Date of Award


Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Stephen M Strittmatter


Spinal Muscular Atrophy (SMA) is an inherited neuromuscular disorder caused by mutation of the Survival Motor Neuron (SMN1) gene. Embryonic lethality is rescued by a nearly identical copy of the gene, SMN2, which exists in variable copy number and produces a small quantity of functional SMN protein. Because disease severity inversely correlates with SMN2 gene copy number and with SMN protein level, one therapeutic strategy has been to increase SMN2 expression. Previous investigators have demonstrated that SMN promoter activity, transcript, and SMN protein are increased in cells treated with histone deacetylase (HDAC) inhibitors, suggesting a role for histone acetylation in the regulation of SMN expression. To further investigate epigenetic regulation of SMN, we used chromatin immunoprecipitation to characterize the acetylation state of histones associated with the SMN promoter locus. We show that the SMN promoter has a reproducible pattern of histone acetylation conserved across species and tissues. Following treatment with HDAC inhibitors, we correlated a 2-fold increase in SMN promoter activity, with an increase in H3 and H4 histone acetylation, particularly in upstream regions 2-3 kb from the translational initiation site. During development in mouse tissues, SMN transcript decreased 40-60%, correlating with a decrease in histone acetylation levels within the region closest to the transcriptional start site. These data indicate that histone acetylation is a biologically relevant determinant of SMN gene expression, and that this epigenetic variable can be manipulated pharmacologically.