Chromatin signatures at Notch‐regulated enhancers reveal large‐scale changes in H3K56ac upon activation

Abstract

The conserved Notch pathway functions in diverse developmental and disease-related processes, requiring mechanisms to ensure appropriate target selection and gene activation in each context. To investigate the influence of chromatin organisation and dynamics on the response to Notch signalling, we partitioned Drosophila chromatin using histone modifications and established the preferred chromatin conditions for binding of Su(H), the Notch pathway transcription factor. By manipulating activity of a co-operating factor, Lozenge/Runx, we showed that it can help facilitate these conditions. While many histone modifications were unchanged by Su(H) binding or Notch activation, we detected rapid changes in acetylation of H3K56 at Notchregulated enhancers. This modification extended over large regions, required the histone acetyl-transferase CBP and was independent of transcription. Such rapid changes in H3K56 acetylation appear to be a conserved indicator of enhancer activation as they also occurred at the mammalian Notch-regulated Hey1 gene and at Drosophila ecdysone-regulated genes. This intriguing example of a core histone modification increasing over short timescales may therefore underpin changes in chromatin accessibility needed to promote transcription following signalling activation.

Genomic integration of Wnt/β-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional programs

“…This is similar to recent findings in Xenopus gastrula and hPSCs (Nakamura et al, 2016;Tsankov et al, 2015), and is consistent with an emerging concept that transcription factor binding is pervasive throughout the genome even when they are not engaged in productive transcription (Nakamura et al, 2016; reviewed by Skalska et al, 2015). One possibility is that these β-catenin/Smad1 binding events are due to earlier Wnt and BMP signaling.…”

The Notch meeting: an odyssey from structure to function

“…E(spl) genes]. This can be interpreted as a longer time spent on DNA, or increased concentration of NICD/Su(H) molecules close to target sites, in line with the recent suggestion that Su(H) binds and modifies predefined (open) loci upon Notch signaling (Skalska et al, 2015).…”

Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases

“…Once NICD enters the nucleus and binds to Su(H), H is no longer able to bind to Su(H)[183]. The active NICD-Su(H)-Mam complex further recruits transcriptional co-activators such as the histone acetyltransferase CBP [CREB (cAMP response element binding protein)-binding protein]/p300 [nejire (nej) in Drosophila, EP300 (E1A binding protein P300) and CREBBP (CREB-binding protein) in human] to initiate transcription of downstream target genes [71,184]. While most genes that are involved in the transcriptional activation complex are conserved between flies and mammals, no direct homolog of Hairless exists in mammalian genomes.…”