Recent genome wide association studies (GWAS) have provided increased insight into the genetic basis of complex cardio-metabolic diseases (CMD) including type-2 diabetes and atherosclerotic cardiovascular diseases. Such discoveries, however, only explain a small proportion of the heritability suggesting genetic influences other than common DNA variation need to be considered. Knowledge of the transcriptome is essential for a more complete understanding of the inherited functional elements of the genome. The advent of high-throughput RNA sequencing (RNA-seq), including our work, demonstrates the existence of a far greater transcriptomic complexity and diversity than previously catalogued. The host response to endotoxin (LPS) provides fundamental insights into transcriptomic regulation of innate immunity while also serving as a model for inflammatory CMD. In the Genetics of Evoked-Responses to Niacin and Endotoxemia (GENE) study, we recruited healthy individuals (N=286) to an inpatient protocol and collected blood and adipose samples before and after administration of endotoxin (1ng/kg intravenously). Here, we propose to perform monocyte and adipose transcriptomic and epigenomic profiling during experimental human endotoxemia in order to discover tissue-specific mechanisms of human disease.
In Aim 1, we will utilize the clinical-inflammatory response in GENE participants to identify extreme """"""""low"""""""" (~<5%PC) and """"""""high"""""""" (~>95%PC) responders in order to detect endotoxin-induced transcriptomic responses of greatest clinical relevance.
In Aim 2, we will replicate LPS- induced transcriptomic changes, define the epigenetic regulation, and pursue clinical translation of replicated findings.
In Aim 3, we hypothesize that basal and endotoxin-evoked epigenome/transcriptome response in differentiated human induced pluripotent stem cells (hiPSC) from GENE participants will resemble that in primary cells and tissues. This proposal combines unique clinical resources, tissue-specific transcriptomics, and ex vivo profiling of hiPSC in order to identify heritable contribution to CMD, discover novel disease mechanisms and therapeutic opportunities, and advance innovation in the study of human disease.
Genome-wide association studies (GWAS) only explain a small proportion of the heritability of complex cardio-metabolic disease. Knowledge of the transcriptome is essential for more complete understanding of the functional elements of the genome. The focus of our translational transcriptomic proposal, applying deep RNA sequencing of human tissue, is identification of novel transcriptomic variations as mechanisms of tissue-specific genetic dysfunction in cardio- metabolic disease. These studies will reveal novel inherited mechanisms and therapeutic targets, beyond DNA variation, for complex cardio-metabolic disease.
|Zhang, Hanrui; Zhang, Nancy R; Li, Mingyao et al. (2018) First Giant Steps Toward a Cell Atlas of Atherosclerosis. Circ Res 122:1632-1634|
|Hu, Yu; Lin, Jennie; Hu, Jian et al. (2018) PennDiff: detecting differential alternative splicing and transcription by RNA sequencing. Bioinformatics 34:2384-2391|
|Huang, Mo; Wang, Jingshu; Torre, Eduardo et al. (2018) SAVER: gene expression recovery for single-cell RNA sequencing. Nat Methods 15:539-542|
|Westerterp, Marit; Fotakis, Panagiotis; Ouimet, Mireille et al. (2018) Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis. Circulation 138:898-912|
|Wang, Jingshu; Huang, Mo; Torre, Eduardo et al. (2018) Gene expression distribution deconvolution in single-cell RNA sequencing. Proc Natl Acad Sci U S A 115:E6437-E6446|
|Ferguson, Jane F; Xue, Chenyi; Gao, Yuanfeng et al. (2018) Tissue-Specific Differential Expression of Novel Genes and Long Intergenic Noncoding RNAs in Humans With Extreme Response to Evoked Endotoxemia. Circ Genom Precis Med 11:e001907|
|Zhang, Xuan; Xue, Chenyi; Lin, Jennie et al. (2018) Interrogation of nonconserved human adipose lincRNAs identifies a regulatory role of linc-ADAL in adipocyte metabolism. Sci Transl Med 10:|
|Zhang, Hanrui; Shi, Jianting; Hachet, Melanie A et al. (2017) CRISPR/Cas9-Mediated Gene Editing in Human iPSC-Derived Macrophage Reveals Lysosomal Acid Lipase Function in Human Macrophages-Brief Report. Arterioscler Thromb Vasc Biol 37:2156-2160|
|Zhang, Hanrui; Reilly, Muredach P (2017) LIPA Variants in Genome-Wide Association Studies of Coronary Artery Diseases: Loss-of-Function or Gain-of-Function? Arterioscler Thromb Vasc Biol 37:1015-1017|
|Zhang, Hanrui; Hinkle, Christine C; O'Neill, Sean M et al. (2017) Synergistic Modulation of Inflammatory but not Metabolic Effects of High-Fat Feeding by CCR2 and CX3CR1. Obesity (Silver Spring) 25:1410-1420|
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