About

Kevin Van Bortle is an Assistant Professor of Cell & Developmental Biology at the School of Molecular & Cellular Biology, Illinois College of Liberal Arts & Sciences. His research primarily focuses on RNA polymerase III (Pol III) transcription regulation and small noncoding (nc)RNA biology. His lab addresses fundamental questions about which genes Pol III transcribes, how its activity is regulated across different cell types, and how its RNA products influence cell function. Despite Pol III’s essential role in producing small noncoding RNAs such as tRNAs and 5S rRNA, it remains understudied due to technical challenges related to its repetitive gene targets and short, chemically modified RNAs. Van Bortle's work aims to develop tailored genomic and biochemical approaches to overcome these barriers and build a comprehensive understanding of Pol III transcription in diverse biological contexts. His recent research has uncovered unexpected Pol III activity at previously unannotated noncoding RNA genes, novel interactions between Pol III and Pol II transcriptional programs, and Pol III-derived small RNAs that influence RNA processing and splicing, challenging traditional views of Pol III as a static 'housekeeping' enzyme and positioning it as a dynamic regulator integrated into broader gene expression networks. His future research aims to define how Pol III transcription is shaped during development, differentiation, and disease, with particular interest in chromatin context and regulatory proteins that modulate Pol III activity, and how misregulation contributes to pathological states.

Research topics

• Genetics
• Biology
• Molecular biology
• Computational biology

Selected publications

• Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells

  Science Advances · 2026-01-01 · 1 citations

  articleOpen access

  Breast and other solid tumors respond poorly to immune therapy. Myeloid cells (MCs) such as macrophages contribute to resistance. Established clinical evidence links cholesterol to cancer outcomes, with MC function being regulated by cholesterol metabolism. We screened MC-expressed regulators of cholesterol homeostasis linked to survival and identified the cholesterol efflux protein ABCA1. ABCA1 activity increases anticancer functions of macrophages: enhancing tumor infiltration, decreasing angiogenic potential, reducing efferocytosis, and improving support of CD8+ T cell activity. Mechanistically, different AKT isoforms are involved, through both PI3K-dependent and PI3K-independent mechanisms. Highlighting the clinical relevance of our findings are correlations between ABCA1 in macrophages and angiogenic potential, VEGFA , and CD8 T cell abundance and activity. The culmination of these activities was demonstrated through increased tumor growth and metastasis in mice lacking MC-expressed ABCA1. Tumors grown in these mice were also more resistant to immune therapy. Therefore, modulating ABCA1 activity within MCs may represent a previously unidentified approach to immune therapy.

  PublisherDOI

• Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations

  Nature Communications · 2025-11-25

  articleOpen accessSenior author

  Expansion of RNA polymerase III (Pol III) activity in cancer can activate the transcription of typically silent small RNA genes, including snaR-A (small NF90-associated RNA isoform A), a hominid-specific noncoding RNA that promotes cell proliferation through unclear mechanisms. Here, we show that snaR-A interacts with mRNA splicing factors, including the U2 small nuclear ribonucleoprotein (snRNP) subunit SF3B2, and localizes near subnuclear foci enriched in splicing machinery. Overexpression of snaR-A increases intron retention, a hallmark of inefficient splicing, whereas its depletion enhances splicing of mRNAs characterized by high U2 snRNP occupancy and nuclear speckle proximity. These improvements in splicing coincide with reduced cell proliferation, consistent with tumor-level patterns linking snaR-A to growth in primary cancers. Together, these findings identify snaR-A as a molecular antagonist of splicing and potential disease driver in cancer. We propose that snaR-A-related splicing perturbation may phenocopy splicing defects attributed to U2 snRNP mutations in cancer, eliciting an alternative, non-mutational mechanism of splicing dysregulation during tumorigenesis.

