About

Daniel McKay is an Associate Professor of Biology and Genetics at the University of North Carolina at Chapel Hill. He is the Director of Graduate Studies within the Genetics and Molecular Biology Curriculum. His office is located in the 3358 Genome Sciences Building. Further details about his research focus, background, and key contributions are not provided on the page.

Research topics

• Biology
• Data Mining
• Cell biology
• Computer Science
• Genetics
• World Wide Web
• Data science
• Database
• Cancer research
• Programming language

Selected publications

• Transcriptomic bases of a polyphenism

  UNC Libraries · 2026-04-15

  articleOpen access

  Polyphenism-in which multiple distinct phenotypes are produced from a single genotype owing to differing environmental conditions-is commonplace, but its molecular bases are poorly understood. Here, we examine the transcriptomic bases of a polyphenism in Mexican spadefoot toads (Spea multiplicata). Depending on their environment, their tadpoles develop into either a default "omnivore" morph or a novel "carnivore" morph. We compared patterns of gene expression among sibships that exhibited high versus low production of carnivores when reared in conditions that induce the carnivore morph versus those that do not. We found that production of the novel carnivore morph actually involved changes in fewer genes than did the maintenance of the default omnivore morph in the inducing environment. However, only body samples showed this pattern; head samples showed the opposite pattern. We also found that changes to lipid metabolism (especially cholesterol biosynthesis) and peroxisome contents and function might be crucial for establishing and maintaining differences between the morphs. Thus, our findings suggest that carnivore phenotype might have originally evolved following the breakdown of robustness mechanisms that maintain the default omnivore phenotype, and that the carnivore morph is developmentally regulated by lipid metabolism and peroxisomal form, function, and/or signaling. This study also serves as a springboard for further exploration into the nature and causes of plasticity in an emerging model system.

  PublisherDOI

• Cohesin stabilization at promoters and enhancers by common transcription factors and chromatin regulators

  Epigenetics & Chromatin · 2025-06-09 · 6 citations

  articleOpen access

  BACKGROUND: Cohesin is a major regulator of three-dimensional genome organization and gene expression. Cohesin associates with DNA and dynamically extrudes a DNA loop, often bringing two cis-regulatory elements physically close together. Extruding cohesin molecules can be stalled or stabilized when they encounter a CTCF insulator protein on DNA, thereby anchoring a DNA loop. However, many enhancer-promoter loops that are bound by cohesin lack CTCF and it is not clear how cohesin is stabilized at or recruited to these sites in the genome. RESULTS: Here, we investigated the localization of cohesin with common chromatin regulators and transcription factors on the mouse embryonic stem cell genome. The SP1 and NFYA transcription factors are ubiquitously expressed proteins known to regulate expression of genes associated with a variety of cellular processes, while WDR5 is a ubiquitous core component of multiple chromatin regulatory complexes. We found that cohesin co-bound promoters and enhancers with WDR5, with SP1, or with NFYA in mESCs. Cohesin physically interacted with and colocalized with WDR5, with SP1, or with NFYA on the same molecule of chromatin. Strikingly, depletion of WDR5, SP1, or NFYA caused a decrease in cohesin binding at shared binding sites, while depletion of cohesin did not alter binding of WDR5, SP1, or NFYA on the genome. CONCLUSIONS: These results indicate that common transcription factors and chromatin regulators stabilize cohesin at specific sites in chromatin and may thereby serve as structural regulators of enhancer-promoter loops via the stabilization of cohesin.

  PublisherOA PDFDOI

• Evidence for dual roles of histone H3 lysine 4 in antagonizing Polycomb group function and promoting target gene expression.

