcf4, a ?-catenin transcriptional partner, is required for oligodendrocyte differentiation. How Tcf7l2 modifies ?-catenin signalling and controls myelination remains elusive. Here we define a stage-specific Tcf7l2-regulated transcriptional circuitry in initiating and sustaining oligodendrocyte differentiation. Multistage genome occupancy analyses reveal that Tcf7l2 serially cooperates with distinct co-regulators to control oligodendrocyte lineage progression. At the differentiation onset, Tcf7l2 interacts with a transcriptional co-repressor Kaiso/Zbtb33 to block ?-catenin signalling. During oligodendrocyte maturation, Tcf7l2 recruits and cooperates with Sox10 to promote myelination. In that context, Tcf7l2 directly activates cholesterol biosynthesis genes and cholesterol supplementation partially rescues oligodendrocyte differentiation defects in Tcf712 mutants. Together, we identify stage-specific co-regulators Kaiso and Sox10 that sequentially interact with Tcf7l2 to coordinate the switch at the transitions of differentiation initiation and maturation during oligodendrocyte development, and point to a previously unrecognized role of Tcf7l2 in control of cholesterol biosynthesis for CNS myelinogenesis.

SUBMITTER: Zhao C

PROVIDER: S-EPMC4786870 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Project description:The members of the TCF/LEF family of DNA-binding proteins are components of diverse gene regulatory networks. As nuclear effectors of Wnt/?-catenin signaling they act as assembly platforms for multimeric transcription complexes that either repress or activate gene expression. Previously, it was shown that several aspects of TCF/LEF protein function are regulated by post-translational modification. The association of TCF/LEF family members with acetyltransferases and deacetylases prompted us to investigate whether vertebrate TCF/LEF proteins are subject to acetylation. Through co-expression with p300 and CBP and subsequent analyses using mass spectrometry and immunodetection with anti-acetyl-lysine antibodies we show that TCF4 can be acetylated at lysine K??? by CBP. K??? acetylation is restricted to TCF4E splice variants and requires the simultaneous presence of ?-catenin and the unique TCF4E C-terminus. To examine the functional consequences of K??? acetylation we substituted K??? with amino acids representing the non-acetylated and acetylated states. Reporter gene assays based on Wnt/?-catenin-responsive promoter regions did not indicate a general role of K??? acetylation in transactivation by TCF4E. However, in the presence of CBP, non-acetylatable TCF4E with a K???R substitution was more susceptible to inhibition by the HBP-1 repressor protein compared to wild-type TCF4E. Acetylation of K??? using a bacterial expression system or amino acid substitutions at K??? alter the electrophoretic properties of TCF4E::DNA complexes. This result suggests that K??? acetylation leads to a conformational change that may also represent the mechanism whereby acetylated TCF4E acquires resistance against HBP1. In summary, TCF4 not only recruits acetyltransferases but is also a substrate for these enzymes. The fact that acetylation affects only a subset of TCF4 splice variants and is mediated preferentially by CBP suggests that the conditional acetylation of TCF4E is a novel regulatory mechanism that diversifies the transcriptional output of Wnt/?-catenin signaling in response to changing intracellular signaling milieus.

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Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation.

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