Abstract
Background: The ERK MAPK pathway plays a pivotal role in regulating numerous cellular processes during normal development and in the adult but is often deregulated in disease scenarios. One of its key nuclear targets is the transcription factor ELK1, which has been shown to play an important role in controlling gene expression in human embryonic stem cells (hESCs). ELK1 is known to act as a transcriptional activator in response to ERK pathway activation but repressive roles have also been uncovered, including a putative interaction with the PRC2 complex. Methods: Here we probe the activity of ELK1 in hESCs by using a combination of gene expression analysis in hESCs and during differentiation following ELK1 depletion and also analysis of chromatin occupancy of transcriptional regulators and histone mark deposition that accompany changes in gene expression. Results: We find that ELK1 can exert its canonical activating activity downstream from the ERK pathway but also possesses additional repressive activities. Despite its co-binding to PRC2 occupied regions, we could not detect any ELK1-mediated repression at these regions. Instead, we find that ELK1 has a repressive role at a subset of co-occupied SRF binding regions. Conclusions: ELK1 should therefore be viewed as a dichotomous transcriptional regulator that can act through SRF to generate both activating and repressing properties at different genomic loci.
Highlights
In vitro studies on human embryonic stem cells are an important step in understanding the molecular basis to human development
Functional interplay between ELK1 and PRC2 Previous studies demonstrated that ELK1 occupies two distinct sets of genomic loci in H1-human embryonic stem cells (hESCs) (Göke et al, 2013)
We asked whether the two classes of ELK1 binding regions showed differences in co-association with the ELK1 binding partner SRF and a variety of histone marks that are characteristic of transcriptional repression or activation
Summary
In vitro studies on human embryonic stem cells are an important step in understanding the molecular basis to human development. ELK1 was found to bind to a different set of genomic loci, which were co-occupied with PRC2 complex components and marked with repressive histone tail modifications. This observation is suggestive of a repressive role in this context, and a model was proposed in which ELK1 promotes PRC2 complex recruitment and transcriptional repression. SIN3A complex recruitment is associated with inactivation of ELK1 following activation by ERK-mediated phosphorylation, whereas SUMO-mediated HDAC2 recruitment is thought to maintain ELK1 in a transcriptionally repressive state prior to growth factor stimulation. Conclusions: ELK1 should be viewed as a dichotomous transcriptional regulator that can act through SRF to generate both activating and repressing properties at different genomic loci
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.
