About

Ian Davis, M.D., Ph.D., is the Principal Investigator of the Davis Lab at The University of North Carolina at Chapel Hill. His research focuses on the application of integrated genome-wide approaches to identify the epigenetic and chromatin biology consequences of genetic alterations in human cancers. A primary focus of his lab is Ewing sarcoma, where they explore the mechanism through which the chromosomal translocation-derived fusion oncoprotein EWSR1-FLI1 regulates chromatin states and target genes. Leveraging their expertise in epigenomics, the lab also collaborates with other research groups across the campus studying various cancers and developmental disorders. In addition to his research, Dr. Davis is a pediatric hematologist-oncologist specializing in the care of children and young adults with bone and soft tissue sarcomas. Outside of his professional work, he enjoys spending time with his family, woodworking, and solving the New York Times crossword puzzle.

Research topics

• Biology
• Genetics
• Computational biology
• Evolutionary biology
• Mathematics
• Cancer research
• Virology
• Statistics

Selected publications

• Comparative effectiveness of first-line targeted therapies in ALK-positive non-small cell lung cancer: real-world evidence of tyrosine kinase inhibitors

  Lung Cancer · 2026-05-10

  article
  PublisherDOI

• Casein Kinase II Phosphorylation of Spt6 Enforces Transcriptional Fidelity by Maintaining Spn1-Spt6 Interaction

  UNC Libraries · 2026-04-14

  articleOpen accessSenior author
  PublisherDOI

• Abstract 2685: Analysis of long-read sequencing data with <i>vmwhere</i> reveals variation in microsatellite length and chromatin state in Ewing sarcoma.

  Cancer Research · 2026-04-03

  articleSenior author

  Abstract Microsatellites (mSats), or short tandem repeats (STRs), are repeated 1-6 bp DNA motifs that are abundantly distributed across the human genome. Variation in STR length contributes to genetic diversity and structural variation, and expansions beyond a pathogenic threshold underlie nearly 60 genetic disorders. mSat repeats can also serve as non-canonical enhancers for transcriptional regulators, including through binding the EWS::FLI1 fusion oncoprotein of Ewing sarcoma. Genome-wide analysis of mSats has been limited by short-read sequencing constraints, including read length and mapping ambiguity. Long-read sequencing has improved analyses of these regions but requires specialized algorithms. We developed a computational pipeline for genome-wide reference-based detection, length genotyping, sequence decomposition, and visualization of tetrameric mSats using long-read nanopore whole-genome sequencing. We applied this approach to GGAA mSats in five Ewing sarcoma cell lines and 100 diverse normal population genomes. We find both EWS::FLI1 binding to GGAA mSats and chromatin accessibility correlated with repeat length. Comparative analysis revealed a subset of mSats (2 - 3%) that were selectively expanded or contracted in Ewing sarcoma relative to normal genomes. Although we hypothesized that this variation in mSat length would converge towards a similar repeat length, we found that expanded loci tend to fall between 11 and 13 whereas contracted loci are commonly between 4 and 6. Further, expanded mSats demonstrated the highest proportion of mSats with EWS::FLI1 occupancy and accessible chromatin, compared to same and contracted. Finally, we show mSats demonstrating cell line-specific gained or lost chromatin accessibility was associated with expansion and contraction, respectively, in those cells. These results reveal a selective expansion of chromatin accessible mSats in Ewing sarcoma and provide a generalizable framework for resolving the genetic and structural complexity of mSats in human disease using long-read sequencing. Citation Format: Sara K. Peterson, A McCauley Massie, Alex Rubinsteyn, Jeremy R. Wang, Ian J. Davis, . Analysis of long-read sequencing data with vmwhere reveals variation in microsatellite length and chromatin state in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2685.

