Welcome to the Van Bortle Lab!
Our group combines biochemical, molecular and genomic approaches to investigate RNA polymerase III (Pol III) transcription dynamics and mechanisms and pathways that regulate Pol III. We are probing the full extent of Pol III transcription, its dynamic, context-specific activities during development, and the regulatory factors and molecular events that modulate Pol III activity. We are also pursuing the functional activities of specific, cancer-associated small ncRNA expressed by Pol III with the overarching goal of understanding how Pol III contributes to cancer growth and metastasis. Our long-term vision includes developing novel approaches to inhibit Pol III transcription as a potential strategy for cancer therapy.
Our genes are expressed by three DNA-dependent RNA polymerase machineries, Pol I, Pol II, and Pol III. RNA polymerase III (Pol III) is unique in that it exclusively transcribes genes encoding small noncoding RNA (ncRNA), many of which are critical for cell growth and proliferation. Upregulation of Pol III activity and specific small ncRNA are hallmarks of cancer. Currently, a mechanistic understanding of the events that give rise to Pol III overactivity and the downstream functions of multiple cancer-associated small RNA species remains lacking.
The Pol III apparatus itself is unique in multiple respects, including the fact that Pol III switches its "identity" by replacing a single subunit during mammalian development. We have recently found that one form of Pol III, which re-emerges in many cancer types and is associated with poor survival outcomes, promotes the expression of snaR-A, a small ncRNA implicated in cancer growth and metastasis. In the Van Bortle lab, we are investigating the mechanisms underlying Pol III identity-driven transcription potential, as well as the downstream function(s) of snaR-A and other Pol III-derived small ncRNA with the goal of deconstructing the relationship between Pol III overactivity, cancer growth, and human health outcomes.
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11.01.21 | Hello World from the Van Bortle Lab. Welcome graduate students Sihang Zhou and Ruiying (Jenny) Cheng from Molecular & Cell Biology (MCB)!
Kevin Van Bortle Assistant Professor
Cell and Developmental Biology | School of Molecular and Cellular Biology | Cancer Center at Illinois | email@example.com
Postdoc. Genetics, Stanford University, 2015-2021 (advisor Mike Snyder)
PhD. Biochemistry, Cell, and Developmental Biology, Emory University, 2009-2014 (advisor Victor Corces)
BS. Biochemistry, University of Rochester, 2005-2009
Sihang Zhou Graduate Student
Molecular and Cellular Biology | B.S. Sun Yat-Sen University - China, M.S. Northwestern University | firstname.lastname@example.org
I'm a PhD student in Cell and Developmental Biology. I study specific Pol III-transcribed small RNA using a combination of biochemical and genomic approaches with the goal of understanding the biological functions and contributions of Pol III-derived small ncRNA to cancer. Outside of the lab you can find me reading manga, watching anime, and catching pokemon on campus.
Ruiying Cheng Graduate Student
Molecular and Cellular Biology | B.S. Shandong University - China | email@example.com
I'm a PhD student in Cell and Developmental Biology. I study the functional difference between RNA polymerase III subunits POLR3G and POLR3GL using biochemical and functional genomic approaches with the goal of understanding how Pol III identity shapes transcription during differentiation. Outside of the lab you can find me checking out new restaurants, hiking, or working on my indoor veggie garden.
Rajendra K C Graduate Student
Biophysics and Quantitative Biology | B.Tech.,M.Tech. Indian Institute of Technology, Kharagpur - India | firstname.lastname@example.org
I'm a PhD student in the Center for Biophysics and Quantitative Biology at Illinois. I study RNA Polymerase III transcription using bioinformatics to integrate and analyze multi-omic data with the goal of identifying the full extent of Pol III recruitment and transcription in cellular models of differentiation. Outside of the lab, you can find me with my friends around the quad.
A cancer-associated RNA polymerase III identity drives robust transcription and expression of snaR-A noncoding RNA
Van Bortle, K., Marciano, D.P., Liu, Q., Chou, T., Lipchik, A.M., Gollapudi, S., Geller, B., Monte, E., Kamakaka, R., Snyder, M.P.
Nature Commun. 2022
RNA polymerase III (Pol III) includes two alternate isoforms, defined by mutually exclusive incorporation of subunit POLR3G (RPC7α) or POLR3GL (RPC7β), in mammals. The contributions of POLR3G and POLR3GL to transcription potential has remained poorly defined. Here, we discover that loss of subunit POLR3G is accompanied by a restricted repertoire of genes transcribed by Pol III. Particularly sensitive is snaR-A, a small noncoding RNA implicated in cancer proliferation and metastasis. Analysis of Pol III isoform biases and downstream chromatin features identifies loss of POLR3G and snaR-A during differentiation, and conversely, re-establishment of POLR3G gene expression and SNAR-A gene features in cancer contexts. Our results support a model in which Pol III identity functions as an important transcriptional regulatory mechanism. Upregulation of POLR3G, which is driven by MYC, identifies a subgroup of patients with unfavorable survival outcomes in specific cancers, further implicating the POLR3G-enhanced transcription repertoire as a potential disease factor.
