Transcriptional Responses to the Environment Group
Chromatin Signatures & Gene Expression
Karen Adelman, Ph.D.
Karen Adelman Talks About Her Group’s Research: Adelman Interview on Transcriptional Responses ("/Rhythmyx/assembler/render?sys_contentid=29381&sys_revision=5&sys_variantid=639&sys_context=0&sys_authtype=0&sys_siteid=&sys_folderid=" sys_dependentvariantid="639" sys_dependentid="29381" inlinetype="rxhyperlink" rxinlineslot="103" sys_dependentid="29381" sys_siteid="" sys_folderid="")
The Transcriptional Responses to the Environment Group investigates the dynamic interplay between signals from the environment and transcription by RNA polymerase II (Pol II). The ability to rapidly integrate multiple extra- and intra-cellular cues to produce specific patterns of gene expression is essential for the growth, development, and survival of all organisms; however, the molecular mechanisms leading from these signals to the coordinated activation of gene networks are not well understood. The group uses genomic approaches in Drosophila and murine model systems to measure changes in Pol II distribution, gene expression, and epigenetic chromatin signatures that occur when a cell receives specific stimuli from the environment. The mechanisms underlying these changes are then probed using a combination of genetic and biochemical techniques.
In particular, the Adelman group is investigating how gene networks can be tune to respond in a rapid yet balanced manner to signals elicited during development, immune challenge or cellular insult. By elucidating how cells dynamically react to external stimuli, this work provides new insights into gene-environment interactions. Moreover, since transcription dysregulation during such responses contributes to the etiology of numerous disease states including chronic inflammation and cancer, this work aims to identify novel targets or approaches for treating disease.
Adelman's group pioneered global studies of the pausing of RNA polymerase II (Pol II) during early transcription elongation (see Figure for details). Further, they uncovered a surprising interplay between paused Pol II and chromatin structure, wherein pausing facilitates gene activity by establishing and maintaining and accessible chromatin architecture around promoters. Recently, work from the lab has revealed that regulated pausing of Pol II governs expression of many genes in signal-responsive pathways. Accordingly, her group has shown that release of paused Pol II into productive elongation is a key step controlling the expression of signal-responsive genes such as proinflammatory cytokines and regulators of FGF signaling. Notably, pausing controls the basal expression of critical hubs in signaling networks, tuning cellular responsiveness to inflammatory cues, and defining the differentiation potential of mouse embryonic stem cells.
Ongoing work will further explore the interactions between pausing and epigenetic features of the genome, as well as the impact of pausing on tuning the transcriptional dynamics of environmentally sensitive gene networks. Approaches include cutting-edge genomic and bioinformatic strategies to further elucidate gene regulation at promoters and enhancers, and mouse models of inflammation and development to investigate the physiological roles of pausing.
Major areas of research:
- Elucidating the role of paused polymerase in coordinating cellular responses to signals from the extracellular environment
- Dissecting the role of pause-inducing factors such as the NELF complex during development, cell differentiation and the response to inflammatory stimuli
- Screening for novel protein factors that regulate promoter-proximal pausing
- Examining the interactions between paused Pol II and epigenetic features of the genome at both promoters and enhancers
- Probing the role of the pause-inducing factor NELF in mammalian development and the inflammatory response, using a conditional knock-out mouse
- Dissecting the cis-acting elements that establish a paused polymerase, including DNA and the sequence of the noncoding RNA transcript
Karen L. Adelman, Ph.D., leads the Transcriptional Responses to the Environment Group within the Epigenetics and Stem Cell Biology Laboratory. 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. She has authored numerous articles and reviews in leading biomedical journals during her career, with more than 25 publications since she joined the NIEHS.