  PublisherOA PDFDOI

• Cholesterol efflux protein, ABCA1, supports anti-cancer functions of myeloid immune cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-19 · 2 citations

  preprintOpen access

  ABSTRACT Although immune therapy has seen significant advances, the majority of breast and other solid tumors do not respond or quickly develop de novo resistance. One factor driving resistance is highly immune suppressive myeloid cells (MCs) such as macrophages. Previous work has established clinical links between cholesterol and cancer outcome, and that MC function can be regulated through disruption in cholesterol metabolism. Thus, we screened for proteins that were expressed in MCs, involved in cholesterol homeostasis and whose expression was associated with survival; we identify the cholesterol efflux protein ABCA1. Preclinical studies revealed that ABCA1 activity resulted in increased anti-cancer functions of macrophages: enhanced tumor infiltration, decreased angiogenic potential, reduced efferocytosis, and improved support of CD8+ T cell activity. Mechanistically, different AKT isoforms are involved, through both PI3K dependent and independent mechanisms. Assessment of human blood and breast tumors revealed correlations between ABCA1 in macrophages and angiogenic potential, VEGFA , and CD8 T cell abundance and activity, highlighting the clinical relevance of our findings. The culmination of the effects of ABCA1 on MC function were demonstrated through increased tumor growth and metastasis in mice with MC specific knockout of ABCA1. Therefore, modulating ABCA1 activity within MCs may represent a novel approach to immune therapy.

  PublisherOA PDFDOI

• An RNA polymerase III tissue and tumor atlas uncovers context-specific activities linked to 3D epigenome regulatory mechanisms

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-01

  preprintOpen accessSenior authorCorresponding

  RNA polymerase III (Pol III) produces a plethora of small noncoding RNA species involved in diverse cellular processes, from transcription regulation and splicing to RNA stability, translation, and proteostasis. Though Pol III activity is broadly coupled with cellular demands for protein synthesis and growth, a more precise understanding of gene-level dynamics and context-specific expression patterns remains missing, in part due to challenges related to sequencing and mapping Pol III-derived small ncRNAs. Here, we establish a predictive multi-tissue map of human Pol III activity across 19 tissues and 23 primary cancer subtypes by comprehensively profiling the chromatin accessibility of canonical Pol III-transcribed gene classes. Our framework relies on the unique relationship between gene accessibility and Pol III transcription, inferring activity through uniform binary classification of ATAC-seq enrichment at Pol III-transcribed genes. By characterizing multi-context gene uniformity, we provide a definition of the core Pol III transcriptome, broadly active across specialized tissues, and catalog genes with varied levels of context specificity. Our genomic Pol III atlas uncovers variable levels of activity across tissues, including sharp contraction of the Pol III transcriptome in heart and brain tissues and frequent expansion across diverse cancers. We show that both tissue- and tumor-specific genes are significantly enriched within lamina-associated domains (LADs), and that aberrant expression of nuclear lamin proteins is sufficient to induce Pol III-emergent patterns at tumor-specific genes. Together, these findings link Pol III dynamics to subnuclear compartmentalization and provide a resource for better understanding Pol III expansion and small RNA biogenesis in cancer.

  PublisherOA PDFDOI

• The NuRD complex shapes RNA polymerase III activity at highly expressed tRNA gene clusters, tuning the dynamic range of cellular tRNA pools

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-13

  preprintOpen accessSenior authorCorresponding

  RNA polymerase III (Pol III) produces noncoding RNAs involved in diverse cellular activities, including translation (tRNA, 5S rRNA, 7SL RNA), RNA processing (U6 snRNA, RPPH1, RMRP), and transcription regulation (7SK snRNA). In this way, Pol III activity must be broadly coupled with cellular demands for protein accumulation and growth, increasing in response to nutrient availability and decreasing during differentiation and exit from proliferation. However, the currently established mechanisms of Pol III regulation remain relatively limited, due in part to the few Pol III-centered protein-protein interaction (PPI) studies performed to date. To address this gap, we first investigated PPIs shared by multiple Pol III subunits to understand the macromolecular interactome of Pol III, with special attention directed at potential regulatory candidates. Our proteomic survey uncovers interactions between Pol III and the NuRD (Nucleosome Remodeling and Deacetylase) complex. Taken further, we show that NuRD localizes to active Pol III-transcribed genes and that its recruitment is Pol III-dependent but nonrandom, with peak occupancy and regulatory hallmarks converging on tRNA gene clusters associated with notably high expression levels. Inhibiting NuRD-associated histone deacetylase function reduces Pol III transcription at these sites, suggesting NuRD restricts Pol III and thereby modulates the global dynamic range of Pol III-derived RNA species. These findings are congruent with the transcriptionally repressive nature of NuRD and bring-to-light a new regulatory mechanism that may couple signaling events and changes in metabolic needs with the dynamic availability of specific tRNA pools.