Topological organization and dynamic regulation of human tRNA genes during macrophage differentiation
Van Bortle, K., Phanstiel, D.H., Snyder, M.P.
Genome Biol. 2017
The human genome is hierarchically organized into local and long-range structures that help shape cell-type-specific transcription patterns. Transfer RNA (tRNA) genes (tDNAs), which are transcribed by RNA polymerase III (RNAPIII) and encode RNA molecules responsible for translation, are dispersed throughout the genome and, in many cases, linearly organized into genomic clusters with other tDNAs. Whether the location and three-dimensional organization of tDNAs contribute to the activity of these genes has remained difficult to address, due in part to unique challenges related to tRNA sequencing. We therefore devised integrated tDNA expression profiling, a method that combines RNAPIII mapping with biotin-capture of nascent tRNAs. We apply this method to the study of dynamic tRNA gene regulation during macrophage development and further integrate these data with high-resolution maps of 3D chromatin structure.
Static and dynamic DNA loops form AP-1-bound activation hubs during macrophage development
Phanstiel, DH.*, Van Bortle, K.*, Spacek, D., Hess, GT., Shamim, MS., Machol, I., Love, MI., Aiden, EL., Bassik, MC., Snyder, MP.
Mol. Cell. 2017
The three-dimensional arrangement of the human genome comprises a complex network of structural and regulatory chromatin loops important for coordinating changes in transcription during human development. To better understand the mechanisms underlying context-specific 3D chromatin structure and transcription during cellular differentiation, we generated comprehensive in situ Hi-C maps of DNA loops in human monocytes and differentiated macrophages. We demonstrate that dynamic looping events are regulatory rather than structural in nature and uncover widespread coordination of dynamic enhancer activity at preformed and acquired DNA loops. Enhancer-bound loop formation and enhancer activation of preformed loops together form multi-loop activation hubs at key macrophage genes. Activation hubs connect 3.4 enhancers per promoter and exhibit a strong enrichment for activator protein 1 (AP-1)-binding events, suggesting that multi-loop activation hubs involving cell-type-specific transcription factors represent an important class of regulatory chromatin structures for the spatiotemporal control of transcription.
Integrated tRNA, transcript, and protein profiles in response to steroid hormone signaling
Van Bortle, K., Nichols, M.H., Ramos, E., Corces, V.G.
The accurate and efficient transfer of genetic information into amino acid sequences is carried out through codon–anticodon interactions between mRNA and tRNA, respectively. In this way, tRNAs function at the interface between gene expression and protein synthesis. Whether tRNA levels are dynamically regulated and to what degree tRNA abundance influences the cellular proteome remains largely unexplored. Here we profile tRNA, transcript and protein levels in Drosophila Kc167 cells, a plasmatocyte cell line that, upon treatment with 20-hydroxyecdysone, differentiates into macrophages. We find that high abundance tRNAs associate with codons that are overrepresented in the Kc167 cell proteome, whereas tRNAs that are in low supply associate with codons that are underrepresented. Ecdysone-induced differentiation of Kc167 cells leads to changes in mRNA codon usage in a manner consistent with the developmental progression of the cell. At both early and late time points, ecdysone treatment concomitantly increases the abundance of tRNAThr(CGU), which decodes a differentiation-associated codon that becomes enriched in the macrophage proteome. These results together suggest that tRNA levels may provide a meaningful regulatory mechanism for defining the cellular proteomic landscape.
CTCF-dependent co-localization of canonical Smad signaling factors at architectural protein binding sites in D. melanogaster
Van Bortle, K., Peterson, A.J., Takenaka, N., O'Connor, M.B., Corces, V.G.
Cell Cycle. 2015
The transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) pathways transduce extracellular signals into tissue-specific transcriptional responses. During this process, signaling effector Smad proteins translocate into the nucleus to direct changes in transcription, but how and where they localize to DNA remain important questions. We have mapped Drosophila TGF-β signaling factors Mad, dSmad2, Medea, and Schnurri genome-wide in Kc cells and find that numerous sites for these factors overlap with the architectural protein CTCF. Depletion of CTCF by RNAi results in the disappearance of a subset of Smad sites, suggesting Smad proteins localize to CTCF binding sites in a CTCF-dependent manner. Sensitive Smad binding sites are enriched at low occupancy CTCF peaks within topological domains, rather than at the physical domain boundaries where CTCF may function as an insulator. In response to Decapentaplegic, CTCF binding is not significantly altered, whereas Mad, Medea, and Schnurri are redirected from CTCF to non-CTCF binding sites. These results suggest that CTCF participates in the recruitment of Smad proteins to a subset of genomic sites and in the redistribution of these proteins in response to BMP signaling.