  PublisherDOI

• Long-read analysis of tetrameric microsatellites with vmwhere supports GGAA repeat length–dependent chromatin state association in Ewing sarcoma

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-10

  articleOpen accessSenior authorCorresponding

  Microsatellites are abundant genomic elements that contribute to genetic diversity and disease-associated regulatory variation. Although long-read sequencing enables accurate resolution of repetitive regions, computational methods for fully resolved microsatellite genotyping remain limited. Here, we introduce variant motif where (vmwhere), a computational framework for identifying, genotyping, decomposing, and visualizing complex tetrameric microsatellites from long-read sequencing data. Using simulated error-free reads, vmwhere accurately measures several genotyping metrics, including allele length, repeat length, maximum consecutive repeat length, and motif density. Applied to long-read whole-genome sequencing data, vmwhere identified sequence interruptions, motif-specific differences in repeat architecture, and ancestry-associated allele variation, including long repeat alleles that exceed short-read sequencing limitations. We applied vmwhere to GGAA microsatellites in Ewing sarcoma, an aggressive pediatric cancer driven by EWS-FLI1 fusion oncoprotein, which binds to microsatellites and remodels chromatin. Genome-wide integration of long-read-defined microsatellite architecture with chromatin accessibility and EWS-FLI1 binding revealed that GGAA repeat structure was associated with chromatin state, with longer consecutive repeat microsatellites exhibiting increased EWS-FLI1 binding and chromatin accessibility. Cell line-specific expansions and contractions of GGAA microsatellite repeat length were associated with gains and losses of chromatin accessibility. Further, we identified haplotype-specific chromatin states, with preferential binding and accessibility at longer alleles. Together, these results establish vmwhere as a scalable framework for resolving population-level microsatellite variation and linking repeat architecture to chromatin state. Repeat structure and length characteristics provides insights into genotype-function relationships at microsatellite repeats in cancer.

  PublisherDOI

• Shared PRAME Epitopes are T-Cell Targets in NUT Carcinoma

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-12 · 2 citations

  preprintOpen access

  Abstract Background NUT carcinoma is a rare but highly lethal solid tumor without an effective standard of care. NUT carcinoma is caused by bromodomain-containing NUTM1 fusion oncogenes, most commonly BRD4::NUTM1 . BRD4::NUTM1 recruits p300 to acetylate H3K27 forming expansive stretches of hyperacetylated chromatin called “megadomains” with the overexpression of corresponding oncogenes, including MYC . We hypothesized that transcriptional dysregulation caused by BRD4::NUTM1 would lead to the generation of cancer-specific antigens that could be therapeutically actionable. Methods We integrated genomics, computational antigen prediction software, targeted immunopeptidomics using single- and double-labeled peptide standards, and gain/loss-of-function genetic experiments on a panel of cell lines (N=5), a patient derived xenograft, a tissue microarray (N=77), and patient samples from the Tempus AI Sequencing Database harboring evidence of NUTM1 fusions (N=165). We created an αPRAME 425 T-cell receptor x SP34 αCD3 bispecific molecule modeled after brenetafusp, an αPRAME 425 T-cell receptor bispecific T-cell engager, as well as αPRAME 425 TCR T-cells based on anzutresgene autoleucel and we applied these products to NUT carcinoma cells in vitro . Results We identified PRAME as the most commonly expressed cancer/testis antigen in patient samples harboring the three canonical NUT carcinoma fusions ( BRD4::NUTM1 , BRD3::NUTM1 , and NSD3::NUTM1 ). Additionally, 56% (43/77) of NUT carcinoma tissue microarray samples stained positive for PRAME. BRD4::NUTM1 expression in HEK 293T cells enhanced PRAME levels and BRD4::NUTM1 knockout in NUT carcinoma cells reduced PRAME levels. Immunopeptidomics detected more PRAME-derived HLA ligands (N=9) than all other cancer/testis antigens combined (N=5). Targeted mass spectrometry detected the HLA-A*02:01/SLLQHLIGL (PRAME 425 ) epitope in 100% (4/4) of HLA-A*02+, PRAME+ NUT carcinoma samples at higher levels (&gt;0.01 fM) than HLA-A*02:01/RLDQLLRHV (PRAME 312 ) or HLA-A*02:01/YLHARLREL (PRAME 462 ). The αPRAME 425 T-cell receptor x SP34 αCD3 bispecific molecule and αPRAME 425 TCR T-cells each exhibited potent, T-cell mediated cytotoxicity against PRAME + NUT carcinoma cells. Conclusions PRAME is highly and frequently expressed in NUT carcinoma and the most common oncoprotein causing NUT carcinoma, BRD4::NUTM1, contributes to these high PRAME levels. PRAME epitopes presented by HLA Class I are a previously unrecognized therapeutic vulnerability for NUT carcinoma that warrant clinical trials testing PRAME targeted immunotherapies in this neglected patient population. What is already known on this topic NUT carcinoma is a devastating malignancy that is recalcitrant to cytotoxic chemotherapy, T-cell checkpoint blockade, and targeted therapies in the form of bromodomain inhibitors. What this study adds NUT carcinoma tumors are high in the cancer/testis gene PRAME . The oncogene most commonly causing NUT carcinoma, BRD4::NUTM1 , contributes to these high levels. NUT carcinoma cells present PRAME epitopes on HLA Class I molecules and are susceptible to PRAME-directed, T-cell mediated cytotoxicity. How this study might affect research, practice or policy Our results argue for phase I/II clinical trials testing PRAME immunotherapies like brenetafusp or anzutresgene autoleucel in PRAME + NUT carcinoma patients. Graphical Abstract

