Access Type

Open Access Dissertation

Date of Award

January 2010

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Molecular Biology and Genetics

First Advisor

Derek E. Wildman

Abstract

Concomitant with an increase in brain volume and mass, the allocation of energetic resources to the brain increased during stem anthropoid evolution, leading to humans. One mechanism by which this allocation may have occurred is through greater use of lactate as a neuronal fuel. Both the production of lactate, and conversion to pyruvate for use in aerobic metabolism, are catalyzed, in part, by the tetrameric enzyme lactate dehydrogenase (LDH). The two primary LDH genes, LDHA and LDHB, confer different rates of substrate turnover to the LDH enzyme, and these rates lend to the argument that LDHA supports anaerobic while LDHB supports aerobic metabolism. The expression profiles of these proteins shifted during primate evolution, with LDHA and LDHB the primary LDH proteins expressed in strepsirrhine and anthropoid brains, respectively. We demonstrate that this expression shift does not coincide with changes to protein structure.

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Previous research has identified critical cis-regulatory elements within the LDHA promoter, demonstrating that transcriptional regulation is critical for proper expression of this gene. In this thesis, we characterize the promoters of LDHA and LDHB in primates, in order to determine the elements responsible for the expression shifts in brain during primate evolution. We identify motifs conserved across mammals, likely responsible for the common expression profiles. We also identify elements that were gained during different periods of primate evolution. Anthropoid-specific elements in the LDHA promoter include a modification of a known Sp1 site, as well as two putative repressor elements. Anthropoid-specific elements in the LDHB promoter include an oxidative phosphorylation element, which may coordinate aerobic metabolism pathways. In addition, both promoters have CpG sites conserved across mammals, which led us to hypothesize that species-specific and/or tissue-specific epigenetic modifications may have also changed during primate evolution. We conduct a cross-tissue, cross-species methylation analysis, and determine that CpG methylation patterns across tissues appear similar between human and dwarf lemur; however, methylation levels across species vary.

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