Neuronal Differentiation Is Regulated by Leucine-rich Acidic Nuclear Protein (LANP), a Member of the Inhibitor of Histone Acetyltransferase Complex

Abstract

Neuronal differentiation is a tightly regulated process characterized by temporal and spatial alterations in gene expression. A number of studies indicate a significant role for histone acetylation in the regulation of genes involved in development. Histone acetylation is regulated by histone deacetylases and histone acetyltransferases. Recent findings suggest that these catalytic activities, in turn, are modulated by yet another set of regulators. Of considerable interest in this context is the possible role of the INHAT (inhibitor of histone acetyltransferase) complex, comprised of a group of acidic proteins that suppress histone acetylation by a novel "histone-masking" mechanism. In this study, we specifically examined the role of the leucine-rich acidic nuclear protein (LANP), a defining member of the INHAT complex whose expression is tightly regulated in neuronal development. We report that depleting LANP in neuronal cell lines promotes neurite outgrowth by inducing changes in gene expression. In addition, we show that LANP directly regulates expression of the neurofilament light chain, an important neuron-specific cytoskeletal gene, by binding to the promoter of this gene and modulating histone acetylation levels. Finally, we corroborated our findings in vivo by demonstrating increased neurite outgrowth in primary neurons obtained from LANP null mice, which is also accompanied by increased histone acetylation at the NF-L promoter. Taken together, these results implicate INHATs as a distinct class of developmental regulators involved in the epigenetic modulation of neuronal differentiation.Development of the nervous system is a well coordinated process that relies on the ability of neurons to differentiate, migrate, extend neurites, and form synapses. Each of these events is regulated by a series of intracellular events that are choreographed by alterations in gene expression. It is becoming increasingly clear that gene expression is regulated not only by the transcriptional machinery per se, but also by chromatin modifications, in particular alterations in DNA methylation and post-translational modifications of histone tails (1, 2).One of the best characterized modifications of histone tails is the dynamic acetylation of the N-terminal domains of histones on a few specific lysine residues (2). Histone acetylation has been traditionally thought to be regulated by a fine balance of two classes of enzymes: histone acetyltransferases (HATs) 2 that incorporate acetyl groups into specific lysine residues of histone tails; and histone deacetylases (HDACs) that reverse these marks (2). Histone acetylation correlates remarkably well with increases in gene expression, both by altering the conformation of chromatin, and also by creating a primed platform for the docking of factors that enable gene expression.There is considerable evidence, both pharmacologic and genetic, for the role of HATs and HDACs in normal differentiation. For instance, drugs that inhibit HDACs affect the ability of cell lines to differentiate...

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