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@ARTICLE{Monastirioti:292522,
      author       = {M. Monastirioti and I. Koltsaki$^*$ and I. Pitsidianaki and
                      E. Skafida and N. Batsiotos and C. Delidakis},
      title        = {{N}otch-{D}ependent {E}xpression of the {D}rosophila {H}ey
                      {G}ene {I}s {S}upported by a {P}air of {E}nhancers with
                      {O}verlapping {A}ctivities.},
      journal      = {Genes},
      volume       = {15},
      number       = {8},
      issn         = {2073-4425},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2024-01768},
      pages        = {1071},
      year         = {2024},
      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.},
      keywords     = {Animals / Drosophila Proteins: genetics / Drosophila
                      Proteins: metabolism / Basic Helix-Loop-Helix Transcription
                      Factors: genetics / Basic Helix-Loop-Helix Transcription
                      Factors: metabolism / Receptors, Notch: genetics /
                      Receptors, Notch: metabolism / Gene Expression Regulation,
                      Developmental / Enhancer Elements, Genetic / Drosophila
                      melanogaster: genetics / Repressor Proteins: genetics /
                      Repressor Proteins: metabolism / Promoter Regions, Genetic /
                      Signal Transduction: genetics / Drosophila (Other) / Hey
                      (Other) / Notch (Other) / Su(H) binding site (Other) / basic
                      helix–loop–helix–orange (Other) / central nervous
                      system (Other) / enhancer (Other) / midgut (Other) /
                      Drosophila Proteins (NLM Chemicals) / Basic Helix-Loop-Helix
                      Transcription Factors (NLM Chemicals) / Receptors, Notch
                      (NLM Chemicals) / N protein, Drosophila (NLM Chemicals) /
                      Repressor Proteins (NLM Chemicals) / Su(H) protein,
                      Drosophila (NLM Chemicals)},
      cin          = {A410},
      ddc          = {570},
      cid          = {I:(DE-He78)A410-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39202431},
      pmc          = {pmc:PMC11353301},
      doi          = {10.3390/genes15081071},
      url          = {https://inrepo02.dkfz.de/record/292522},
}