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Xiaoyong Yang, PhD

Professor

Contact Information

Xiaoyong Yang, PhD

Mailing Address

  • Comparative Medicine

    310 Cedar Street, PO Box 208016

    New Haven, CT 06520-8016

    United States

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Research Summary

Metabolism drives all biological processes, dysregulation of which fuels a plethora of human diseases including diabetes, obesity, cancer, aging, cardiovascular and neurodegenerative diseases. The long-range goal of our research is to unravel temporal and spatial regulation of metabolic pathways in response to environmental and genetic cues, and to design strategies to battle metabolic diseases. Diet and the light/dark cycle are principle environmental cues that control intermediary metabolism. Nutrient flux into the cell triggers the posttranslational modification of intracellular proteins by the amino sugar called N-acetylglucosamine (O-GlcNAc). Our first goal is to elucidate how O-GlcNAc acts as a molecular switch that couples nutrient cues to cellular regulation of signal transduction, transcription and protein degradation. Both light and diet affect the body’s circadian rhythms. Our second goal is to depict molecular pathways that couple the circadian clock to metabolic physiology. We are employing a combination of experimental approaches, including biochemistry, molecular and cellular biology, mouse genetics, genomics, proteomics and metabolomics, to accomplish our research goals.

Specialized Terms: Nutrient Sensing; Cell Signaling; Circadian Rhythm; Post-translational Modifications; Metabolic Physiology; Diabetes; Cancer; Aging; Systems Biology

Extensive Research Description

The long-range goal of our research is to understand signaling and transcriptional mechanisms governing metabolism in response to environmental and genetic cues, and to design strategies to battle metabolic diseases.

Diet and the day/night cycle are principle environmental cues that control intermediary metabolism. Nutrient flux into the cell triggers protein modification by the amino sugar called N-acetylglucosamine (O-GlcNAc). This dynamic and reversible posttranslational modification is emerging as a key regulator of diverse cellular processes. Our first goal is to elucidate how O-GlcNAc acts as a nutrient sensor to couple systemic metabolic status to cellular regulation of signal transduction, transcription, and protein degradation. It is crucial to understand how perturbations in this posttranslational modification contribute to human diseases including diabetes, obesity, cancer and aging.

Both diet and light affect the body’s circadian rhythms. Our second goal is to unravel molecular links between the circadian clock and metabolic physiology. On the basis of our finding of broad expression and tissue-specific oscillation of nuclear receptors, we would like to determine potential roles of nuclear receptors in integrating circadian signals from nutritional cues and the light-sensing central clock to entrain peripheral clocks, and in coupling peripheral clocks to divergent metabolic outputs. There are the emerging links between circadian rhythm disorders and diabetes, obesity, and cardiovascular disease. We plan to explore novel strategies for treating these interrelated diseases.

To approach these goals, a combination of cutting-edge tools are employed, including biochemistry, molecular and cellular biology, mouse genetics, genomics, proteomics, metabolomics, and physiology.

Positions are available in my lab for highly motivated graduate students and postdoctoral fellows who are interested in exploring the frontier of research on metabolic physiology.

Coauthors

Research Interests

Biochemistry; Circadian Rhythm; Diabetes Mellitus; Genetics; Molecular Biology; Neoplasms; Physiology; Signal Transduction; Genomics; Proteomics; Systems Biology

