ABSTRACT
The precise spatial and temporal orchestration of gene expression is crucial for the ontogeny of an organism and is mainly governed by transcription factors (TFs). The mechanism of recognition of cognate sites amid millions of base pairs in the genome by TFs is still incompletely understood. In this study, we focus on DNA sequence composition, shape, and flexibility preferences of 28 quintessential TFs from Drosophila melanogaster that are critical to development and body patterning mechanisms. Our study finds that TFs exhibit distinct predilections for DNA shape, flexibility, and sequence compositions in the proximity of transcription factor binding sites (TFBSs). Notably, certain zinc finger proteins prefer GC-rich areas with less negative propeller twist, while homeodomains mainly seek AT-rich regions with a more negative propeller twist at their sites. Intriguingly, while numerous cofactors share similar binding site preferences and bind closer to each other in the genome, some cofactors that have different preferences bind farther apart. These findings shed light on TF DNA recognition and provide novel insights into possible cofactor binding and transcriptional regulation mechanisms.
ABSTRACT
Functioning of the nervous system requires proper formation and specification of neurons as well as accurate connectivity and signalling between them. Locomotor behaviour depends upon these events that occur during neural development, and any aberration in them could result in motor disorders. Transcription factors are believed to be master regulators that control these processes, but very few linked to behaviour have been identified so far. The Drosophila homologue of BCL11A (CTIP1) and BCL11B (CTIP2), Chronophage (Cph), was recently shown to be involved in temporal patterning of neural stem cells but its role in post-mitotic neurons is not known. We show that knockdown of Cph in neurons during development results in animals with locomotor defects at both larval and adult stages. The defects are more severe in adults, with inability to stand, uncoordinated behaviour and complete loss of ability to walk, climb, or fly. These defects are similar to the motor difficulties observed in some patients with mutations in BCL11A and BCL11B. Electrophysiological recordings showed reduced evoked activity and irregular neuronal firing. All Cph-expressing neurons in the ventral nerve cord are glutamatergic. Our results imply that Cph modulates primary locomotor activity through configuration of glutamatergic neurons. Thus, this study ascribes a hitherto unknown role to Cph in locomotor behaviour of Drosophila melanogaster.
