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Lab Location: #5-14
email:
yluo@imcb.a-star.edu.sg
tel:65869592
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R.-P. Dai, F-X. Yu, S.-R. Goh, Y.-L. Tan, J.-L. Fu, L. Zheng & Y. Luo. 2007. Oscillated NAD+/NADH redox signaling regulates histone expression and S-phase progression. Nature Structural & Molecular Biology; submitted.
L. Zheng, R. G. Roeder & Y. Luo. 2003. S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Cell 114: 255-266.
R. Casellas, M. Jankovic, G. Meyer, A. Gazumyan, Y. Luo, R.G. Roeder & M.C. Nussenzweig. 2002. OCA-B is required for normal transcription and V(D)J recombination of a subset of immunoglobulin k genes. Cell 110: 575-585.
U. Kim, X.-F. Qin, S. Gong, S. Stevens, Y. Luo, M.C. Nussenzweig & R.G. Roeder. 1996. The B-cell-specific transcription coactivator OCA-B/OBF-1/Bob-1 is essential for the normal production of immunoglobulin isotypes. Nature 383: 542-547.
Y. Luo & R.G. Roeder. 1995. Cloning, functional characterization, and mechanism of action of the B-cell-specific transcriptional coactivator OCA-B. Molecular and Cellular Biology 15: 4115-4124.
Y. Luo, H. Fujii, T. Gerster, & R.G. Roeder. 1992. A novel B cell-derived coactivator potentiates the activation of immunoglobulin promoters by octamer-binding transcription factors. Cell 71: 231-241.
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Luo YAN |
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Luo Yan obtained his undergraduate education in China with the genetics major. Afterwards he went to the US to obtain a PhD in biochemistry. His post-doctoral years were mentored by Bob Roeder, focusing on a gene regulation pathway of the immune system and culminating in discovery of a B cell specific transcription co-activator OCA-B. He was promoted to the junior faculty at the Rockefeller University in 1997, switched research interest to cell cycle, and discovered an S-phase transcription co-activator OCA-S. He moved to IMCB in 2004 to become a principal investigator in the Laboratory of Gene Expression and Regulatory Biology.
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Transcription machineries and mechanisms involved in histone expression |
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OCA-S is an Oct-1 co-activator involved in the S-phase-specific histone 2B (H2B) transcription. Its characterization at the time (Zheng et al., 2003, Cell 114: 255-266) was provocative, for the OCA-S components include the glycolytic enzymes p38/GAPDH and p36/LDH. Intriguingly, the OCA-S function in vitro was modulated by NAD(H), implying an in vivo linkage of the activity to redox status and/or metabolic states of a cell. The multi-component OCA-S is anchored to the H2B promoter via a direct interaction between Oct-1 and p38/GAPDH; this interaction is redox sensitive and thus may be a key step towards regulating the OCA-S function in living cells. It is this issue that has been further addressed by our research team.
By changing the redox balance, we demonstrated that the H2B transcription in vivo required a proper redox status, dubbed as a "window" at which the H2B transcription is optimal. Intriguingly, the NAD/NADH ratio naturally fluctuates during cell cycle with oscillatory H2B expression, thus defining an S-phase “redox window” within which OCA-S occupies the H2B promoter with p38/GAPDH being a central (nucleating) component. This is in line with an in vitro NAD(H)-modulated OCA-S function. Importantly, transcription of other histone genes in vivo is sensitive to the redox status as well, hence suggesting a direct coordination mechanism by which cell cycle-related differences in the NAD/NADH redox status and/or cellular metabolism are coupled to alterations of the histone expression program.
Having resolved issues relating to the significance of the redox for OCA-S activity in vivo and the major redox target--p38/GAPD—for regulation of the activity, we wish to ask if the H2B promoter recruitment is the only step at which the redox plays a role in H2B transcription. More recent study suggests that p36/LDH is also essential for in vivo H2B transcription and that the OCA-S-associated p36/LDH possesses an intrinsic enzymatic activity that re-oxidizes NADH to NAD. This modulated redox status is sensed by p38/GAPDH to bring about an increased H2B transcriptional output in vitro, thus a proposition of redox modulator/sensor roles of the two OCA-S constituents for OCA-S function thus H2B transcription. We plan to use p36/LDH and p38/GAPDH mutants to analyze moonlighting functions of the two classical enzymes on histone (H2B) transcription, by taking advantage of both in vitro and cell assay systems.
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