Epigenetics of Neuronal Differentiation: KIF5A Mediated Transport and Dynamics of Mitochondria During Neuron Development Is Facilitated by FAK Mediated Down Regulation of Chromatin Modifiers

Abstract

Well controlled development of mammals, including humans is the pre-requisite of fruitful reproduction. Nervous system plays distinct roles in reproduction. Aberrant gene expression and uncontrolled neuronal differentiation leads to neuroblastoma. Chromatin modifications, including DNA methylation and various types of chemical modifications of histone regulates gene expression. Neuronal stem cells differentiate into mature neurons essential for brain activities like memory, learning and cognition. Dysfunctions of this process lead to developmental disorders and neurodegenerative diseases. KIF5A is a motor protein and associated with neuronal development and impacts various neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). The concept before our study was that, KIF5A primarily function in the mitochondrial transport to the long neurites from neuronal cell body in eukaryotes. Our study established that KIF5A is vital for neuronal differentiation by altering mitochondrial structure through rapid fission and fusion processes. Abundance of KIF5A protein during neuronal cell fate determination is maintained through epigenetic regulation of the KIF5A gene by reversible DNA methylation and histone 3 lysine 4 (H3K4) trimethylation. Retinoic acid induced differentiation activate FAK which downregulates DNMT1 and KDM5A, also observed by ectopic expression of FAK. DNMT1 and KDM5A conjointly repress KIF5A gene during early stage of neuronal differentiation i.e., in neuronal progenitors or NSCs and removal of this repressive burden reverse the effects.