Transcriptional Responses to the Environment Group
Chromatin Signatures & Gene Expression
-
-
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
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. 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 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 recent work has revealed that many genes in signal-responsive pathways are pre-loaded with Pol II prior to full-scale gene activation, poising them for future increases in expression (Muse et al., 2007; Zeitlinger et al., 2007). This Pol II is engaged in early transcription elongation, but has paused after synthesizing a short (25-60 nt) mRNA transcript. Importantly, the group finds that release of Pol II from promoter-proximal pausing into productive elongation is a critical regulatory step that is rate-limiting for expression of a number of DNA damage-responsive and inflammatory genes (e.g. the inflammatory cytokine TNF-alpha; Adelman et al., PNAS 2009). 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 these highly-regulated genes.
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 techniques 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 critical role in establishing an accessible chromatin architecture around gene promoters (Gilchrist et al., 2008; Gilchrist et al., 2010) that facilitates further or future gene activation. Future work will probe the interactions between pausing and chromatin structure, as well as the impact of pausing on tuning the transcriptional dynamics of environmentally-sensitive networks.
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.
- Zeitlinger, J., Stark, A., Kellis, M., Hong, J.W., Nechaev, S., Adelman, K., Levine, M., & Young, R.A. (2007) RNA Polymerase Stalling at Developmental Control Genes in the Drosophila Embryo. Nat Genet; 39 (12): 1512-16.
- 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.
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 cell differentiation, cell proliferation 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 pause-inducing factors like the Negative ELongation Factor (NELF) in mammalian development and the inflammatory response
- Dissecting the cis-acting elements that establish a paused polymerase, including upstream DNA and the sequence of the 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 30 articles and reviews in leading biomedical journals during her career, including 15 since she joined the NIEHS.
