title: Genome-wide features of neuroendocrine regulation in Drosophila by the basic helix-loop-helix transcription factor DIMMED.
abstract: Neuroendocrine (NE) cells use large dense core vesicles (LDCVs) to traffic, process, store and secrete neuropeptide hormones through the regulated secretory pathway. The dimmed (DIMM) basic helix-loop-helix transcription factor of Drosophila controls the level of regulated secretory activity in NE cells. To pursue its mechanisms, we have performed two independent genome-wide analyses of DIMM's activities: (i) in vivo chromatin immunoprecipitation (ChIP) to define genomic sites of DIMM occupancy and (ii) deep sequencing of purified DIMM neurons to characterize their transcriptional profile. By this combined approach, we showed that DIMM binds to conserved E-boxes in enhancers of 212 genes whose expression is enriched in DIMM-expressing NE cells. DIMM binds preferentially to certain E-boxes within first introns of specific gene isoforms. Statistical machine learning revealed that flanking regions of putative DIMM binding sites contribute to its DNA binding specificity. DIMM's transcriptional repertoire features at least 20 LDCV constituents. In addition, DIMM notably targets the pro-secretory transcription factor, creb-A, but significantly, DIMM does not target any neuropeptide genes. DIMM therefore prescribes the scale of secretory activity in NE neurons, by a systematic control of both proximal and distal points in the regulated secretory pathway.
authors: Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors: Tarik
authors: T
authors: Hadžić
authors: Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors: Dongkook
authors: D
authors: Park
authors: Howard Hughes Medical Institute, National Center for Behavioral Genomics, Department of Biology, Brandeis University, Waltham, MA 02454, USA.
authors: Katharine C
authors: KC
authors: Abruzzi
authors: Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors: Lin
authors: L
authors: Yang
authors: Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors: Jennifer S
authors: JS
authors: Trigg
authors: Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors: Remo
authors: R
authors: Rohs
authors: Howard Hughes Medical Institute, National Center for Behavioral Genomics, Department of Biology, Brandeis University, Waltham, MA 02454, USA.
authors: Michael
authors: M
authors: Rosbash
authors: Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA taghertp@pcg.wustl.edu.
authors: Paul H
authors: http://orcid.org/0000-0002-5399-2993
authors: PH
authors: Taghert
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D017124:Conserved Sequence; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D024721:E-Box Elements; D049750:Genome, Insect; D059014:High-Throughput Nucleotide Sequencing; D055099:Neuroendocrine Cells / Q000378:metabolism*; D055571:Secretory Pathway / Q000235:genetics; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000378:metabolism; D059467:Transcriptome
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D029721:Drosophila Proteins; D015534:Trans-Activators; C491313:dimm protein, Drosophila
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