Weiwei Dang, Ph.D.
Assistant Professor of Molecular and Human Genetics
CPRIT Scholar in Cancer Research
Assistant Professor, Huffington Center on Aging
Ph.D., Southern Illinois University, 2006
Postdoctoral fellow, University of Pennsylvania, 2011
Our laboratory is studying epigenetic regulation mechanisms during aging and oncogenesis. Aging is the single greatest risk factor for diseases that are principal causes of mortality, including cardiovascular diseases, diabetes, neurodegenerative diseases and infectious diseases. A breakthrough in aging research resulting in even a moderate retardation of aging and a delay in the onset of age-associated diseases, such as cancer, would have tremendous impact on the quality of life for the general public. However, aging and how it contributes to the development of age-associated diseases remain poorly understood. Epigenetic changes, including histone modifications and proteome, are critical regulatory mechanisms, involved in all developmental processes including aging and age-associated diseases. The goal of our research is to discover novel chromatin and proteomics regulation pathways that modulate longevity and regulate the development of age-associated diseases, such as cancer. This mechanistic study will form the basis in future development of therapeutic target for treating age-associated diseases and improving human health span.
Epigenetics generally includes all cellular alterations beyond genetic changes that result in observable phenotypes. In practice, epigenetics usually means persistent covalent alterations to chromatin, such as histone acetylation and DNA methylation. Recent proteomics and acetylomics studies have broadened our views of epigenetics and many more enzymes and factors can carry modifications that confer epigenetic phenomena. It is very clear now epigenetics represents a complex regulation network on top of the genetic code. In medicine, epigenetics holds a very promising future because interventions in epigenetics can alter genetic outcomes and the strength of such intervention can be fine-tuned.
Replicative aging of budding yeast has been a powerful system for aging studies, providing fundamental genetic and molecular insights into both cellular and organismal aging. Studies of chromatin biology have also immensely benefited from the yeast model, since it provides a uniquely tractable system for such studies and also because many molecular mechanisms of chromatin are highly conserved from yeast to complex eukaryotes. We use the budding yeast replicative aging as a model to study how epigenetic regulations can modulate longevity. In the past, we have shown that elevated levels of histone H4K16 acetylation near telomeres is a hallmark of old cells. It is regulated by a pair of enzymes Sir2 and Sas2 in yeast and is a causal factor in determining lifespan. Furthermore, through a series of unbiased lifespan screens and other high throughput systems biology approaches, we have identified more chromatin regulation pathways that seem to also alter lifespan. Such pathways include those involved in transcription regulation, DNA damage response, cellular stress response, chromatin compaction and heterochromatin formation, etc. Further studies are currently carried out in our lab to elucidate the molecular mechanisms and their causal relationship to aging.
Stem cell aging and cellular senescence are important processes that contribute to the aging pathology and development of cancer. As a complement to our yeast replicative aging model, we are using mammalian primary cell lines and adult stem cells to study whether and how chromatin and epigenetic regulation pathways identified in yeast are involved in stem cell aging and cellular senescence. Changes in aging and senescence phenotype are investigated by knocking down conserved enzymes. Epigenetic features are tracked during senescence and compared between young and old stem cells. Studying mechanistic conservation using mammalian cell models will provide valuable insights into mammalian aging and conditions predisposed to cancer development.
- Dang W (2012). The controversial world of sirtuins. Drug Discovery Today: Technologies, in press. Epub ahead of print
- Yuan H, Rossetto D, Mellert H, Dang W, Srinivasan M, Johnson J, Hodawadekar S, Ding EC, Speicher K, Abshiru N, Perry R, Wu J, Yang C, Zheng YG, Speicher DW, Thibault P, Verreault A, Johnson FB, Berger SL, Sternglanz R, McMahon SB, Côté J, Marmorstein R (2012). MYST protein acetyltransferase activity requires active site lysine autoacetylation. EMBO J. 31(1): 58-70. PubMed PMID: 22020126
- Edwards CR, Dang W, Berger SL (2011). Histone H4 lysine 20 of Saccharomyces cerevisiae is monomethylated and functions in subtelomeric silencing. Biochemistry 50(48): 10473-83. PubMed PMID: 21985125
- Kozak ML, Chavez A, Dang W, Berger SL, Ashok A, Guo X, Johnson FB (2010). Inactivation of the Sas2 histone acetyltransferase delays senescence driven by telomere dysfunction. EMBO J. 29(1): 158-70. PubMed PMID: 19875981
- Dang W, Steffen KK, Perry R, Dorsey JA, Johnson FB, Shilatifard A, Kaeberlein M, Kennedy BK, Berger SL (2009). Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459(7248): 802-7. PubMed PMID: 19516333
- Sanders BD, Jackson B, Brent M, Taylor AM, Dang W, Berger SL, Schreiber SL, Howitz K, Marmorstein R (2009). Identification and characterization of novel sirtuin inhibitor scaffolds. Bioorg. Med. Chem. 17(19): 7031-41. PubMed PMID: 19734050
- Lin YY, Lu JY, Zhang J, Walter W, Dang W, Wan J, Tao SC, Qian J, Zhao Y, Boeke JD, Berger SL, Zhu H (2009). Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis. Cell 136(6): 1073-84. PubMed PMID: 19303850
- Dang W, Bartholomew B (2007). Domain architecture of the catalytic subunit in the ISW2-nucleosome complex. Mol. Cell. Biol. 27(23): 8306-17. PubMed PMID: 17908792
- Dang W, Kagalwala MN, Bartholomew B (2007). The Dpb4 subunit of ISW2 is anchored to extranucleosomal DNA. J. Biol. Chem. 282(27): 19418-25. PubMed PMID: 17491017
- Dang W, Kagalwala MN, Bartholomew B (2006). Regulation of ISW2 by concerted action of histone H4 tail and extranucleosomal DNA. Mol. Cell. Biol. 26(20): 7388-96. PubMed PMID: 17015471
Weiwei Dang, Ph.D.
Huffington Center on Aging
Baylor College of Medicine
One Baylor Plaza, MS BCM230
Houston, TX 77030, U.S.A.