Maicas, Miren, Chirivella, Laura, Flames, Nuria, Lloret-Fernandez, Carla, Jimeno, Angela, Weinberg , Peter, Artacho, Alejandro, Mora, Carlos
[
International Worm Meeting,
2017]
Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains unknown. Here, we identify the cis-regulatory transcriptional code that controls the differentiation of serotonergic (5HT) HSN neurons in C. elegans. Loss of function mutant and cis-regulatory analyses reveal that direct activation of the HSN transcriptome is orchestrated by a collective of six TFs. This TF code is composed by AST-1 (ETS TF family), UNC-86 (POU TF family), SEM-4 (SPALT TF family), HLH-3 (bHLH TF family), EGL-46 (INSM TF family) and EGL-18 (GATA TF family). Bioinformatically identified binding site clusters for these six TFs are enriched in known HSN expressed genes compared to a random set of genes. Through in vivo reporter analysis, we demonstrate that the clustering of TF collective binding sites constitutes a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. This regulatory signature contains certain syntactic constrains that further improve the prediction of enhancer expression in the cell. Mouse orthologs of most members of this TF collective are known regulators of mammalian 5HT differentiation programs and can functionally substitute for their worm counterparts. Finally, Principal Coordinates Analysis suggests that, among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse 5HT neurons, which reveals deep homology. Our results?identify rules governing the transcriptional regulatory code of a critically important neuronal type in two species separated by over 700 million years.