Hormone-dependent control of developmental timing through regulation of chromatin accessibility

Abstract

Specification of tissue identity during development requires precise coordination of gene expression in both space and time. Spatially, master regulatory transcription factors are required to control tissue-specific gene expression programs. However, the mechanisms controlling how tissue-specific gene expression changes over time are less well understood. Here, we show that hormone-induced transcription factors control temporal gene expression by regulating the accessibility of DNA regulatory elements. Using the Drosophila wing, we demonstrate that temporal changes in gene expression are accompanied by genome-wide changes in chromatin accessibility at temporal-specific enhancers. We also uncover a temporal cascade of transcription factors following a pulse of the steroid hormone ecdysone such that different times in wing development can be defined by distinct combinations of hormone-induced transcription factors. Finally, we show that the ecdysone-induced transcription factor E93 controls temporal identity by directly regulating chromatin accessibility across the genome. Notably, we found that E93 controls enhancer activity through three different modalities, including promoting accessibility of late-acting enhancers and decreasing accessibility of early-acting enhancers. Together, this work supports a model in which an extrinsic signal triggers an intrinsic transcription factor cascade that drives development forward in time through regulation of chromatin accessibility.

Developmental Transcriptional Enhancers: A Subtle Interplay between Accessibility and Activity

“…Uyehara et al. [ 29 ] identified a set of genomic intervals that remained accessible during an entire window of D. melanogaster wing development, yet displayed a quantitative increase or decrease of their FAIRE‐seq signal at different timepoints. Notably, these temporally dynamic regions drove transcription of a reporter gene at the timepoint that coincided with their highest accessibility.…”

“…[ 15,36,45 ] In fact, compaction into inaccessible chromatin was shown to be a gradual process, which occurs with a considerable delay upon repression of enhancers. [ 29 ] Thus, inactivation of transcription by a repressor TF and loss of enhancer accessibility are distinct regulatory events that take place on different time scales.…”

“…[ 55 ] In the plethora of studies on PcG and TrxG, the chromatin state is evaluated through different histone modifications [ 56–60 ] and the actual chromatin accessibility is not directly examined. It is therefore difficult to reconcile the pattern of local, discrete, and dynamic peaks of accessibility seen at individual enhancers [ 15,29,36 ] with the broad control of chromatin states from PREs and TREs. Do subtle interactions between PREs and individual enhancers modulate local accessibility within a broad Polycomb repressive domain?…”

Regenerative capacity inDrosophilaimaginal discs is controlled by damage-responsive, maturity-silenced enhancers

“…Signal tracks were generated from individual replicates using Deeptools v2.4.1 (Ramirez et al, 2016). Signal in browser shots are represented as z scores of pooled replicates as described previously (Uyehara et al, 2017).…”

The temporal transcription factor E93 controls dynamic enhancer activity and chromatin accessibility during development

“…During specification of the pigmented bract cells, which are induced adjacent to bristles during pupal leg development, E93 expression makes the Distal-less gene competent to respond to EGFR signaling (Mou et al, 2012). However, in contrast to Hunchback, recent work from pupal wings suggest a direct role for E93 in regulating chromatin accessibility (Uyehara et al, 2017). During metamorphosis, the wing imaginal disc undergoes dramatic morphological, cell fate, and gene expression changes to form the notum (back), hinge, and wing blade of the adult.…”