A unique bipartite Polycomb signature regulates stimulus-response transcription during development

Abstract

Rapid cellular responses to environmental stimuli are fundamental for development and maturation. Immediate early genes (IEGs) can be transcriptionally induced within minutes in response to a variety of signals. How their induction levels are regulated and their untimely activation by spurious signals prevented during development is poorly understood. We found that in developing sensory neurons, prior to perinatal sensory activity-dependent induction, IEGs are embedded into a unique bipartite Polycomb chromatin signature, carrying active H3K27ac on promoters but repressive Ezh2-dependent H3K27me3 on gene bodies. This bipartite signature is widely present in developing cell types, including embryonic stem cells (ESCs). Polycomb marking of gene bodies inhibits mRNA elongation, dampening productive transcription, while still allowing for fast stimulus-dependent mark removal and bipartite gene induction. We reveal a developmental epigenetic mechanism regulating rapidity and amplitude of the transcriptional response to relevant stimuli, while preventing inappropriate activation of stimulus-response genes.

Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis

“…Most recently, bivalent or bivalent-related bipartite regulation was reported in stem cell aging or neurogenesis (Kitazawa et al, 2021;Koester et al, 2021). Here, we performed a comprehensive mapping of transcriptome and histone modifications in VEGF-stimulated primary ECs.…”

GLI transcriptional repression is inert prior to Hedgehog pathway activation

“…For other genes enriched for both marks, like Ptch1, the distribution of these modifications is offset, supporting the potential for these mutually exclusive marks to be present at the same locus (Figure 4I, black brackets). The dual enrichment of H3K27ac and H3K27me3 may enable fast induction of these genes upon presence of relevant stimuli, while preventing inappropriate expression of them from non-relevant stimuli, as others have proposed (Kitazawa et al, 2021).…”

Epigenetic and Transcriptional Regulation of Spontaneous and Sensory Activity Dependent Programs During Neuronal Circuit Development

“…In unstimulated neurons, IEG (e.g., Fos ) enhancers and promoters are accessible and marked by transcription permissive chromatin modifications such as H3K4me1 and H3K4me3, respectively ( Kim et al, 2010 ; Tyssowski et al, 2018 ). These elements even carry modest basal levels of transcriptionally active H3K27ac mark in unstimulated neurons ( Malik et al, 2014 ; Kitazawa et al, 2021 ). Regulatory elements are also pre-bound by transcriptional activators such as CREB and SRF, which are post-translationally activated in a stimulus-dependent manner downstream of calcium signaling ( West and Greenberg, 2011 ).…”

“…While the elucidation of chromatin mechanisms of IEG induction by sensory-evoked activity has seen much progress, our understanding of how IEGs are developmentally regulated before sensory stimulation is still poorly understood. Kitazawa and colleagues used comprehensive genome-wide approaches to analyze the chromatin state and regulation of ARGs during the development of whisker-related barrelette neurons in the brainstem ( Kitazawa et al, 2021 ). This study found that during early development, prior to their sensory activity-dependent induction, IEGs are embedded in a specific Polycomb chromatin signature, named “bipartite” ( Figure 2 ; Kitazawa et al, 2021 ).…”