Journal Article

DKFZ-2024-01768

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Notch-Dependent Expression of the Drosophila Hey Gene Is Supported by a Pair of Enhancers with Overlapping Activities.

Monastirioti, M. ; Koltsaki, I.DKFZ* ; Pitsidianaki, I. ; Skafida, E. ; Batsiotos, N. ; Delidakis, C.

2024
MDPI Basel

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Please use a persistent id in citations: doi:10.3390/genes15081071

Abstract: Drosophila Hey is a basic helix-loop-helix-orange (bHLH-O) protein with an important role in the establishment of distinct identities of postmitotic cells. We have previously identified Hey as a transcriptional target and effector of Notch signalling during the asymmetric division of neuronal progenitors, generating neurons of two types, and we have shown that Notch-dependent expression of Hey also marks a subpopulation of the newborn enteroendocrine (EE) cells in the midgut primordium of the embryo. Here, we investigate the transcriptional regulation of Hey in neuronal and intestinal tissues. We isolated two genomic regions upstream of the promoter (HeyUP) and in the second intron (HeyIN2) of the Hey gene, based on the presence of binding motifs for Su(H), the transcription factor that mediates Notch activity. We found that both regions can direct the overlapping expression patterns of reporter transgenes recapitulating endogenous Hey expression. Moreover, we showed that while HeyIN2 represents a Notch-dependent enhancer, HeyUP confers both Notch-dependent and independent transcriptional regulation. We induced mutations that removed the Su(H) binding motifs in either region and then studied the enhancer functionality in the respective Hey mutant lines. Our results provide direct evidence that although both enhancers support Notch-dependent regulation of the Hey gene, their role is redundant, as a Hey loss-of-function lethal phenotype is observed only after deletion of all their Su(H) binding motifs by CRISPR/Cas9.

Keyword(s): Animals (MeSH) ; Drosophila Proteins: genetics (MeSH) ; Drosophila Proteins: metabolism (MeSH) ; Basic Helix-Loop-Helix Transcription Factors: genetics (MeSH) ; Basic Helix-Loop-Helix Transcription Factors: metabolism (MeSH) ; Receptors, Notch: genetics (MeSH) ; Receptors, Notch: metabolism (MeSH) ; Gene Expression Regulation, Developmental (MeSH) ; Enhancer Elements, Genetic (MeSH) ; Drosophila melanogaster: genetics (MeSH) ; Repressor Proteins: genetics (MeSH) ; Repressor Proteins: metabolism (MeSH) ; Promoter Regions, Genetic (MeSH) ; Signal Transduction: genetics (MeSH) ; Drosophila ; Hey ; Notch ; Su(H) binding site ; basic helix–loop–helix–orange ; central nervous system ; enhancer ; midgut ; Drosophila Proteins ; Basic Helix-Loop-Helix Transcription Factors ; Receptors, Notch ; N protein, Drosophila ; Repressor Proteins ; Su(H) protein, Drosophila

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Contributing Institute(s):

1. Metabolismus und Microenvironment (A410)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2024

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