  UNC Libraries · 2025-05-20

  articleOpen access

  Tight control over cell identity gene expression is necessary for proper adult form and function. The opposing activities of Polycomb and trithorax complexes determine the on/off state of cell identity genes such as the Hox factors. Polycomb group complexes repress target genes, whereas trithorax group complexes are required for their expression. Although trithorax and its orthologs function as methyltransferases specific to histone H3 lysine 4 (H3K4), there is no direct evidence that H3K4 regulates Polycomb group target genes in vivo. Using histone gene replacement in <em>Drosophila</em>, we provide evidence of two key roles for replication-dependent histone H3.2K4 in Polycomb target gene control. First, we found that H3.2K4 mutants mimic H3.2K4me3 in antagonizing methyltransferase activity of the PRC2 Polycomb group complex. Second, we found that H3.2K4 is also required for proper activation of Polycomb targets. We conclude that H3.2K4 directly regulates Polycomb target gene expression.

  PublisherDOI

• Heterochromatic 3D genome organization is directed by HP1a- and H3K9-dependent and independent mechanisms

  UNC Libraries · 2025-06-07

  articleOpen access
  PublisherDOI

• A small-molecule VHL molecular glue degrader for cysteine dioxygenase 1

  Nature Chemical Biology · 2025-06-24 · 27 citations

  article
  PublisherDOI

• Redesigning the Drosophila histone gene cluster: an improved genetic platform for spatiotemporal manipulation of histone function

  UNC Libraries · 2025-07-23

  articleOpen access

  Mutating replication-dependent (RD) histone genes is an important tool for understanding chromatin-based epigenetic regulation. Deploying this tool in metazoans is particularly challenging because RD histones in these organisms are typically encoded by many genes, often located at multiple loci. Such gene arrangements make the ability to generate homogenous histone mutant genotypes by site-specific gene editing quite difficult. Drosophila melanogaster provides a solution to this problem because the RD histone genes are organized into a single large tandem array that can be deleted and replaced with transgenes containing mutant histone genes. In the last ∼15 years several different RD histone gene replacement platforms were developed using this simple strategy. However, each platform contains weaknesses that preclude full use of the powerful developmental genetic capabilities available to Drosophila researchers. Here we describe the development of a newly engineered platform that rectifies many of these weaknesses. We used CRISPR to precisely delete the RD histone gene array (HisC), replacing it with a multifunctional cassette that permits site-specific insertion of either one or two synthetic gene arrays using selectable markers. We designed this cassette with the ability to selectively delete each of the integrated gene arrays in specific tissues using site-specific recombinases. We also present a method for rapidly synthesizing histone gene arrays of any genotype using Golden Gate cloning technologies. These improvements facilitate generation of histone mutant cells in various tissues at different stages of Drosophila development and provide an opportunity to apply forward genetic strategies to interrogate chromatin structure and gene regulation.

  PublisherDOI

• An RNAi-based platform for spatiotemporal control of histone gene expression during animal development

  Research Square · 2025-06-04 · 1 citations

  preprintOpen accessSenior author
  PublisherOA PDFDOI

• Heterochromatic 3D genome organization is directed by HP1a- and H3K9-dependent and independent mechanisms

  Molecular Cell · 2024-05-24 · 22 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Supramolecular assembly of the beta-catenin destruction complex and the effect of Wnt signaling on its localization, molecular size, and activity in vivo

