The bHLH transcription factor ASCL1 (HASH1/MASH1) is essential for neuronal differentiation and sub-type specification of multiple neuronal cell-types throughout the brain, spinal cord, and autonomic nervous system, as well as cells in sensory systems such as the retina and olfactory epithelia. ASCL1 function is balanced with NOTCH signaling activity to control progenitor proliferation and differentiation. ASCL1 has also been identified as a pioneering factor and a key component of cocktails directly reprogramming fibroblasts to neurons. With these important functions attributed to ASCL1, and its requirement for controlled spatial and temporal expression in vivo for viability postnatally, it is surprising how little is known about regulation of ASCL1 gene transcription. This gap in knowledge reflects past technical challenges in identifying and manipulating cis-regulatory elements (REs) found at large distances from the gene of interest. REs functioning at long-distances to control key developmental genes are being discovered using advances in technologies that can interrogate and manipulate the spatial genome. Here we will exploit these technologies to gain much needed insights into transcriptional control of ASCL1 using cell culture and in vivo models of neural development. Each model has a particular strength that allows unique aspects of ASCL1 regulation to be uncovered.
Aims i nclude identifying and testing functions of long-range REs controlling ASCL1 during neuronal differentiation in mouse (in vivo) and human (in vitro) models. Success in these aims will provide functional non-coding regulatory sequences controlling ASCL1 expression. This is important for future projects to identify molecular components of the signaling complexes working through these REs to reach the goal of providing an understanding of how a key lineage defining transcriptional regulator is controlled during development and disease.
ASCL1 is a key neurodevelopmental transcription factor with essential functions in neurogenesis and neuronal subtype specification, and a pioneering factor with activity in reprogramming non-neural cells to neurons. Successful completion of this project will identify non-coding genomic regulatory elements controlling the transcription of this key neurodevelopmental gene, regulatory elements that may be dysfunctional in neurodevelopmental, neurodegenerative and neuropsychiatric diseases.
