Despite the utility of the mouse and other non-primate vertebrates in studying human lipid metabolism, many human metabolic features are best modeled in primates, particularly our response to dietary cholesterol. The differential regulation of genes involved in cholesterol homeostasis in humans and mice is believed to significantly contribute to differences in response to dietary cholesterol between these species. We have previously shown that sequence comparisons of multiple primate species are successful at identifying functional elements specific to primates and complement traditional sequence comparisons with non-primate mammals, such as between human and mouse. Accordingly, the goal of this proposal is to couple multiple primate sequence comparisons with functional studies to discover primate-specific regulatory elements impacting on lipid metabolism. This will include the analysis of several genes participating in lipid metabolism, with an emphasis on the dissection of the transcriptional network of the nuclear hormone receptor LXR-a and its target genes, crucial regulators of cholesterol homeostasis which appear to have differential regulation in human and mouse. We will: 1) identify and functionally characterize regulatory sequences preferentially conserved in the primate lineage through the comparative analysis of large genomic intervals containing known """"""""lipid"""""""" genes;2) identify and functionally characterize primate specific transcription factor binding sites in both known and computationally predicted regulatory elements shared between primates and non-primate mammals;and 3) investigate the function of primate-specific regulatory sequences on their neighboring human genes in cell culture and in vivo studies and determine their contribution to primate-specific phenotypes. These studies will provide genomically derived insights into the clinically relevant regulation of cholesterol homeostasis and contribute to our understanding of primate-specific responses to environmental stimuli. The mouse, while a valuable model of human diseases such as plasma lipid disorders leading to atherosclerosis, has many differences from human, with the immediate consequence that many drugs first tested successfully in mice fail in later clinical studies in humans. In this proposal, we plan to identify segments of the human genome which determine differences in plasma lipid metabolism between human and mouse. Discovery of this kind of molecular genomic structures will shed new light into the pathogenic mechanisms leading to human lipid disorders, promising to lead to the engineering of better mouse models for this important human disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084474-04
Application #
7799857
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2007-04-04
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$402,500
Indirect Cost
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609
Yamtich, Jennifer; Heo, Seok-Jin; Dhahbi, Joseph et al. (2015) piRNA-like small RNAs mark extended 3'UTRs present in germ and somatic cells. BMC Genomics 16:462
Takayama, Sachiko; Dhahbi, Joseph; Roberts, Adam et al. (2014) Genome methylation in D. melanogaster is found at specific short motifs and is independent of DNMT2 activity. Genome Res 24:821-30
Dhahbi, Joseph M; Atamna, Hani; Boffelli, Dario et al. (2012) mRNA-Seq reveals complex patterns of gene regulation and expression in the mouse skeletal muscle transcriptome associated with calorie restriction. Physiol Genomics 44:331-44
Boffelli, Dario; Martin, David I K (2012) Epigenetic inheritance: a contributor to species differentiation? DNA Cell Biol 31 Suppl 1:S11-6
Meacham, Frazer; Boffelli, Dario; Dhahbi, Joseph et al. (2011) Identification and correction of systematic error in high-throughput sequence data. BMC Bioinformatics 12:451
Dhahbi, Joseph M; Atamna, Hani; Boffelli, Dario et al. (2011) Deep sequencing reveals novel microRNAs and regulation of microRNA expression during cell senescence. PLoS One 6:e20509
Martin, David I K; Singer, Meromit; Dhahbi, Joseph et al. (2011) Phyloepigenomic comparison of great apes reveals a correlation between somatic and germline methylation states. Genome Res 21:2049-57
Singer, Meromit; Boffelli, Dario; Dhahbi, Joseph et al. (2010) MetMap enables genome-scale Methyltyping for determining methylation states in populations. PLoS Comput Biol 6:e1000888