TY - JOUR
T1 - Genome-wide features of neuroendocrine regulation in Drosophila by the basic helix-loop-helix transcription factor DIMMED
AU - Hadzić, Tarik
AU - Park, Dongkook
AU - Abruzzi, Katharine C.
AU - Yang, Lin
AU - Trigg, Jennifer S.
AU - Rohs, Remo
AU - Rosbash, Michael
AU - Taghert, Paul H.
N1 - Funding Information:
National Institutes of Health [P01 NS044232, P30-NS045713]; Howard Hughes Medical Institute [to M.R.]; National Institutes of Health [R01GM106056, U01GM103804]; Alfred P. Sloan Research Fellowship [to R.R.]; Bakewell Neuroimaging Laboratories and National Institutes of Health [P30 NS057105, R01NS21749 to P.H.T.]. Funding for open access charge: National Institutes of Health [R01 NS27419]. Conflict of interest statement. None declared.
Publisher Copyright:
© 2015 The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2015/2/27
Y1 - 2015/2/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84941114631&partnerID=8YFLogxK
U2 - 10.1093/nar/gku1377
DO - 10.1093/nar/gku1377
M3 - Article
C2 - 25634895
AN - SCOPUS:84941114631
VL - 43
SP - 2199
EP - 2215
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 4
ER -