Karen Adelman, Ph.D.
Associate Member, Broad Institute
The Adelman lab studies the changes in gene regulation and epigenetics that drive development and stress-responses.
Cell-type and condition-specific patterns of gene expression are established through a sophisticated network of interactions between protein-coding gene promoters and distal cis-regulatory sequences such as enhancers. The Adelman lab is actively engaged in probing how these interactions are established and how they control transcription profiles during development and in response to external signals. Gaining this information is critical to develop treatments for the many diseases where transcription becomes dysregulated.
Interestingly, RNA polymerase II (Pol II) is recruited to and transcribes RNA at both promoters and enhancers. However, the RNAs generated at promoters and enhancers have dramatically different fates: whereas promoters produce long, highly processed and stable mRNA species, the vast majority of non-coding RNAs are short (<120nt) poorly conserved RNAs that are degraded rapidly upon release by Pol II. Understanding how the processes of productive RNA elongation and termination are regulated differently at genes and enhancer regions, and how the distinct RNA species generated impact cellular behavior are central goals of the Adelman lab. We are embarking on both experimental and computational searches for the underlying mechanisms that define how Pol II processivity and the fate of nascent RNA are determined.
In addition, we are taking genomic approaches to identify enhancers in varying developmental stages and disease states using nascent RNA sequencing techniques (Start-seq, PRO-seq). This information on the location and sequence context of regulatory regions sheds new light on gene expression profiles, local epigenetic features, and three-dimensional chromatin architecture.
The Adelman group pioneered global studies of Pol II pausing during early transcription elongation. Pausing, and the regulated release of Pol II into productive RNA synthesis have emerged as central aspects of mRNA synthesis, and our recent work has demonstrated the importance of pause regulation at enhancers as well. We hypothesize that paused Pol II plays similar roles at promoters and enhancers: maintaining accessible chromatin; stabilizing a scaffold of general transcription factors; and presenting nascent RNA for interaction with transcription and epigenetic regulators. To elucidate the importance of Pol II at enhancers, we are carrying out massively parallel reporter assays to determine which sequence motifs and contexts enable a sequence to act as an enhancer, promoter, or both. Design principles inferred from these experiments are then tested at endogenous loci using CRISPR/Cas9.
To understand the interplay between coding and non-coding transcription, we are leveraging the sensitivity of nascent RNA sequencing techniques (Start-seq, PRO-seq) to identify active genes and enhancers at during mammalian development. This high-resolution information on the location and sequence context of regulatory regions is combined with parallel assays of gene expression profiles and local epigenetic features, to define the series of events that takes place as new enhancers emerge and others are decommissioned. Specific steps in the process are then perturbed (using inhibitors of transcription, chromatin modifications, etc.) and the direct consequences defined on both the enhancer region and target genes.
Ongoing work will further explore how RNA polymerase elongation impacts epigenetic features and organization of metazoan genomes. Approaches include cutting-edge genomic and bioinformatic strategies to use ‘in vivo biochemistry’ to further elucidate gene regulation at promoters and enhancers, complemented with powerful biochemical and biophysical techniques.
Henriques, T., Scruggs, B.S., Inouye, M.O., Muse, G.W., Williams, L.H., Burkholder, A.B., Lavender, C.A., Fargo, D.C. & Adelman, K. (2018) Widespread transcriptional pausing and elongation control at enhancers. Genes Dev.; 32 (1): 26-41.
Meers, M.P., Adelman, K., Duronio, R.J., Strahl, B.D., McKay, D.J. & Matera, A.G. (2018) Transcription start site profiling uncovers divergent transcription and enhancer associated RNAs in Drosophila melanogaster. BMC Genomics; 19 (1): 157.
Kaikkonen, M.U. & Adelman, K. (2018) Emerging roles of non-coding transcription. Trends Biochem Sci. 43 (9): 654-667. PMID: 30145998
Dorighi, K.M., Swigut, T., Henriques, T., Bhanu, N.V., Scruggs, B.S., Nady, N., Still, C.D., Garcia, B.A., Adelman, K. & Wysocka, J. (2017) Mll3 and Mll4 facilitate enhancer RNA synthesis and transcription from promoters independently of H3K4 monomethylation. Mol Cell; 66 (4): 568-76. PMID: 28483418
Urban, J., Kuzu, G., Bowman, S., Scruggs, B., Henriques, T., Kingston, R., Adelman, K., Tolstorukov, M. & Larschan, E. (2017) Enhanced chromatin accessibility of the dosage compensated Drosophila male X-chromosome requires the CLAMP zinc finger protein. PLoS One; 12 (10) e0186855. PMID: 29077765
Pai, A.A, Henriques, T., Paggi, J., Burkholder, A., Adelman, K. & Burge, C.B. (2017) The kinetics of pre-mRNA splicing in the Drosophila genome and the influence of gene architecture. Elife; Dec 27;6. pii: e32537. doi: 10.7554/eLife.32537. PMID: 29280736
Williams, L.H., Fromm, G., Gokey, N.G., Henriques, T., Muse, G.W., Burkholder, A., Fargo, D.C., Hu, G. & Adelman, K. (2015) Pausing of RNA polymerase II regulates mammalian developmental potential through control of signaling networks. Mol Cell; 58 (2) 311-22. PMCID: PMC4402150
Scruggs, B.S., Gilchrist, D.A., Nechaev, S., Muse, G.W., Burkholder, A., Fargo, D.C & Adelman, K. (2015) Bidirectional transcription arises from two distinct hubs of transcription factor binding and active chromatin. Mol Cell; 58 (6) 1101-12. PMCID: PMC4475495
45 Shattuck St.
Harvard Medical School
Boston, MA 02115