Robert Tjian

Howard Hughes Investigator and Professor of Biochemistry and Molecular Biology*
*And Affiliate, Division of Genetics and Development

Full Directory Information

Research Interests

Decipher mechanisms of eukaryotic transcription that control stem cell pluripotency, differentiation and disease.

Current Projects

Biochemistry of Transcription and Chromatin Transactions: Over the past 20 years, our lab has identified, isolated and characterized a large number (~100) of essential drosophila and human transcription factors. These regulatory proteins that include enhancer/promoter recognition factors, core RNA pol II initiation factors and co-activators form large multi-subunit complexes at promoter DNA to mediate transcription initiation and decode the genome. Our recent studies indicate that large co-activator complexes play a critical role in mediating both universal as well as cell type specific networks of gene transcription and can serve as the interface between transcription and chromatin regulation. Although our early studies focused on in vitro biochemistry and conventional molecular genetics approaches, our current research is directed at the more challenging task of integrating specific molecular transactions with in vivo mechanisms in cells and whole organisms under physiologically relevant conditions. Single Cell Biochemistry, Structural Biology and Single Molecule Measurements: In order to address in vivo function and mechanism of transcriptional control we will be using a combination of structural biological methods such as cryo EM/3D particle reconstruction, X-ray crystallography and single molecule measurements. Another recent effort has been to develop strategies for measuring the assembly and movement of transcription complexes at the single cell level. These studies aim to track the movement and function of target transcription factors in live cells by various optical methods. In addition, we continue to utilize tools such as siRNA mediated knockdown of transcription factors as well as in vitro reconstitution of regulated transcription to link specific molecular mechanisms of control with in vivo physiology. Transcription Mechanisms in Stem Cells and Disease: Diabetes, Cancer, Huntington's and Parkinsons: Our multi-pronged experimental strategy has subsequently allowed us to tackle various disease mechanisms that strongly implicate transcriptional regulation. For example, we recently completed a study revealing the mechanism by which the mutant Htt protein (responsible for Huntington's, a glutamine expansion neuro-degenerative disease) disrupts specific interactions between the human transcription factor Sp1 and its' target co-activator. We are also deciphering mechanisms of transcriptional disregulation in the insulin signaling pathway controlled by the transcription factor FOXO. This regulator mediates a novel feedback control of the insulin receptor via a unique IRES dependent coupling of transcription and translation. Another rapidly growing area of research in our lab has been the analysis of transcription factors that control embryonic stem cells to either maintain the pluripotent state and self renewal (Oct4, Nanog, Sox2) or that direct cellular differentiation. In particular, we have focused on the transcription factor Lmxla which appears to be a key regulator that drives the differentiation of dopaminergic neurons implicated in Parkinsons disease. A major effort in the lab has been to generate molecular reagents and tools to specifically identify transcriptional regulators that direct gene expression profiles in differentiated cells including muscle, neurons and ovarian follicle cells. Using techniques such as ChIP-sequence analysis, systematic RNAi mutagenesis, transgenic animals or cells and in vitro transcription assays, we have developed complimentary experimental strategies to dissect in vivo mechanisms of transcriptional regulation and tease out how these various protein/DNA and protein/protein transactions influence gene expression and diseases.

Selected Publications

Ping Hu, Kenneth G. Geles Ji-Hye Paik, Ronald A. DePinho, and Robert Tjian. (2008) Co-dependent Activators Direct Myoblast Specific MyoD Transcription. Dev Cell in press Maria Divina E. Deato1 Michael T. Marr, Theo Sottero, Carla Inouye, Ping Hu1 and Robert Tjian (2008) MyoD targets TAF3 /TRF3 to activate Myogenin transcription. Mol Cell in press.

Wei-Li Liu, Robert A. Coleman, Patricia Grob, Kenneth G. Geles, David S King, Vincent Ramey, Eva Nogales, and Robert Tjian, (2008) "Structural changes in TAF4b-TFIID correlate with promoter selectivity" Mol. Cell 29(1):81-91.

Maria Divina E. Deato and Robert Tjian (2007) " Switching of the core transcription machinery during myogenesis. " Genes & Dev. 21:17, 2137-2149.

Lemon, B., Inouye, C., King, D.S., and Tjian, R. (2001) Selectivity of chromatin-remodelling cofactors for ligand-activated transcription. Nature 414, 924-928.

Freiman, R., Albright, S., Zheng, S., Sha, W., Hammer, R. and Tjian, R. (2001) Tissue-selective TBP-associated factor TAFII105 is essential for ovarian development. Science 293, 2084-2087.

Last Updated 2008-09-12