Ann L. Kirchmaier

Ann L. Kirchmaier Profile Picture

Associate Professor of Biochemistry
University of Wisconsin, Madison

Contact Info:

kirchmaier@purdue.edua 
765-494-0977
BCHM321

Training Group(s):
Chromatin and Regulation of Gene Expression
Molecular Signaling and Cancer Biology
Microbiology, Immunology and Infectious Diseases

Active Mentor - currently hosting PULSe students for laboratory rotations and recruiting PULSe students into the laboratory; serves on preliminary exam committees

Current Research Interests:

The research in my lab focuses on understanding how cells regulate chromatin and epigenetic processes. Our research examines the role of metabolism, the cell cycle and DNA replication in assembly or maintenance of chromatin structures and the effects of these structures on DNA replication and DNA repair. We are interested in how the cell restricts heterochromatin to specific genomic loci, why heterochromatin formation is regulated by the cell cycle, how transcription of genes is prevented in silenced regions, and whether epigenetic processes are influenced by or influence events including DNA damage and the initiation of DNA replication. We are intrigued by how epigenetic states are maintained throughout the cell cycle and are duplicated and inherited each time the chromosome itself is replicated and the cell divides. We investigate how environmental factors perturb epigenetic processes and can contribute to inappropriate gene expression, developmental defects, tumorogenesis and other catastrophic disorders. Our laboratory combines genetic, molecular biology, biochemical, and quantitative microscopy-based approaches with mammalian cell culture and yeast genetics to understand the impact of genetic and external factors on chromatin modifications and epigenetic gene regulation.

Silencing in Saccharomyces cerevisiae:

We use silent chromatin in S. cerevisiae as a model for understanding how epigenetically regulated chromatin structures are established, maintained and inherited. Silenced chromatin in budding yeast, is akin to heterochromatin in organisms such as maize, flies, and mammals. S. cerevisiae uses epigenetically inherited chromosomal structures to regulate a variety of cellular activities including controlling cell-type specific gene expression, modulating ribosomal RNA levels, and preserving telomere structure and stability. Silenced regions in S. cerevisiae that are regulated, in part, by the Silent Information Regulator, or Sir, proteins include the silent mating-type loci, HML and HMR, the rDNA locus and the telomeres. To mediate silencing at a given site on a chromosome, an organism must first have a way to recruit the proteins that compose silenced chromatin to that locus. In yeast, regulatory sites known as silencers flank the silent mating-type loci. Silencers contain binding sites for the Origin Recognition Complex (ORC), and the transcriptional regulators Rap1p and Abf1p. In addition, the Sir proteins, Sir1p, Sir2p, Sir3p and Sir4p, are structural components of silenced chromatin in yeast. Unlike ORC, Rap1p and Abf1p, however, the Sir proteins do not bind to DNA site-specifically. Instead, Sir proteins associate with silencers through protein-protein interactions between each other, proteins bound at silencers, and histones H3 and H4. Once initiated, silencing spreads along the chromosome over several kilobases of DNA and inactivates gene expression. Once established, the transcriptionally inactive state of this region of the chromosome is maintained throughout the cell cycle, is copied faithfully during DNA replication and can be stably inherited in subsequent cell generations. Many proteins involved in silencing in yeast have homologs in a wide variety of organisms, including humans where several are involved in development and differentiation or have been implicated in cancer.

Epigenetic Processes and Replication-Coupled Chromatin Assembly:

We are investigating how a network of chromatin assembly factors, histone-modifying enzymes and replication factors interact to assemble appropriately modified nucleosomes during DNA replication and thereby promote epigenetic processes and genome integrity. We have been characterizing how silencing is affected by the DNA polymerase processivity factor PCNA through pathways involving several factors including the chromatin assembly factors, PCNA loading complex RF-C and histone acetyltransferases. As nucleosomal DNA serves as the foundation upon which silent chromatin is built, perturbations in replication-coupled chromatin assembly can alter the efficiency and location of silent chromatin formation as well as lead to defects in maintaining and inheriting epigenetic states. We are also exploring how repair of DNA damage can be compromised in mutants with defects linked to histone modifications and replication-coupled chromatin assembly pathways.

Influences of Metabolism on Chromatin:

Genome integrity is fundamental to the health of an organism, and, when disrupted, can lead to cancer. We are uncovering how metabolite availability influences chromatin-regulated processes, including cell survival during DNA replication stress. We have discovered that accumulation of the metabolite fumarate, or loss of TCA cycle enzyme fumarase (ortholog of the tumor suppressor FH), promote resistance to replication stress, in part, by inhibiting histone demethylation, and bypassing requirements for proteins involved in processing or restarting stalled replication forks.

