Understanding the transcriptional programs that define cell type and regulate the inflammatory responses in macrophages and vascular endothelium is of central interest in understanding/preventing prevalent cardiovascular diseases. The molecular strategies that dictate these critical transcriptional programs reflect, in large part, the actions of dedicated repression """"""""checkpoints"""""""" and the functions of enhancers that modulate cell type-specific gene expression programs. How the programs dictated by an enhancer """"""""code"""""""" underlying such programs remains a fundamental question in regulatory and cardiovascular biology. Our studies under this Grant have linked integration of inflammatory and anti-inflammatory signaling pathways and inhibiting atherosclerosis, uncovering functionally-distinct pathways utilized by PPAR? and LXRs, and provided initial insights into the large programs of transrepression critical for blocking inflammatory pathways. Here, we will use genetic and epigenetic approaches to uncover the in vivo roles of dedicated enhancer networks in cardiovascular disease. We propose to focus on the molecular determinants of cel type-specific gene enhancer programs and three-dimensional genomic interaction networks that underlie developmental and newly discovered regulatory programs in the cardiovascular system and macrophages. We will link these programs to two important myocardial infarction susceptibility loci, based on results from genome-wide association studies (GWAS), providing an unprecedented opportunity, based on human genetic models, to further define and delineate the role of three-dimensional """"""""enhancer networks"""""""" and epigenetic strategies in development and disease of the cardiovascular system. These studies should provide a general approach to investigating disease susceptibility loci for many classes of disease.
Coronary artery disease, the predominant cause of myocardial infarction, is caused by coronary artery atherosclerosis, with an estimated 1.5 million Americans experiencing a coronary attack/infarction in 2009. Because atherosclerosis reflects both inflammatory and lipid metabolism disorder in which monocytes/macrophages play a central role in all phases of atherosclerosis, our proposal to link the discovery of the key regulated enhancer codes in tissues that underlie cardiovascular disease and regulation of their nuclear architecture to genome-wide association studies of susceptibility to coronary artery disease can provide new insights and approaches to the prevention and treatment of this major disease of the cardiovascular system.
|Wang, Jianxun; Saijo, Kaoru; Skola, Dylan et al. (2018) Histone demethylase LSD1 regulates hematopoietic stem cells homeostasis and protects from death by endotoxic shock. Proc Natl Acad Sci U S A 115:E244-E252|
|Wang, Jianxun; Telese, Francesca; Tan, Yuliang et al. (2015) LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nat Neurosci 18:1256-64|
|Telese, Francesca; Ma, Qi; Perez, Patricia Montilla et al. (2015) LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation. Neuron 86:696-710|
|Zhang, Feng; Tanasa, Bogdan; Merkurjev, Daria et al. (2015) Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program. Proc Natl Acad Sci U S A 112:1380-5|
|Puc, Janusz; Kozbial, Piotr; Li, Wenbo et al. (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160:367-80|
|Li, Wenbo; Hu, Yiren; Oh, Soohwan et al. (2015) Condensin I and II Complexes License Full Estrogen Receptor ?-Dependent Enhancer Activation. Mol Cell 59:188-202|
|Basnet, Harihar; Su, Xue B; Tan, Yuliang et al. (2014) Tyrosine phosphorylation of histone H2A by CK2 regulates transcriptional elongation. Nature 516:267-71|
|Liu, Zhijie; Merkurjev, Daria; Yang, Feng et al. (2014) Enhancer activation requires trans-recruitment of a mega transcription factor complex. Cell 159:358-73|
|Skowronska-Krawczyk, Dorota; Ma, Qi; Schwartz, Michal et al. (2014) Required enhancer-matrin-3 network interactions for a homeodomain transcription program. Nature 514:257-61|
|Li, Wenbo; Notani, Dimple; Ma, Qi et al. (2013) Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498:516-20|
Showing the most recent 10 out of 35 publications