Richard Goodman, M.D., Ph.D.

Background

Richard Goodman is director of the Vollum Institute. He also holds appointments as professor of Cell and Developmental Biology and Biochemistry and Molecular Biology. After receiving his B.S. degree in Chemistry at the Massachusetts Institute of Technology, he entered the Medical Scientist Training Program at the University of Pennsylvania. He received his M.D. and Ph.D. degrees in 1976. Goodman trained in clinical medicine at Tufts-New England Medical Center from 1976 to 1978 and was an endocrinology fellow at New England Medical Center and Massachusetts General Hospital. He was appointed as an assistant professor of Medicine at Harvard Medical School in 1982 and returned to Tufts-New England Medical Center in 1983, where he rose to the rank of professor of Medicine and chief of the Division of Molecular Medicine. He has been at the Vollum since 1990.

Summary of Current Research

The major focus of the Goodman lab is to determine how extracellular and intracellular signals are integrated to control the onset and level of gene expression. The cAMP-regulated enhancer (CRE), initially identified in the Goodman lab, is now recognized to be a critical control element in many genes expressed in the nervous system and other tissues. The presence of this element in multiple gene promoters provides a mechanism that may allow the coordinate regulation of various patterns of gene expression. Transcriptional signals mediated by the CRE depend upon the transcription factor CREB, which is activated through a variety of signaling pathways including cAMP, calcium, and growth factors. Phosphorylation of a single site in the CREB activation domain leads to the recruitment of the CREB binding protein, CBP, which was also identified in the Goodman lab. CBP was the first example in metazoans of a transcriptional coactivator and has been shown to participate in virtually all positively-regulated transcriptional pathways. Thus, one can imagine a hierarchy in which multiple phosphorylation-dependent signaling pathways activate CREB, and multiple transcription factors, activated by an even wider variety of signaling events, recruit CBP. Not surprisingly, perturbation of CBP function has profound effects on cell growth, differentiation, and development. CBP activates gene expression through at least two mechanisms—by directing the recruitment of basal transcription factors to the promoter and by reversing the repressive effects of chromatin. A few years ago, the lab developed an approach called Serial Analysis of Chromatin Occupancy (SACO) to identify transcription factor binding sites in vivo. This method showed that, in addition to protein-coding genes, CREB regulates many genes that do not encode proteins. Among this group are microRNAs that have important roles in controlling gene expression at the post-transcriptional level. The lab provided the first evidence for microRNAs modulating synaptic plasticity and is developing novel methods to identify microRNA targets in the brain, heart, and other tissues.

Selected Publications

Wayman, G.A., Davare, M., Ando, H., Fortin, D., Varlamova, O., Cheng, H.Y., Marks, D., Obrietan, K., Soderling, T.R., Goodman, R.H., and Impey, S. (2008) An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc. Natl. Acad. Sci. USA 105:9093-9098.

Yochum, G.S., Cleland, R., and Goodman, R.H. (2008) A genome-wide screen for ß-catenin binding sites identifies a downstream enhancer element that controls c-myc gene expression. Mol. Cell. Biol. 28:7368-7379.

Klein, M.E., Lioy, D.T., Ma, L., Impey, S., Mandel, G., and Goodman, R.H. (2007) Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nature Neurosci. 10:1513-1514.

Vo, N., Klein, M.E., Varlamova, O., Keller, D.M., Yamamoto, T., Goodman, R.H., and Impey, S. (2005) A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc. Natl. Acad. Sci. USA 102:16426-16431.

Impey, S., McCorkle, S.R., Cha-Molstad, H., Dwyer, J.M., Yochum, G.S., Boss, J.M., McWeeney, S., Dunn, J.J., Mandel, G., and Goodman, R.H. (2004) Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119:1041-1054.

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