Assistant Professor, Department of Anatomy & Structural Biology
Nanoscale probing of gene expression
A number of devastating human diseases arise from aberrant protein-coding gene expression in cells. Indeed, precise gene expression in humans is tightly controlled. This process requires highly coordinated interactions between the transcription initiation machinery and specific activators to ensure proper response to various physiological stimuli. The development of potent and novel disease treatments demands a nanoscale and fundamental understanding of how the transcription machinery and activators interact to initiation gene expression programs that direct cell growth/death, differentiation, aging, etc. in human cells. Therefore, the principal focus of our work is to interrogate how protein-coding genes are transcribed at the early stage of gene expression in human cells in order to express a number of critical factors that participate in diverse cellular processes including stem cell-/cell type- specific differentiation, proliferation, cell cycle arrest, and apoptosis.
To accurately transcribe a gene, a pre-initiation complex (PIC) is required to form at specific regions of the promoter DNA. TFIID is a principal component within the transcriptional machinery responsible for recognizing and binding specific promoter DNA. TFIID directs a recruitment of eight other basal transcription complexes including TFIIA and RNA Polymerase II to produce RNA from an accurate, discrete location of a gene. In order to properly respond to various physiological cues, sequence-specific DNA binding activators act as key regulators of gene expression to stimulate transcription, in part by targeting TFIID and aiding in its recruitment to promoter DNA.
We currently use a combination of high-resolution single particle electron microscopy (cryo-EM), high-precision single molecule microscopy, and a number of biochemical assays to visualize several distinct human mega-Dalton size macromolecule transcription assemblies during activated transcription initiation involved in tumor suppression, embryonic stem cell differentiation, and ovarian development.
Key Words: gene expression, transcription, TFIID, single particle cryo-EM imaging
1. Liu WL, Coleman RA, Ma E, Grob P, Yang JL, Dailey G, Nogales E, and Tjian R. (2009) Structures of three distinct activator-TFIID complexes. Genes & Development 23(13):1510-21.
2. Liu WL, Coleman RA, Grob P, King DS, Florens L, Washburn MP, Geles KG, Yang JL, Ramey V, Nogales E, and Tjian R. (2008) Structural changes in TAF4b-TFIID correlate with promoter selectivity. Molecular Cell 29: 81-91.
3. Geles KG, Freiman RN, Liu WL, Zheng S, Voronina E, and Tjian R. (2006) Cell type- selective induction of c-Jun by TAF4b directs ovarian-specific transcription networks. Proc Natl Acad Sci U S A.103(8):2594-9.
4. Liu WL, Midgley C, Stephen CW, Saville M, and Lane DP. (2001) Biological significance of a small highly conserved region in the N-terminus of the p53 tumour suppressor protein. Journal of Molecular Biology 313(4): 711-731.
5. Bottger A, Bottger V, Sparks A, Liu WL, Howard SF, and Lane DP. (1997) Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo. Current Biology 7: 860-869.
6. Hsu YS, Tang FM, Liu WL, Chung JY, Lai MY, and Lin YS. (1995) Transcriptional Regulation by p53- Functional interactions among multiple regulatory domains. The Journal of Biological Chemistry 270: 6966-6974.
More Information About Dr. Wei-Li Liu
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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Forchheimer Building, Room 628D
Bronx, NY 10461