Assistant Professor of Medicinal Chemistry
B.S. University of North Carolina at Chapel Hill
Ph.D. University of Texas at Austin
Katharine Diehl's Lab Page
Katharine Diehl's PubMed Literature Search
Biological Chemistry Program
Chromatin and histone modifications, Epigenetics and metabolism, Protein chemistry, Metabolite sensors
The eukaryotic genome is regulated by a variety of epigenetic mechanisms that establish and maintain proper gene expression profiles to control cell identity and fate. One of these vital mechanisms is accomplished by chromatin, which is the packaging medium for genomic DNA. The chromatin polymer consists of individual nucleosomes in which the DNA is wrapped around an octamer of the canonical histone proteins H2A, H2B, H3, and H4. The histone proteins are highly post-translationally modified, and these modifications (PTMs) have an impact on the local chromatin environment through both direct biophysical perturbations and recruitment of downstream effectors. Different PTM chemotypes (e.g., methylation, acetylation, ADP-ribosylation) at different sites within the histones act as dynamic signals to delineate specific chromatin states. Thus, far from being a passive scaffold for the genome, chromatin actively controls access to the underlying genetic material to aid in regulating transcription, translation, and repair. Importantly, when histone PTMs and other epigenetic factors are disrupted, these processes are misregulated leading to diseases such as cancer and developmental disorders.
Our lab studies how the deposition, removal, and recognition of these histone PTMs are regulated and what downstream effects these PTMs have on DNA-mediated processes. In particular, our focus is studying how metabolism is linked to genomic regulation via the metabolites that fuel chromatin dynamics. We seek to elucidate mechanisms by which the metabolic state of the cell (e.g., acetyl-CoA level) is reported to the genome via chromatin (e.g., histone acetylation) to lead to changes in DNA transcription, translation, or repair. To do so, my lab will utilize a range of techniques across organic chemistry, peptide/protein chemistry, biochemistry, and molecular and cell biology.
Some project areas include 1) biochemical and in cell characterization of mechanisms by which the histone deacetylases called sirtuins sense and report on cellular metabolism, 2) development of fluorescent sensors for metabolites and histone post-translational modifications (PTMs) for obtaining detailed metabolite/PTM profiles in live cells, 3) investigation of NAD+ and ATP dynamics during the DNA damage response, and 4) characterization of mechanisms for the subnuclear localization of metabolic enzymes and development of strategies to target this localization.
- Ge, E. J., Jani, K. S., Diehl, K. L., Müller, M. M., Muir. T. W. Nucleation and propagation of heterochromatin by the histone methyltransferase PRC2: geometric constraints and impact of the regulatory subunit JARID2. J. Am. Chem. Soc. Accepted: https://doi.org/10.1021/jacs.9b02321.
- Jain, S. U., Do, T. J., Lund, P. L., Rashoff, A. Q., Diehl, K. L., Cieslik, S., Bajic, A., Juretic, A., Deshmukh, S., Venneti, S., Muir, T. W., Garcia, B. A., Jabado, N., Lewis, P. W. PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. Nat. Commun. 10, 2146 (2019).
- Jani, K. S., Jain, S. U., Ge, E. J., Diehl, K. L., Lundgren, S. M., Müller, M. M., Lewis, P. W., Muir, T. W. Histone H3 tail binds a unique sensing pocket in EZH2 to activate the PRC2 methyltransferase. Proc. Nat. Acad. Sci.116, 8295-8300 (2019).
- Liszczak, G.*, Diehl, K. L.*, Dann, G. P., Muir, T. W. Acetylation blocks DNA-damage induced chromatin ADP-ribosylation. Nat. Chem. Biol. 14, 837-840 (2018).
- *co-first authors
- Dann, G. P., Liszczak, G., Bagert, J. D., Müller, M. M., Nguyen, U. T. T., Wojcik, F., Brown, Z. Z., Bos, J., Panchenko, T., Pihl, R., Pollock, S. B., Diehl, K. L., Allis, C. D., Muir, T. W. ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference. Nature548. 607-611 (2017).
- Diehl, K.L., Bachman, J. L., Anslyn, E.V. Tuning thiol addition to squaraines by ortho-substitution and the use of serum albumin. Dyes Pigm.141. 316-324 (2017).
- Diehl, K. L., Kolesnichenko, I. V., Robotham, S. A., Bachman, J. L., Zhong, Y., Brodbelt, J. S., and Anslyn, E. V. Click and chemically triggered declick reactions through reversible amine and thiol coupling via a conjugate acceptor. Nat. Chem.8. 968-973 (2016).
- Diehl, K. L., Ivy, M. A., Rabidoux, S., Müller, G., Petry, S. M., and Anslyn, E. V. Differential sensing for the regio- and stereoselective identification of glycerides. Proc. Nat. Acad. Sci.112. E3977-E3986 (2015).