Defining the Functional Composition of Chromatin: The simplest structural unit of chromatin, the nucleosome, can exist in a variety of configurations depending on the histone variants and post-translational modifications present. The composition of individual nucleosomes influences chromatin structure and function and provides signals to the cellular machinery to promote gene activation or repression. These signals tend to be dynamic and can vary as a function of the cell cycle or growth conditions. Yet, our understanding of the patterns found within individual nucleosomes and presented to the cellular machinery is limited. Population-based approaches widely used to characterize chromatin composition have been valuable in identifying and mapping individual modifications within histones, but have been limited in describing which modifications are combined within the same nucleosomes. As a powerful complement to standard approaches, we are utilizing single molecule strategies in vitro and in single mammalian and yeast cells to probe epigenetic processes that regulate transcriptional states, and responses to DNA damage in several collaborative projects.

Selected Publications:

Saatchi, F., and Kirchmaier, A.L. 2019. Tolerance of DNA replication stress is promoted by fumarate through modulation of histone demethylation and enhancement of replicative intermediate processing in Saccharomyces cerevisiae. Genetics. 212:631-654.

Young, T.J., Cui, Y., Irudayaraj, J., and Kirchmaier, A.L. 2019. Modulation of gene silencing by Cdc7p via H4 K16 acetylation and phosphorylation of chromatin assembly factor CAF-1 in Saccharomyces cerevisiae. Genetics. 211:1219-1237.

Balduf, H., Pepe, A. and Kirchmaier A.L. 2017. Synthesis and Application of Cell-Permeable Metabolites for Modulating Chromatin Modifications Regulated by alpha-Ketoglutarate-Dependent Enzymes. In Epigenetics and Gene Expression in Cancer, Inflammatory and Immune Diseases. Methods in Pharmacology and Toxicology, Springer Protocols. Barbara Stefanska and David MacEwan, Eds. Ch. 5, pp. 63-79. Humana Press. New York, NY. ISBN 978-1-4939-6743-8.

 Jacobi J.L., Yang B., Li X, Menze A.K., Laurentz S.M., Janle E.M., Ferruzzi M.G., McCabe G.P., Chapple C., and Kirchmaier A.L. 2016. Impacts on Sirtuin Function and Bioavailability of the Dietary Bioactive Compound Dihydrocoumarin. PLoS ONE. 11(2):e0149207.

Miller, A., & Kirchmaier, A.L. 2014. Analysis of silencing in Saccharomyces cerevisiae. In Yeast Genetics: Methods and Protocols, Methods Mol. Biol. (1205, 275-302). NY: Humana Press, Springer Science+Business Media.

Chen J., Miller A., Kirchmaier A.L., and Irudayaraj J.M. 2012. Single Molecule Tools Elucidate H2A.Z Nucleosome Composition. J. Cell Sci. 125:2954-2964.

 Miller A., Chen J., Takasuka T.E., Jacobi J.L., Kaufman P.D., Irudayaraj J.M.K., and Kirchmaier A.L. 2010. Proliferating Cell Nuclear Antigen (PCNA) Is Required for Cell-Cycle Regulated Silent Chromatin on Replicated and Nonreplicated Genes. J. Biol. Chem. 285:35142-35154.

Yang B., Miller A., and Kirchmaier A.L. 2008. HST3/HST4-Dependent Deacetylation of Lysine 56 of Histone H3 in Silent Chromatin. Mol. Biol. Cell. 19:4993-5005. Yang B., Britton J., and Kirchmaier A.L. 2008. Insights into the Impact of Histone Acetylation and Methylation on Sir Protein Spreading and Silencing in Saccharomyces cerevisiae. J. Mol. Biol. 381:826-844.

Miller A., Yang B., Foster T., and Kirchmaier A.L. 2008. Proliferating Cell Nuclear Antigen and ASF1 Modulate Silent Chromatin in Saccharomyces cerevisiae via Lysine 56 on Histone H3. Genetics 179:793-809.

Yang B. and Kirchmaier A.L., 2006. Bypassing the Catalytic Activity of Sir2 for SIR Protein Spreading in S. cerevisiae. Mol. Biol. Cell 17:5287-5297.

Kirchmaier A.L. and Rine J., 2006. Cell Cycle Requirements in Assembling Silent Chromatin in Saccharomyces cerevisiae. Mol. Cell. Biol. 26:852-862.

 Rusché L.N., Kirchmaier A.L. and Rine J. 2002. Ordered Nucleation and Spreading of Silenced Chromatin in S. cerevisiae. Mol. Biol. Cell 13:2207-2222. Kirchmaier A.L. and Rine J. 2001. DNA Replication-Independent Silencing in S. cerevisiae. Science. 291:646-650.

Tu G., Kirchmaier A.L., Ligitt D., Liu Y., Yu W.H., Liu S., Heath T.D., Thor A. and Debs R.J. 2000. Non-Replicating Epstein-Barr Virus-based Plasmids Extend Gene Expression and Can Improve Gene Therapy in vivo. J. Biol. Chem. 275:30408-30416

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