  PublisherOA PDFDOI

• Discrete Adaptive Responses to MEK Inhibitor in Subpopulations of Triple-Negative Breast Cancer

  UNC Libraries · 2025-10-10

  articleOpen access

  Triple-negative breast cancers contain a spectrum of epithelial and mesenchymal phenotypes. SUM-229PE cells represent a model for this heterogeneity, maintaining both epithelial and mesenchymal subpopulations that are genomically similar but distinct in gene expression profiles. We identified differential regions of open chromatin in epithelial and mesenchymal cells that were strongly correlated with regions of H3K27ac. Motif analysis of these regions identified consensus sequences for transcription factors that regulate cell identity. Treatment with the MEK inhibitor trametinib induced enhancer remodeling that is associated with transcriptional regulation of genes in epithelial and mesenchymal cells. Motif analysis of enhancer peaks downregulated in response to chronic treatment with trametinib identified AP-1 motif enrichment in both epithelial and mesenchymal subpopulations. Chromatin immunoprecipitation sequencing (ChIP-seq) of JUNB identified subpopulation-specific localization, which was significantly enriched at regions of open chromatin. These results indicate that cell identity controls localization of transcription factors and chromatin-modifying enzymes to enhancers for differential control of gene expression. We identified increased H3K27ac at an enhancer region proximal to CXCR7, a G-protein-coupled receptor that increased 15-fold in expression in the epithelial subpopulation during chronic treatment. RNAi knockdown of CXCR7 inhibited proliferation in trametinib-resistant cells. Thus, adaptive resistance to chronic trametinib treatment contributes to proliferation in the presence of the drug. Acquired amplification of KRAS following trametinib dose escalation further contributed to POS cell proliferation. Adaptive followed by acquired gene expression changes contributed to proliferation in trametinib-resistant cells, suggesting inhibition of early transcriptional reprogramming could prevent resistance and the bypass of targeted therapy. IMPLICATIONS: We defined the differential responses to trametinib in subpopulations of a clinically relevant <em>in vitro</em> model of TNBC, and identified both adaptive and acquired elements that contribute to the emergence of drug resistance mediated by increased expression of CXCR7 and amplification of KRAS.

