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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
adelmank@niehs.nih.gov
P.O. Box 12233
Mail Drop D4-02
Research Triangle Park, North Carolina 27709
Delivery Instructions

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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 quantify the alterations 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 Transcriptional Responses to the Environment Group is investigating how gene networks can be "poised" to respond in a rapid yet balanced manner to signals that arise during development, immune challenge or cellular insult. By expanding basic understanding of 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.

Notably, Adelman's work has revealed that expression of many genes in signal-responsive pathways is regulated at the level of early transcription elongation, through a phenomenon called pausing (e.g. Muse et al., 2007). Paused Pol II is stably engaged in transcription elongation, but is induced to pause within the promoter-proximal region by protein factors such as DSIF and NELF. Her group finds that release of paused Pol II into productive elongation is a key regulatory step that facilitates the expression of a number of signal-responsive genes (e.g. the inflammatory cytokine TNF-alpha; Adelman et al., 2009). Furthermore, pausing governs the basal expression of critical hubs in signaling networks, tuning cellular responsiveness to environmental cues (Gilchrist et al., 2012). These findings, together with work from others, have led to an explosion of interest in better understanding promoter-proximal pausing of Pol II, and how pausing facilitates precise control and coordination of highly-regulated gene networks.

Highly-regulated Genes Use Pol II Pausing to Keep Nucleosomes Off Their Promoters, Whereas Housekeeping Genes That Are Less Paused Are Accessible By Default.

Figure 1. Highly-regulated Genes Use Pol II Pausing to Keep Nucleosomes Off Their Promoters, Whereas Housekeeping Genes That Are Less Paused Are Accessible By Default.

 

Top panel: The most highly paused and highly-regulated genes (left) have strong promoter motifs that efficiently recruit Pol II to the transcription start site (black arrow); however these promoters would be masked by nucleosomes due to DNA sequences that promote nucleosome formation (red curve). Less paused genes (right), which tend to be more constitutively active and serve housekeeping functions, have weak promoters that are generally accessible, thanks to DNA sequences that disfavor promoter nucleosome occupancy (blue curve).

 

Middle panel: In the absence of Pol II binding, in vivo nucleosome occupancy (red and blue curves) approaches the default chromatin states specified by DNA sequence (compare in vivo curves in middle panel to predicted curves in top panel).

 

Lower panel: However, at the most paused promoters (left), the presence of paused Pol II displaces the promoter nucleosome allowing access to these strong promoters and permitting further or future gene activation in response to signaling events. The weak promoters of less paused genes (right) are constitutively deprived of nucleosomes, allowing for continued RNA synthesis in the absence of pausing.

Adelman's group is currently using cutting-edge genomic and bioinformatic strategies to determine the global distribution of promoter-proximally paused polymerase (Nechaev et al., 2010) and to further elucidate the role of paused Pol II. Surprisingly, the Adelman group finds that Pol II pausing plays a vital role in establishing an accessible chromatin architecture around promoters that facilitates gene activity (Gilchrist et al., 2008; Gilchrist et al., 2010). Ongoing work will further explore the interactions between pausing and chromatin structure, as well as the impact of pausing on tuning the transcriptional dynamics of environmentally-sensitive networks (Gilchrist et al., 2012).

 

References:

  • Muse, G.W., Gilchrist, D.A., Nechaev, S., Shah, R., Parker, J.S., Grissom, S.F., Zeitlinger, J., & Adelman, K. (2007) RNA polymerase is poised for activation across the genome. Nat Genet; 39 (12): 1507-11.
  • Gilchrist, D.A., Nechaev, S., Lee, C., Gosh, S.K.B, Collins, J., Li, L., Gilmour, D.S. & Adelman, K. (2008) NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly. Genes Dev; 22 (14): 1921-33.
  • Adelman K., Kennedy M.A., Nechaev S., Gilchrist D.A., Muse G.W., Chinenov Y. & Rogatsky I. (2009) Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase stalling. Proc Natl Acad Sci USA; 106 (43): 18207-12.
  • Nechaev, S. Fargo, D.C., dos Santos, G., Liu, L., Gao, Y. & Adelman, K. (2010) Global Analysis of Short RNAs Reveals Widespread Promoter-Proximal Stalling and Arrest of Pol II in Drosophila. Science; 327 (5963): 335-8.
  • Gilchrist, D.A., dos Santos, G., Fargo, D.C., Xie, B., Gao, Y. Li, L., & Adelman, K. (2010) Pausing of RNA polymerase II Disrupts DNA-specified Nucleosome Organization to Enable Precise Gene Regulation. Cell; 143 (4) 540-51.
  • Gilchrist D.A., Fromm, G., dos Santos G., Pham, L., McDaniel I., Burkholder, A., Fargo, D.C., and Adelman, K. (2012) Regulating the Regulators: the Pervasive Effects of Pol II Pausing on Stimulus-responsive Gene Networks. Genes Dev.; 26(9): 933-44.

 

Major areas of research:

  • Investigating 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 environmental exposures

Current projects:

  • Screening for novel protein factors that regulate promoter-proximal pausing
  • Examining the interactions between paused Pol II and nucleosomes, focusing on the role of pausing in generating a permissive chromatin environment surrounding target gene promoters
  • Probing the role of the pause-inducing factor NELF in mammalian development and the inflammatory response, using a newly generated 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 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. She has published more than 35 articles and reviews in leading biomedical journals during her career, including 20 since she joined the NIEHS.

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