Resumen de Study of the role of the histone demethylase jmjd3 as a transcriptional regulator
Neural development is a coordinated process in which signaling pathways cooperate with transcription factors and histone modifying enzymes to generate different gene programs that will ultimately lead to the required phenotypical traits. At the megabase level, topological associated domains constrain the transcription factor accessibility and the potential enhancer-promoter interactions occurring in a specific time and space. At the same time, at the local level, DNA sequences present at enhancers exhibit binding sites for a plethora of transcription factors that are necessary in specific cell decisions. How dynamic signaling pathways coordinate transcription factor recruitment in the context of enhancer-promoter interactions and to which extent chromatin modifiers cooperating with the cascades impact genomic loops has been addressed in this doctoral thesis.
The work of Raquel Fueyo Arévalo, demonstrates that in mouse neural stem cells obtained from E12.5 embryo cortices, TGFβ signaling pathway is orchestrating the neuronal developmental gene program by activating a specific set of enhancers. Using CRISPR-Cas9 experiments, we decipher the involvement of the TGFβ-induced NEUROG2 enhancer and promoter in the neuronal differentiation process and we establish a hierarchical order of recruitment of the activating proteins within the three dimensional chromatin structure.
Considering genome-wide data, we point to the proneural factor ASCL1 as the pioneer factor required for SMAD3 recruitment to cis-regulatory regions and we indicate that the known interactor of SMAD3, JMJD3 histone demethylase, is as a new partner of ASCL1 in enhancer activation. Additionally, we address the role of JMJD3 at enhancers in the linear conformation and in the 3D-conformation.
To further deepen into the specific mechanism operating on these neural enhancers, we discover a novel JMJD3 interacting partner: the autism-related protein CHD8.
Altogether, our results describe new roles of the histone demethylase JMJD3 and other proteins acting downstream the TGFβ-signaling cascade in neural development, contributing to the scientific knowledge of this pathway in stem cells and disease.