  PublisherDOI

• Abstract B063: The cholesterol efflux protein, ABCA1, plays a critical role in modulating anti-tumor myeloid immune cell functions

  Cancer Immunology Research · 2025-02-23

  article

  Abstract Although significant strides have been made in immune-targeting therapies such as immune checkpoint blockade (ICB), many solid tumors do not respond and acquired resistance is common, especially for metastatic disease. For example, ICB is only FDA approved for metastatic breast cancer of the triple negative subtype (TNBC) where tumors stain positive for PD-L1, but even amongst this cohort, the response rate modest. Although multifactorial, a major driver of resistance is thought to be contributed by immune suppressive myeloid immune cells, such as macrophages. Interestingly, we and others have found that regulators of cholesterol homeostasis have profound effects on myeloid cell function. Therefore, we performed in silico screens to identify potential targets that (1) are involved in cholesterol homeostasis, (2) are expressed in myeloid cells, and (3) whose expression in tumors is associated with survival. In so doing, we identified ABCA1, a protein involved in cholesterol efflux. ABCA1 was found to modulate several functions of macrophages important for tumor pathophysiology: increased ability to infiltrate tumor spheroids, decreased angiogenic potential, decreased efferocytosis, and enhanced support of CD8+ T cell expansion and their anti-cancer cytotoxic activity. Importantly, immunohistochemistry assessment of breast tumor microarrays found an inverse correlation between myeloid cell expression of ABCA1 and CD8+ cells, highlighting the clinical relevance of our results. Syngeneic mammary and melanoma tumors grew at a significantly enhanced rate in mice lacking myeloid cell ABCA1 (ABCA1+/+;LysMcre+ vs. ABCA1fl/fl;LysMcre+). Therefore, our data strongly suggest that ABCA1 is able to ‘re-educate’ myeloid immune cells towards an anti-cancer phenotype. As such, it represents a novel therapeutic target. This work was supported by the an Era of Hope Scholar Award from the Department of Defense Breast Cancer Research Program grant (BC200206) and the Cancer Center at Illinois. Citation Format: Shruti V Bendre, Natalia Krawczynska, Rajendra K C, Yu Wang, Shaunak Bhogale, Erin Weisser, Basel Hajyousif, Simon Han, Avni Singh, Claire P. Schane, Adam T. Nelczyk, Dhanya Pradeep, Anasuya Das Gupta, Lara Kockaya, Hashni Epa Vidana Gamage, Kevin Van Bortle, Emad Tajkorshid, Saurabh Sinha, Wendy A. Woodward, Wonhwa Cho, Erik R Nelson. The cholesterol efflux protein, ABCA1, plays a critical role in modulating anti-tumor myeloid immune cell functions [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B063.

  PublisherDOI

• Evidence of RNA polymerase III recruitment and transcription at protein-coding gene promoters

  Molecular Cell · 2024-10-10 · 11 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• MANCR lncRNA Modulates Cell-Cycle Progression and Metastasis by Cis-Regulation of Nuclear <i>Rho-GEF</i>

  Molecular and Cellular Biology · 2024-08-12 · 6 citations

  articleOpen access

  -regulation of gene expression.

