Karen Adelman, Ph.D.
The Adelman laboratory is interested in the regulation of gene expression and chromatin structure in response to specific environmental and developmental signals. By elucidating the fundamental molecular basis for transcriptional responses to extracellular cues, we aim to provide insights into gene-environment interactions during the maintenance of homeostasis and reaction to injury, as well as during development.
Our laboratory has discovered that many genes in stimulus-responsive networks are regulated differently than housekeeping genes. Prior to activation, RNA polymerase II (Pol II) is recruited to these genes and initiates RNA synthesis, but transcription elongation pauses within the first hundred nucleotides. Upon gene activation, this paused Pol II is rapidly released from the promoter-proximal region into the gene, allowing for extremely efficient and robust RNA synthesis. This form of transcription regulation, called promoter-proximal pausing or stalling, had previously been described at several stimulus-responsive genes, but had been presumed to be a rare phenomenon. In contrast to this expectation, our recent results reveal that Pol II pausing is widespread in metazoans, and plays a key role in cellular responses to both environmental and developmental signals. These findings challenge the current paradigms for how gene expression is regulated, and indicate the importance of this form of transcription regulation.
Our long term goals are to elucidate the mechanisms that modulate polymerase pausing and release at key genes involved in responses to both immune challenge and developmental cues, in order to better understand how the regulated expression of genes in these critical pathways is achieved. Notably, our recent data reveal that disrupting Pol II pausing leads to defects in both basal and activated expression of key inflammatory genes, as well as perturbing the normal process of cell differentiation in both early murine embryogenesis and hematopoiesis. Furthermore, we have elucidated a novel function for Pol II pausing in regulating chromatin structure, epigenetic marks and DNA accessibility around promoters. We find that paused Pol II maintains a nucleosome-free region around promoters in stimulus-responsive pathways, allowing them to be accessible and particularly receptive for gene activation immediately after stimulation.
Karen L. Adelman, Ph.D., leads the Transcriptional Responses to the Environment Group within the Laboratory of Molecular Carcinogenesis. She earned her Ph.D. in 1999 at Universite de Paris VI, working at the Institut Pasteur. She was a postdoctoral fellow in the laboratory of John Lis, Ph.D., at Cornell University before joining NIEHS in 2005. Dr. Adelman has received a number of honors and awards during her tenure at NIEHS, including the Early Career Award in 2006 and the NIH Director's Award in 2010. She has published more than 35 articles and reviews in leading biomedical journals during her career, including more than 20 since she joined the NIEHS.
Adelman K, Lis JT. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat Rev Genet. 2012;13(10):720-31.
Scruggs BS, Gilchrist DA, Nechaev S, Muse GW, Burkholder A, Fargo DC, Adelman K. Bidirectional Transcription Arises from Two Distinct Hubs of Transcription Factor Binding and Active Chromatin. Mol Cell. 2015;58(6):1101-12.
Gilchrist DA, Dos Santos G, Fargo DC, Xie B, Gao Y, Li L, Adelman K. Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation. Cell. 2010;143(4):540-51.
Nechaev S, Fargo DC, dos Santos G, Liu L, Gao Y, Adelman K. Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila. Science. 2010;327(5963):335-8.
Muse GW, Gilchrist DA, Nechaev S, Shah R, Parker JS, Grissom SF, Zeitlinger J, Adelman K. RNA polymerase is poised for activation across the genome. Nat Genet. 2007;39(12):1507-11.