An Enhancer Composed of Interlocking Submodules Controls Transcriptional Autoregulation of Suppressor of Hairless

Abstract

SUMMARY Positive autoregulation is an effective mechanism for the long-term maintenance of a transcription factor’s expression. This strategy is widely deployed in cell lineages, where the autoregulatory factor controls the activity of a battery of genes that constitute the differentiation program of a post-mitotic cell type. In Drosophila, the Notch pathway transcription factor Suppressor of Hairless activates its own expression specifically in the socket cell of external sensory organs, via an autoregulatory enhancer called the ASE. Here we show that the ASE is composed of several enhancer sub-modules, each of which can independently initiate weak Su(H) autoregulation. Cross-activation by these sub-modules is critical to ensuring that Su(H) rises above a threshold level necessary to activate a maintenance sub-module, which then sustains long-term Su(H) autoregulation. Our study reveals the use of interlinked positive feedback loops to control autoregulation dynamically, and provides mechanistic insight into initiation, establishment, and maintenance of the autoregulatory state.

The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force

“…Other transcriptional inputs have also been found in association with CSL binding sites (Liu and Posakony, 2012, 2014). For example, Runx binding sites were found to be associated with potential CSL regulated enhancers in a number of studies in both Drosophila and vertebrates.…”

Negative control of CSL gene transcription by stress/DNA damage response and p53

“…5 The Drosophila melanogaster and Caenorhabditis elegans homologs of CSL, Suppressor of Hairless (SuH) and LAG-1 respectively, can either activate or repress their own expression, determining cell fate. 6,7 Little else is known of control mechanisms of CSL gene transcription. At the protein level, other pathways converge on control of its function.…”

Structure and cis‐regulatory analysis of a Drosophila grainyhead neuroblast enhancer

“…For example, the sparkling enhancer, a Notch/EGFR/Runx- Summaries of expression of deletion constructs each lacking a conserved sequence block of the grh-15a enhancer. Other examples include the ASE5 Suppressor of Hairless which has 10 CSBs (Liu and Posakony, 2014), malpha, which has eight CSBs (Liu and Posakony, 2014) and nerfin-1 NB enhancer, which has 12 CSBs (Kuzin et al, 2011). A summary of the expression patterns of grh-15a deletion constructs described in Figure 5 and illustrated in Figure 6, and Supporting Information Figure S1.…”

“…The evolutionary analysis of Drosophila enhancers has also proved to be a useful model to study the integration of multiple transcriptional inputs into enhancer function. Similarly, interlocking submodules control Notch pathway regulated expression of Suppressor of Hairless (Liu & Posakony, 2014) and, more recently, sloppy paired has been shown to be regulated by cis-regulatory elements that integrate inputs for multiple TFs (Hang & Gergen, 2017). Similarly, interlocking submodules control Notch pathway regulated expression of Suppressor of Hairless (Liu & Posakony, 2014) and, more recently, sloppy paired has been shown to be regulated by cis-regulatory elements that integrate inputs for multiple TFs (Hang & Gergen, 2017).…”