  PublisherOA PDFDOI

• Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-07-03 · 2 citations

  preprintOpen accessSenior authorCorresponding

  RNA polymerase III (Pol III) activity in cancer is linked to the production of small noncoding (nc)RNAs that are otherwise silent in most tissues. snaR-A (small NF90-associated RNA isoform A) - a hominid-specific ncRNA shown to enhance cell proliferation, migration, and invasion - is a cancer-emergent Pol III product that remains largely uncharacterized despite promoting growth phenotypes. Here, we applied a combination of genomic and biochemical approaches to study the biogenesis and subsequent protein interactions of snaR-A and to better understand its role as a putative driver of cancer progression. By profiling the chromatin landscapes across a multitude of primary tumor types, we show that predicted snaR-A upregulation is broadly linked with unfavorable outcomes among cancer patients. At the molecular level, we unexpectedly discover widespread interactions between snaR-A and mRNA splicing factors, including SF3B2 - a core component of the U2 small nuclear ribonucleoprotein (snRNP). We find that SF3B2 levels are sensitive to high snaR-A abundance and that depletion of snaR-A alone is sufficient to decrease intron retention levels across subpopulations of mRNA enriched for U2 snRNP occupancy. snaR-A sensitive genes are characterized by high GC content, close spatial proximity to nuclear bodies concentrated in pre-mRNA splicing factors, and functional enrichment for proteins involved in deacetylation and autophagy. We highlight examples of splicing misregulation and increased protein levels following snaR-A depletion for a wide-ranging set of factors, suggesting snaR-A-driven splicing defects may have far-reaching effects that re-shape the cellular proteome. These findings clarify the molecular activities and consequences of snaR-A in cancer, and altogether establish a novel mechanism through which Pol III overactivity may promote tumorigenesis.

  PublisherDOI

• Evidence of RNA polymerase III recruitment and transcription at protein-coding gene promoters

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-09 · 4 citations

  preprintOpen accessSenior authorCorresponding

  RNA polymerase (Pol) I, II, and III are most commonly described as having distinct roles in synthesizing ribosomal RNA (rRNA), messenger RNA (mRNA), and specific small noncoding (nc)RNAs, respectively. This delineation of transcriptional responsibilities is not definitive, however, as evidenced by instances of Pol II recruitment to genes conventionally transcribed by Pol III, including the co-transcription of RPPH1 - the catalytic RNA component of RNase P. A comprehensive understanding of the interplay between RNA polymerase complexes remains lacking, however, due to limited comparative analyses for all three enzymes. To address this gap, we applied a uniform framework for quantifying global Pol I, II, and III occupancies that integrates currently available human RNA polymerase ChIP-seq datasets. Occupancy maps are combined with a comprehensive multi-class promoter set that includes protein-coding genes, noncoding genes, and repetitive elements. While our genomic survey appropriately identifies recruitment of Pol I, II, and III to canonical target genes, we unexpectedly discover widespread recruitment of the Pol III machinery to promoters of specific protein-coding genes, supported by colocalization patterns observed for several Pol III-specific subunits. We show that Pol III-occupied Pol II promoters are enriched for small, nascent RNA reads terminating in a run of 4 Ts, a unique hallmark of Pol III transcription termination and evidence of active Pol III activity at these sites. Pol III disruption differentially modulates the expression of Pol III-occupied coding genes, which are functionally enriched for ribosomal proteins and genes broadly linked to unfavorable outcomes in cancer. Our map also identifies additional, currently unannotated genomic elements occupied by Pol III with clear signatures of nascent RNA species that are sensitive to disruption of La (SSB) - a Pol III-related RNA chaperone protein. These findings reshape our current understanding of the interplay between Pols II and III and identify potentially novel small ncRNAs with broad implications for gene regulatory paradigms and RNA biology.

  PublisherOA PDFDOI

Recent grants

• Integrated Personalized Epigenome Profiling and the Effect of Dietary Exposure on Individuals at Risk for Type-2-Diabetes

  NIH · $162k · 2015–2018

Frequent coauthors

• Victor G. Corces

  Emory University

  22 shared

• M Snyder

  17 shared

• Joseph C. Wu

  12 shared

• Andrew M. Lipchik

  Eugene Applebaum College of Pharmacy and Health Sciences

  9 shared

• Qing Liu

  Commonwealth Scientific and Industrial Research Organisation

  8 shared

• Chao Jiang

  Zhejiang University

  8 shared

• Naomi Takenaka

  8 shared

• Douglas H. Phanstiel

  University of North Carolina at Chapel Hill

  7 shared

Labs

• Van Bortle LabPI

Awards & honors

• NIH Pathway to Independence Award (K99/R00) (2019-2024)
• Ruth L. Kirschstein National Research Service Award (NRSA F3…