The Wnt Transcriptional Switch: TLE Removal or Inactivation?

Abstract

Many targets of the Wnt/β-catenin signaling pathway are regulated by TCF transcription factors, which play important roles in animal development, stem cell biology, and oncogenesis. TCFs can regulate Wnt targets through a "transcriptional switch," repressing gene expression in unstimulated cells and promoting transcription upon Wnt signaling. However, it is not clear whether this switch mechanism is a general feature of Wnt gene regulation or limited to a subset of Wnt targets. Co-repressors of the TLE family are known to contribute to the repression of Wnt targets in the absence of signaling, but how they are inactivated or displaced by Wnt signaling is poorly understood. In this mini-review, we discuss several recent reports that address the prevalence and molecular mechanisms of the Wnt transcription switch, including the finding of Wnt-dependent ubiquitination/inactivation of TLEs. Together, these findings highlight the growing complexity of the regulation of gene expression by the Wnt pathway.

Chromatin accessibility and histone acetylation in the regulation of competence in early development

“…As HDAC inhibition extends the window of competence to induce dorsal development in response to Wnt signaling, we propose that HDACs mediate the loss of competence at dorsal Wnt target genes. The T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors are downstream mediators of canonical Wnt/ß-catenin signaling that in the absence of Wnt signaling bind diverse corepressors, including Groucho/transducin-like enhancer of split (Gro/TLE) family, C-terminal binding protein (CtBP), Silencing Mediator for Retinoid and Thyroid hormone receptor (SMRT) and Nuclear receptor Co-Repressor (NCoR), and others, all of which recruit HDACs (Cadigan, 2012;Ramakrishnan et al, 2018). In addition, the transcription repressor Kaiso binds to both TCF3 and Wnt-response elements and represses sia expression (Cadigan, 2012;Park et al, 2005;Ramakrishnan et al, 2018).…”

“…The T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors are downstream mediators of canonical Wnt/ß-catenin signaling that in the absence of Wnt signaling bind diverse corepressors, including Groucho/transducin-like enhancer of split (Gro/TLE) family, C-terminal binding protein (CtBP), Silencing Mediator for Retinoid and Thyroid hormone receptor (SMRT) and Nuclear receptor Co-Repressor (NCoR), and others, all of which recruit HDACs (Cadigan, 2012;Ramakrishnan et al, 2018). In addition, the transcription repressor Kaiso binds to both TCF3 and Wnt-response elements and represses sia expression (Cadigan, 2012;Park et al, 2005;Ramakrishnan et al, 2018). Thus, although the mechanisms of repression by Kaiso are controversial (Cadigan, 2012;Park et al, 2005;Ramakrishnan et al, 2018;Ruzov et al, 2009), the repressive function of Kaiso may also contribute to the loss of competence at dorsal Wnt target genes.…”

“…In addition, the transcription repressor Kaiso binds to both TCF3 and Wnt-response elements and represses sia expression (Cadigan, 2012;Park et al, 2005;Ramakrishnan et al, 2018). Thus, although the mechanisms of repression by Kaiso are controversial (Cadigan, 2012;Park et al, 2005;Ramakrishnan et al, 2018;Ruzov et al, 2009), the repressive function of Kaiso may also contribute to the loss of competence at dorsal Wnt target genes. We propose that TCFs bind to Wnt responsive elements throughout competent tissues.…”

“…Chromatin accessibility is mediated by post-translational modifications of histones, and increased histone acetylation contributes to openness of chromatin and a generally favorable environment for transcription (Shahbazian and Grunstein, 2007). As HDAC inhibition extends the window of competence to induce dorsal development in response to Wnt signaling, we and Nuclear receptor Co-Repressor (NCoR), and others, all of which recruit HDACs (Cadigan, 2012;Ramakrishnan et al, 2018). In addition, the transcription repressor Kaiso binds to both TCF3 and Wnt-response elements and represses sia expression (Cadigan, 2012;Park et al, 2005;Ramakrishnan et al, 2018).…”

“…Wnt signaling promotes acetylation of target gene promoters by stabilizing ß-catenin, which binds to the transcription factor TCF and recruits the histone acetyltransferase p300 (Hecht et al, 2000). In the absence of Wnt signaling, TCF proteins repress target gene expression by recruiting histone deacetylases (HDACs) through diverse corepressors (Cadigan, 2012;Ramakrishnan et al, 2018). Therefore, in regions of the embryo that are competent to respond but do not receive a Wnt signal, such as ventral blastomeres in the cleavage stage embryo, dorsal Wnt target gene promoters may become deacetylated and inaccessible, as we observed for sia and Xnr3 at the early gastrula stage.…”