biostudies-literatureUnknown13(1)Tamberg LDaughterless (Da), the <i>Drosophila melanogaster</i> homolog of mammalian E-protein transcription factor 4 (TCF4), is well studied in fruit fly embryonic development but its functions in adult nervous system are poorly understood. Mutations in human <i>TCF4</i> gene lead to intellectual disabilities such as Pitt-Hopkins syndrome and <i>TCF4</i> has also been linked to schizophrenia. Here, to explore the roles of Da in the <i>Drosophila</i> mature brain, we map Da DNA binding sites and study the transcriptomics of the brains where Da function is inhibited by pan-neuronal Extramacrohaete (Emc) overexpression, in both male and female <i>Drosophila</i> Our transcriptome analyses reveal that in the adult brain Da regulates the expression of genes involved in behavior, memory, synaptic signaling, protein translation, and metabolic processes. Moreover, combining the RNA sequencing data with Da ChIP sequencing results indicates that genes associated with neuronal projection guidance, metabolism, and translation are direct targets of Da. In addition, we validate the involvement of Da in memory formation. Overall, our results provide valuable information about the functions of Da in the adult brain and aid in better understanding the mechanisms of TCF4-related disorders.eNeuroENEURO.0051-25.2025https://www.ebi.ac.uk/biostudies/studies/S-EPMC12834652biostudies-literatureThe E-Protein Daughterless Regulates Olfactory Learning of Adult &lt;i&gt;Drosophila melanogaster&lt;/i&gt;.PMC12834652Palgi MKoppel ITimmusk TKiir CSTamberg LTuvikene JRannaste KfalseThe E-Protein Daughterless Regulates Olfactory Learning of Adult &lt;i&gt;Drosophila melanogaster&lt;/i&gt;.Daughterless (Da), the <i>Drosophila melanogaster</i> homolog of mammalian E-protein transcription factor 4 (TCF4), is well studied in fruit fly embryonic development but its functions in adult nervous system are poorly understood. Mutations in human <i>TCF4</i> gene lead to intellectual disabilities such as Pitt-Hopkins syndrome and <i>TCF4</i> has also been linked to schizophrenia. Here, to explore the roles of Da in the <i>Drosophila</i> mature brain, we map Da DNA binding sites and study the transcriptomics of the brains where Da function is inhibited by pan-neuronal Extramacrohaete (Emc) overexpression, in both male and female <i>Drosophila</i> Our transcriptome analyses reveal that in the adult brain Da regulates the expression of genes involved in behavior, memory, synaptic signaling, protein translation, and metabolic processes. Moreover, combining the RNA sequencing data with Da ChIP sequencing results indicates that genes associated with neuronal projection guidance, metabolism, and translation are direct targets of Da. In addition, we validate the involvement of Da in memory formation. Overall, our results provide valuable information about the functions of Da in the adult brain and aid in better understanding the mechanisms of TCF4-related disorders.2026-01-01T00:00:00Z2026 Jan2026-06-09T03:15:52.112Z2026-06-09T03:11:35.616ZS-EPMC128346524150083410.1523/ENEURO.0051-25.2025