title: The dual role of LSD1 and HDAC3 in STAT5-dependent transcription is determined by protein interactions, binding affinities, motifs and genomic positions.
abstract: STAT5 interacts with other factors to control transcription, and the mechanism of regulation is of interest as constitutive active STAT5 has been reported in malignancies. Here, LSD1 and HDAC3 were identified as novel STAT5a interacting partners in pro-B cells. Characterization of STAT5a, LSD1 and HDAC3 target genes by ChIP-seq and RNA-seq revealed gene subsets regulated by independent or combined action of the factors and LSD1/HDAC3 to play dual role in their activation or repression. Genes bound by STAT5a alone or in combination with weakly associated LSD1 or HDAC3 were enriched for the canonical STAT5a GAS motif, and such binding induced activation or repression. Strong STAT5 binding was seen more frequently in intergenic regions, which might function as distal enhancer elements. Groups of genes bound weaker by STAT5a and stronger by LSD1/HDAC3 showed an absence of the GAS motif, and were differentially regulated based on their genomic binding localization and binding affinities. These genes exhibited increased binding frequency in promoters, and in conjunction with the absence of GAS sites, the data indicate a requirement for stabilization by additional factors, which might recruit LSD1/HDAC3. Our study describes an interaction network of STAT5a/LSD1/HDAC3 and a dual function of LSD1/HDAC3 on STAT5-dependent transcription, defined by protein-protein interactions, genomic binding localization/affinity and motifs.
authors.affiliation: Basic Research Center, Biomedical Research Foundation, Academy of Athens, Soranou tou Ephessiou 4, 115 27 Athens, Greece.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Nanou
authors.affiliation: Basic Research Center, Biomedical Research Foundation, Academy of Athens, Soranou tou Ephessiou 4, 115 27 Athens, Greece.
authors.forename: Chrisavgi
authors.initials: C
authors.lastname: Toumpeki
authors.affiliation: Basic Research Center, Biomedical Research Foundation, Academy of Athens, Soranou tou Ephessiou 4, 115 27 Athens, Greece.
authors.forename: Matthieu D
authors.initials: MD
authors.lastname: Lavigne
authors.affiliation: Basic Research Center, Biomedical Research Foundation, Academy of Athens, Soranou tou Ephessiou 4, 115 27 Athens, Greece.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Lazou
authors.affiliation: Proteomics Center, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Demmers
authors.affiliation: Basic Research Center, Biomedical Research Foundation, Academy of Athens, Soranou tou Ephessiou 4, 115 27 Athens, Greece.
authors.forename: Triantafillos
authors.initials: T
authors.lastname: Paparountas
authors.affiliation: Basic Research Center, Biomedical Research Foundation, Academy of Athens, Soranou tou Ephessiou 4, 115 27 Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Thanos
authors.affiliation: Basic Research Center, Biomedical Research Foundation, Academy of Athens, Soranou tou Ephessiou 4, 115 27 Athens, Greece ekatsantoni@bioacademy.gr.
authors.forename: Eleni
authors.initials: E
authors.lastname: Katsantoni
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D059372:Nucleotide Motifs; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D056466:Histone Demethylases; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D000099186:Histone Deacetylase 3; C494093:Stat5a protein, mouse; C504076:KDM1a protein, mouse