Chromatin remodeling as a guide to transcriptional regulatory networks in mammals

An important challenge of genome biology is a dissection of transcriptional regulatory networks that operate inside the nucleus during ontogeny and disease (Wyrick and Young [2002] Curr. Opin. Genet. Dev. 12:130). Limitations of existing experimental tools greatly complicate such analysis in the human genome: for example, genome-wide expression profiling of cells responding to a stimulus fails to reveal a majority of the genes involved in the functional network of responding to that stimulus [Giaver et al., 2002; Birrell et al., 2002]. This article discusses recent advances in analyzing mammalian transcriptional regulatory circuits [Nikiforov et al., 2002; Weinmann et al., 2002; Ren et al., 2000]. As evidenced by these and other data, paucity of information about the location of regulatory DNA elements in the human genome presents an obstacle to comprehensive transcription network analysis. It has been known since the late 1970s that chromatin over active regulatory DNA stretches is stably remodeled into "nuclease hypersensitive sites" [Elgin, 1988; Gross and Garrard 1988]. Massively parallel analysis of such remodeling in cell nuclei identifies regulatory DNA that is difficult to map comprehensively using other approaches, reveals genes poised for rapid activation, and offers a novel perspective on the "epigenome"--the regulatory program being executed by the genome in a given cell type.