The effect of intrauterine growth restriction on ATP citrate lyase and elastin histone acetylation in rat lung
T h e U n i v e r s i t y o f U t a h G r a d u a t e S c h o o l STATEMENT OF THESIS APPROVAL The thesis of Sara Jane Shupe Fausett has been approved by the following supervisory committee members: Lisa A. Joss-Moore , Chair ABSTRACT Intrauterine growth restriction (IUGR) increases risk of neonatal lung disease. In animal models, the predisposition to neonatal lung disease is associated with a decrease in elastin production. Production of elastin is necessary for development of the lung.
... of the lung. Cellular expression of elastin is encoded by the elastin gene. The expression of the elastin gene is modified by histone acetylation. Histone acetylation is made possible by the enzyme ATP-citrate lyase (ACL) in the nucleus, which provides Acetyl-CoA groups to acetylate histones. However, it is unknown whether IUGR is associated with changes in ACL mRNA and protein levels, global histone acetylation patterns, or elastin histone acetylation patterns. We hypothesize that IUGR will decrease ACL mRNA and protein levels and decrease global and elastin acetylation patterns. IUGR was induced by bilateral uterine artery ligation in Sprague Dawley rat dams at E19 of gestation. Lung tissue was collected from newborn control and IUGR rat offspring and ACL mRNA was quantified using real-time RT-PCR, ACL protein levels were quantified by Western blotting, global and elastin specific acetylation patterns were quantified using Western blotting and chromatin immunoprecipitation. Results are IUGR as % of sex matched control ± SD. IUGR decreased ACL mRNA levels in male and female IUGR rats (44 ± 8 and 75 ± 16, respectively) and ACL protein levels in male IUGR rats (32 ± 13). IUGR decreased ACL protein levels in the cytoplasm for males (92 ± 16) and in the nucleus for females (67 ± 25). Global histone acetylation patterns are decreased in males only (73 ± 13). Elastin specific acetylation patterns are decreased only in females (promoter 71 ± 13, exon 24 78 ± 16, and exon 33 48 ± 11). We conclude that IUGR sex specifically affects ACL mRNA and protein levels and global histone and elastin histone acetylation patterns in newborn rat lung. We speculate that, in female rat lung, decreased elastin is associated with decreased nuclear ACL protein levels. To my loving husband and supportive family, thank you for all of your patience and love.