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Your Environment. Your Health.

Transcriptional Responses to the Environment Group

Chromatin Signatures & Gene Expression

Karen Adelman, Ph.D.
Karen Adelman, Ph.D.
Principal Investigator
Tel (919) 541-0001
Fax (919) 541-0146
P.O. Box 12233
Mail Drop D4-02
Research Triangle Park, NC 27709

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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="")

Research Summary

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 Figure
Establishment and release of paused Pol II are key regulated steps in mammalian gene expression. Adapted from Fromm, Gilchrist and Adelman (2013) Cell

A. The promoter region for a gene is shown with the transcription start site labeled as an arrow. Nucleosomes, depicted in grey, can occlude promoter sequences and prevent gene expression.
B. Promoter opening often involves the binding of a sequence specific transcription factor (TF) that brings in chromatin remodelers (green) to remove nucleosomes from around the promoter and render the region accessible for recruitment of the transcription machinery.
C. TF binding also facilitates recruitment of RNA polymerase II (Pol II, red), a set of general transcription factors (GTFs, brown) and Mediator (blue).
D. Pol II pausing occurs shortly after transcription initiation and involves the association of pausing factors DSIF (purple) and NELF (orange). Pol II can pause stably, associated with a 25-60 nucleotide nascent RNA transcript (blue), while awaiting a signal for release downstream into the gene body.
E. Pause release is triggered by the recruitment of the kinase P-TEFb (green). P-TEFb phosphorylates the C-terminal domain of Pol II (red ‘tail’ on the polymerase) DSIF and NELF (phosphorylation events shown as green Ps). Phosphorylation dissociates NELF from the elongation complex and transforms DSIF into a positive elongation factor that associates with Pol II throughout the gene.
F. Escape of the paused Pol II into productive elongation is followed rapidly by entry of another Pol II into the pause site, allowing for efficient RNA production.  

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

Current projects:

  • 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.

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