Abstract
A precisely balanced activity of canonical Wnt signaling is essential for a number of biological processes and its perturbation leads to developmental defects or diseases. Here, we demonstrate that alternative isoforms of the KDM2A and KDM2B lysine demethylases have the ability to negatively regulate canonical Wnt signaling. These KDM2A and KDM2B isoforms (KDM2A-SF and KDM2B-SF) lack the N-terminal demethylase domain, but they still have the ability to bind to CpG islands in promoters and to interact with their protein partners via their other functional domains. We have observed that KDM2A-SF and KDM2B-SF bind to the promoters of axin 2 and cyclin D1, two canonical Wnt signaling target genes, and repress their activity. Moreover, KDM2A-SF and KDM2B-SF are both able to strongly repress a Wnt-responsive luciferase reporter. The transcriptional repression mediated by KDM2A-SF and KDM2B-SF, but also by KDM2A-LF, is dependent on their DNA binding domain, while the N-terminal demethylase domain is dispensable for this process. Surprisingly, KDM2B-LF is unable to repress both the endogenous promoters and the luciferase reporter. Finally, we show that both KDM2A-SF and KDM2B-SF are able to interact with TCF7L1, one of the transcriptional mediators of canonical Wnt signaling. KDM2A-SF and KDM2B-SF are thus likely to negatively affect the transcription of canonical Wnt signaling target genes by binding to their promoters and by interacting with TCF7L1 and other co-repressors.
Highlights
KDM2A and KDM2B (KDM2A/B) are two closely related lysine demethylases with the ability to bind to non-methylated CpG islands through their CXXC DNA binding domain
Since KDM2A-LF has been previously shown to strongly repress the Wnt-responsive luciferase Topflash reporter activated by elevated levels of beta-catenin [14], we set out to test whether the KDM2A-SF and KDM2B-SF isoforms are able to repress this reporter despite lacking the demethylase domain
To complement our luciferase reporter data and to analyze whether KDM2A-SF and KDM2B-SF are able to repress endogenous canonical Wnt signaling target genes, we focused on the axin 2 (AXIN2) and cyclin D1 (CCND1) genes
Summary
KDM2A and KDM2B (KDM2A/B) are two closely related lysine demethylases with the ability to bind to non-methylated CpG islands through their CXXC DNA binding domain. After binding to non-methylated CpG islands in transcriptionally active promoters, KDM2A/B demethylate mono- and di-methylated H3K36 lysines (H3K36me1/2) using their N-terminal Jumonji-C demethylase domain [1, 2]. KDM2A/B function as transcriptional repressors of the promoters that contain CpG islands [1, 7,8,9,10]. KDM2A and KDM2B have very similar structure, they have been shown to interact with different protein partners to repress different target regions. KDM2A interacts with HP1a to repress the pericentromeric heterochromatin [11,12,13], whereas KDM2B forms complex with the PRC1 complex to silence developmentally important genes in embryonic stem cells [10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