  PublisherDOI

• Genome-wide cancer-specific chromatin accessibility patterns derived from archival processed xenograft tumors

  UNC Libraries · 2025-11-18

  articleOpen access

  Chromatin accessibility states that influence gene expression and other nuclear processes can be altered in disease. The constellation of transcription factors and chromatin regulatory complexes in cells results in characteristic patterns of chromatin accessibility. The study of these patterns in tissues has been limited because existing chromatin accessibility assays are ineffective for archival formalin-fixed, paraffin-embedded (FFPE) tissues. We have developed a method to efficiently extract intact chromatin from archival tissue via enhanced cavitation with a nanodroplet reagent consisting of a lipid shell with a liquid perfluorocarbon core. Inclusion of nanodroplets during the extraction of chromatin from FFPE tissues enhances the recovery of intact accessible and nucleosome-bound chromatin. We show that the addition of nanodroplets to the chromatin accessibility assay formaldehyde-assisted isolation of regulatory elements (FAIRE), does not affect the accessible chromatin signal. Applying the technique to FFPE human tumor xenografts, we identified tumor-relevant regions of accessible chromatin shared with those identified in primary tumors. Further, we deconvoluted non-tumor signal to identify cellular components of the tumor microenvironment. Incorporation of this method of enhanced cavitation into FAIRE offers the potential for extending chromatin accessibility to clinical diagnosis and personalized medicine, while also enabling the exploration of gene regulatory mechanisms in archival samples.

  PublisherDOI

• A SETD2–CDK1–lamin axis maintains nuclear morphology and genome stability

  Nature Cell Biology · 2025-08-01 · 6 citations

  articleOpen access
  PublisherOA PDFDOI

• Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma

  UNC Libraries · 2024-10-22

  articleOpen accessSenior author
  PublisherDOI

• PBRM1 Inactivation Promotes Upregulation of Human Endogenous Retroviruses in a HIF-Dependent Manner

  UNC Libraries · 2024-07-27

  articleOpen access1st authorCorresponding

  Clear cell renal cell carcinoma (ccRCC) is considered an immunotherapy-responsive disease; however, the reasons for this remain unclear. Studies have variably implicated PBRM1 mutations as a predictive biomarker of immune checkpoint blockade (ICB) response, and separate studies demonstrate that expression of human endogenous retroviruses (hERV) might be an important class of tumor-associated antigens. We sought to understand whether specific mutations were associated with hERV expression. Two large, annotated genomic datasets, TCGA KIRC and IMmotion150, were used to correlate mutations and hERV expression. PBRM1 mutations were consistently associated with increased hERV expression in primary tumors. In vitro silencing of PBRM1, HIF1A, and HIF2A followed by RNA sequencing was performed in UMRC2 cells, confirming that PBRM1 regulates hERVs in a HIF1α- and HIF2α-dependent manner and that hERVs of the HERVERI superfamily are enriched in PBRM1-regulated hERVs. Our results uncover a role for PBRM1 in the negative regulation of hERVs in ccRCC. Moreover, the HIF-dependent nature of hERV expression explains the previously reported ccRCC-specific clinical associations of PBRM1-mutant ccRCC with both a good prognosis as well as improved clinical outcomes to ICB. See related Spotlight by Labaki et al., p. 274.

  PublisherDOI

Recent grants

• Chromatin maintenance in cancer progression

  NIH · $2.3M · 2015–2022

• NIH Grant R01CA166447

  NIH · $1.6M · 2017

• The application of Enhanced Cavitation to enable DNA and Chromatin Extraction from Archived Tissues

  NIH · $1.1M · 2017–2021

• NIH Grant K08CA100400

  NIH · $684k · 2009

• Targeting EWS-FLI1 protein stability as therapeutic strategy for Ewing sarcoma

  NIH · $372k · 2019–2021

Frequent coauthors

• Rory Johnson

  University Hospital of Bern

  178 shared

• W. Kimryn Rathmell

  174 shared

• Roland Eils

  154 shared

• Thomas J. Mitchell

  Wellcome Sanger Institute

  154 shared

• P. Andrew Futreal

  144 shared

• Lars Feuerbach

  German Cancer Research Center

  138 shared

• L. Sylvia

  Mirai Hospital

  135 shared

• Geoff Macintyre

  Spanish National Cancer Research Centre

  130 shared

Labs

• The Davis LabPI

  Meet our Team!

Education

• MD

  Northwestern University Feinberg School of Medicine

  1995

• PhD

  University of Illinois at Chicago

  1994

• BA

  Northwestern University

  1987