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

•An autoregulatory enhancer is composed of functionally separable submodules•Autoregulation is subject to dynamic combinatorial control•Interlinked positive-feedback loops establish rapid and irreversible autoregulation•A transcription factor threshold level is essential for the autoregulatory state

SummaryPositive 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 postmitotic 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 submodules, each of which can independently initiate weak Su(H) autoregulation. Cross-activation by these submodules is critical to ensure that Su(H) rises above a threshold level necessary to activate a maintenance submodule, 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.

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