Histone post-translational modification (PTM, or histone mark) is critical to dynamic modulation of chromatin structure and function. Dysregulation of histone modification processes contributes to the development of many diseases, such as cancer, cardiovascular and neurological diseases. We recently reported a new, evolutionarily-conserved histone mark, lysine 2-hydroxyisobutyrylation (Khib). We showed that Khib is present among 63 histone lysine residues in both human and mouse, more than the known numbers of the widely studied histone acetylation (Kac) and methylation (Kme) sites. We also obtained multiple lines of evidence that suggest important and unique biological functions of histone Khib: this class of histone modification shows distinct genomic distributions from the widely studied histone Kac during male germ cell differentiation; it is associated with active gene transcription and H4K8hib is a better indicator for high gene expression than its corresponding H4K8ac; histone Khib can direct in vitro transcription in a manner dependent on 2-hydroxyisobutyryl CoA, suggesting that histone Khib impacts chromatin structure and transcriptional activity; histone Khib has different profiles between transcriptionally active and transcriptionally silent chromatin in Tetrahymena thermophile, in different cell cycle stages, and during mouse spermotogenesis. These results suggest that histone Khib is structurally and mechanistically different from histone Kac. The major players regulating histone Khib pathway would break new ground in epigenetic research and improve our understanding of cellular physiology and human disease. In the proposed research, we will study histone Khib pathway using an integrated approach. We will identify histone Khib-regulatory enzymes and direct binding proteins of histone Khib marks. We will also investigate genomic distributions of key histone Khib marks in mouse genome, and compare these data with those of the well-studied histone acetylation and methylation marks. Our team is well positioned to carry out this project, because of our extensive expertise in the areas of epigenomics, biochemistry, proteomics, stem cell biology, and the tremendous preliminary results we generated. This study will overcome a major hurdle to study biology of histone Khib pathway by revealing key regulatory elements and likely characterize novel epigenetic mechanisms, perhaps analogous to the characterization of histone Kac and Kme pathways.
This project will use a systems-biology approach to investigate the epigenetic function of histone lysine 2-hydroxyisobutyrylation and identify key molecules that mediate this function in embryonic stem cells and their differentiation. Molecular understanding of this type of histone mark may help understand epigenetic mechanism and its roles in diverse diseases such as cardiovascular, cancer, diabetes, and immune disorders.
| Huang, He; Tang, Shuang; Ji, Ming et al. (2018) EP300-Mediated Lysine 2-Hydroxyisobutyrylation Regulates Glycolysis. Mol Cell 70:663-678.e6 |
| Local, Andrea; Huang, Hui; Albuquerque, Claudio P et al. (2018) Identification of H3K4me1-associated proteins at mammalian enhancers. Nat Genet 50:73-82 |
| Huang, He; Zhang, Di; Wang, Yi et al. (2018) Lysine benzoylation is a histone mark regulated by SIRT2. Nat Commun 9:3374 |
| Huang, He; Tang, Shuang; Ji, Ming et al. (2018) p300-Mediated Lysine 2-Hydroxyisobutyrylation Regulates Glycolysis. Mol Cell 70:984 |
| Kaczmarska, Zuzanna; Ortega, Esther; Goudarzi, Afsaneh et al. (2017) Structure of p300 in complex with acyl-CoA variants. Nat Chem Biol 13:21-29 |
| Huang, Jing; Luo, Zhouqing; Ying, Wantao et al. (2017) 2-Hydroxyisobutyrylation on histone H4K8 is regulated by glucose homeostasis in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 114:8782-8787 |
| Sabari, Benjamin R; Zhang, Di; Allis, C David et al. (2017) Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol 18:90-101 |
| Aramsangtienchai, Pornpun; Spiegelman, Nicole A; He, Bin et al. (2016) HDAC8 Catalyzes the Hydrolysis of Long Chain Fatty Acyl Lysine. ACS Chem Biol 11:2685-2692 |
| Xie, Zhongyu; Zhang, Di; Chung, Dongjun et al. (2016) Metabolic Regulation of Gene Expression by Histone Lysine ?-Hydroxybutyrylation. Mol Cell 62:194-206 |
| Goudarzi, Afsaneh; Zhang, Di; Huang, He et al. (2016) Dynamic Competing Histone H4 K5K8 Acetylation and Butyrylation Are Hallmarks of Highly Active Gene Promoters. Mol Cell 62:169-180 |
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