Selected Publications

  • Trefoil factor 2 secreted from damaged hepatocytes activates hepatic stellate cells to induce fibrogenesis.Zhang B, Lapenta K, Wang Q, Nam JH, Chung D, Robert ME, Nathanson MH, Yang X. Trefoil factor 2 secreted from damaged hepatocytes activates hepatic stellate cells to induce fibrogenesis. The Journal Of Biological Chemistry 2021, 297: 100887. PMID: 34146542, PMCID: PMC8267550, DOI: 10.1016/j.jbc.2021.100887.
  • IL-27 signalling promotes adipocyte thermogenesis and energy expenditure.Wang Q, Li D, Cao G, Shi Q, Zhu J, Zhang M, Cheng H, Wen Q, Xu H, Zhu L, Zhang H, Perry RJ, Spadaro O, Yang Y, He S, Chen Y, Wang B, Li G, Liu Z, Yang C, Wu X, Zhou L, Zhou Q, Ju Z, Lu H, Xin Y, Yang X, Wang C, Liu Y, Shulman GI, Dixit VD, Lu L, Yang H, Flavell RA, Yin Z. IL-27 signalling promotes adipocyte thermogenesis and energy expenditure. Nature 2021, 600: 314-318. PMID: 34819664, DOI: 10.1038/s41586-021-04127-5.
  • O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth.Singh JP, Qian K, Lee JS, Zhou J, Han X, Zhang B, Ong Q, Ni W, Jiang M, Ruan HB, Li MD, Zhang K, Ding Z, Lee P, Singh K, Wu J, Herzog RI, Kaech S, Wendel HG, Yates JR, Han W, Sherwin RS, Nie Y, Yang X. O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth. Oncogene 2020, 39: 560-573. PMID: 31501520, PMCID: PMC7107572, DOI: 10.1038/s41388-019-0975-3.
  • OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance.Yang Y, Li X, Luan HH, Zhang B, Zhang K, Nam JH, Li Z, Fu M, Munk A, Zhang D, Wang S, Liu Y, Albuquerque JP, Ong Q, Li R, Wang Q, Robert ME, Perry RJ, Chung D, Shulman GI, Yang X. OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 16616-16625. PMID: 32601203, PMCID: PMC7368321, DOI: 10.1073/pnas.1916121117.
  • O-GlcNAc transferase inhibits visceral fat lipolysis and promotes diet-induced obesity.Yang Y, Fu M, Li MD, Zhang K, Zhang B, Wang S, Liu Y, Ni W, Ong Q, Mi J, Yang X. O-GlcNAc transferase inhibits visceral fat lipolysis and promotes diet-induced obesity. Nature Communications 2020, 11: 181. PMID: 31924761, PMCID: PMC6954210, DOI: 10.1038/s41467-019-13914-8.
  • O-GlcNAc transferase suppresses necroptosis and liver fibrosis.Zhang B, Li MD, Yin R, Liu Y, Yang Y, Mitchell-Richards KA, Nam JH, Li R, Wang L, Iwakiri Y, Chung D, Robert ME, Ehrlich BE, Bennett AM, Yu J, Nathanson MH, Yang X. O-GlcNAc transferase suppresses necroptosis and liver fibrosis. JCI Insight 2019, 4 PMID: 31672932, PMCID: PMC6948774, DOI: 10.1172/jci.insight.127709.
  • Adipocyte OGT governs diet-induced hyperphagia and obesity.Li MD, Vera NB, Yang Y, Zhang B, Ni W, Ziso-Qejvanaj E, Ding S, Zhang K, Yin R, Wang S, Zhou X, Fang EX, Xu T, Erion DM, Yang X. Adipocyte OGT governs diet-induced hyperphagia and obesity. Nature Communications 2018, 9: 5103. PMID: 30504766, PMCID: PMC6269424, DOI: 10.1038/s41467-018-07461-x.
  • Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation.Ruan HB, Ma Y, Torres S, Zhang B, Feriod C, Heck RM, Qian K, Fu M, Li X, Nathanson MH, Bennett AM, Nie Y, Ehrlich BE, Yang X. Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation. Genes & Development 2017, 31: 1655-1665. PMID: 28903979, PMCID: PMC5647936, DOI: 10.1101/gad.305441.117.
  • Protein O-GlcNAcylation: emerging mechanisms and functions.Yang X, Qian K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nature Reviews. Molecular Cell Biology 2017, 18: 452-465. PMID: 28488703, PMCID: PMC5667541, DOI: 10.1038/nrm.2017.22.
  • Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation.Xie Z, Zhang D, Chung D, Tang Z, Huang H, Dai L, Qi S, Li J, Colak G, Chen Y, Xia C, Peng C, Ruan H, Kirkey M, Wang D, Jensen LM, Kwon OK, Lee S, Pletcher SD, Tan M, Lombard DB, White KP, Zhao H, Li J, Roeder RG, Yang X, Zhao Y. Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation. Molecular Cell 2016, 62: 194-206. PMID: 27105115, PMCID: PMC5540445, DOI: 10.1016/j.molcel.2016.03.036.
  • O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat.Ruan HB, Dietrich MO, Liu ZW, Zimmer MR, Li MD, Singh JP, Zhang K, Yin R, Wu J, Horvath TL, Yang X. O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell 2014, 159: 306-17. PMID: 25303527, PMCID: PMC4509746, DOI: 10.1016/j.cell.2014.09.010.
  • O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination.Li MD, Ruan HB, Hughes ME, Lee JS, Singh JP, Jones SP, Nitabach MN, Yang X. O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination. Cell Metabolism 2013, 17: 303-10. PMID: 23395176, PMCID: PMC3647362, DOI: 10.1016/j.cmet.2012.12.015.
  • O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability.Ruan HB, Han X, Li MD, Singh JP, Qian K, Azarhoush S, Zhao L, Bennett AM, Samuel VT, Wu J, Yates JR, Yang X. O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability. Cell Metabolism 2012, 16: 226-37. PMID: 22883232, PMCID: PMC3480732, DOI: 10.1016/j.cmet.2012.07.006.
  • Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance.Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, Kudlow JE, Michell RH, Olefsky JM, Field SJ, Evans RM. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 2008, 451: 964-9. PMID: 18288188, DOI: 10.1038/nature06668.
  • Nuclear receptor expression links the circadian clock to metabolism.Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, Mangelsdorf DJ, Evans RM. Nuclear receptor expression links the circadian clock to metabolism. Cell 2006, 126: 801-10. PMID: 16923398, DOI: 10.1016/j.cell.2006.06.050.
  • Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A: coupling protein O-GlcNAcylation to transcriptional repression.Yang X, Zhang F, Kudlow JE. Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A: coupling protein O-GlcNAcylation to transcriptional repression. Cell 2002, 110: 69-80. PMID: 12150998, DOI: 10.1016/s0092-8674(02)00810-3.
  • Regulation of the urea cycle by CPS1 O-GlcNAcylation in response to dietary restriction and aging.Wu J, Liu J, Lapenta K, Desrouleaux R, Li MD, Yang X. Regulation of the urea cycle by CPS1 O-GlcNAcylation in response to dietary restriction and aging. Journal Of Molecular Cell Biology 2022 PMID: 35285892, DOI: 10.1093/jmcb/mjac016.
  • The steroid hormone estriol (E3) regulates epigenetic programming of fetal mouse brain and reproductive tract.Zhou Y, Gu B, Brichant G, Singh JP, Yang H, Chang H, Zhao Y, Cheng C, Liu ZW, Alderman MH, Lu L, Yang X, Gao XB, Taylor HS. The steroid hormone estriol (E3) regulates epigenetic programming of fetal mouse brain and reproductive tract. BMC Biology 2022, 20: 93. PMID: 35491423, PMCID: PMC9059368, DOI: 10.1186/s12915-022-01293-4.
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