1. ¹Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, The Advanced Technology Center, Bethesda, MD, USA
2. ²Meso Scale Discovery, Gaithersburg, MD, USA
3. ³Clinical Immunology Section, Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, Baltimore, MD, USA

Correspondence: Dr K Gardner, Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, The Advanced Technology Center, Room 133, 8717 Grovemont Circle, Bethesda, MD 20892-4605, USA. Tel: +1 301 496 1055; Fax: +1 301 435 7558; E-mail: gardnerk@mail.nih.gov

Received 23 February 2005; Revised 17 May 2005; Accepted 8 June 2005; Published online 26 July 2005.

Abstract

The blueprint for cellular diversity and response to environmental change is encoded in the cis-acting regulatory sequences of most genes. Deciphering this 'cis-regulatory code' requires multivariate data sets that examine how these regions coordinate transcription in response to diverse environmental stimuli and therapeutic treatments. We describe a transcriptional approach that profiles the activation of multiple transcriptional targets against combinatorial arrays of therapeutic and signal transducing agents. Application of this approach demonstrates how cis-element composition and promoter context combine to influence transcription downstream of mitogen-induced signaling networks. Computational dissection of these transcriptional profiles in activated T cells uncovers a novel regulatory synergy between IGF-1 and CD28 costimulation that modulates NF-B and AP1 pathways through signaling cascades sensitive to cyclosporin A and wortmannin. This approach provides a broader view of the hierarchical signal integration governing gene expression and will facilitate a practical design of combinatorial therapeutic strategies for exploiting critical control points in transcriptional regulation.