  UNC Libraries · 2024-08-14

  articleOpen access

  Wnt signaling provides a paradigm for cell-cell signals that regulate embryonic development and stem cell homeostasis and are inappropriately activated in cancers. The tumor suppressors APC and Axin form the core of the multiprotein destruction complex, which targets the Wnt-effector beta-catenin for phosphorylation, ubiquitination and destruction. Based on earlier work, we hypothesize that the destruction complex is a supramolecular entity that self-assembles by Axin and APC polymerization, and that regulating assembly and stability of the destruction complex underlie its function. We tested this hypothesis in Drosophila embryos, a premier model of Wnt signaling. Combining biochemistry, genetic tools to manipulate Axin and APC2 levels, advanced imaging and molecule counting, we defined destruction complex assembly, stoichiometry, and localization in vivo, and its downregulation in response to Wnt signaling. Our findings challenge and revise current models of destruction complex function. Endogenous Axin and APC2 proteins and their antagonist Dishevelled accumulate at roughly similar levels, suggesting competition for binding may be critical. By expressing Axin:GFP at near endogenous levels we found that in the absence of Wnt signals, Axin and APC2 co-assemble into large cytoplasmic complexes containing tens to hundreds of Axin proteins. Wnt signals trigger recruitment of these to the membrane, while cytoplasmic Axin levels increase, suggesting altered assembly/disassembly. Glycogen synthase kinase3 regulates destruction complex recruitment to the membrane and release of Armadillo/beta-catenin from the destruction complex. Manipulating Axin or APC2 levels had no effect on destruction complex activity when Wnt signals were absent, but, surprisingly, had opposite effects on the destruction complex when Wnt signals were present. Elevating Axin made the complex more resistant to inactivation, while elevating APC2 levels enhanced inactivation. Our data suggest both absolute levels and the ratio of these two core components affect destruction complex function, supporting models in which competition among Axin partners determines destruction complex activity.

  PublisherDOI

• A phase 2 safety and efficacy study of neoadjuvant/adjuvant darovasertib for localized ocular melanoma.

  Journal of Clinical Oncology · 2024-06-01 · 7 citations

  article

  9510 Background: Darovasertib is a protein kinase C (PKC) inhibitor with meaningful activity in metastatic uveal melanoma (UM) due to its effect on PKC delta downstream of canonical GNAQ/GNA11 mutations. To date, its clinical activity in patients with localized primary disease has not been assessed in either neoadjuvant or adjuvant settings. Methods: Patients planned for enucleation with localized UM were treated in an initial safety cohort with darovasertib 300mg BID for 1 month (n=3 patients), and then following DSMB agreement in an expansion cohort for up to 6 months (n=12 patients) as neoadjuvant treatment prior to definitive management (enucleation, plaque brachytherapy or EBRT) across 3 Australian centers. All patients were eligible to receive up to 6 months of adjuvant treatment with darovasertib at investigator discretion after definitive management of their primary tumour. Tumour volume was calculated by the rotational ellipsoid method. Results: 15 patients (male n=7, female n=8; median age 62 years (range, 33-76 years)) were enrolled. At baseline, AJCC tumor stages were T3a (n=5), T3b (n=4), T4a (n=4), T4b (n=2), and the median tumor size (maximum thickness/diameter/volume) was 9.7mm/ 15.6 mm/ 2463 mm 3 . At datalock; 11/15 patients had completed primary treatment, 4/15 remained on neoadjuvant treatment, 6 patients received adjuvant darovasertib after primary treatment of their UM with 3 patients completing the planned 6-months . Median tumor shrinkage (maximum height/base/volume change) was 11.2%/ 7.6%/ 22.7% after 1 month of treatment and 31.7%/ 11.9% /45.3% after 6 months. At datalock, 6/9 (66%) currently completed neoadjuvant patients were converted to plaque brachytherapy (n=5) or EBRT (n=1) with 3 ongoing. One patient with high-risk cytogenetic features had relapsed with metastatic disease despite receiving 6-months of neoadjuvant darovasertib and another 6-months of adjuvant treatment. Treatment emergent adverse events included postural hypotension (Gr1/2 – 13/13%), syncope (Gr3 – 13%), rash (Gr1/2 – 33/5%), pruritis (Grr1 – 13%), dizziness (Gr1 – 27%), fatigue (Gr1/2 – 30/5%), nausea (Gr1/2 – 73/6%), vomiting (Gr1 – 40%), and diarrhea (Gr1 – 60%). Updated results, histopathological and genomic outcomes will be presented. Conclusions: NADOM provides the first evidence that a globe-salvage neoadjuvant treatment strategy in UM is feasible, safe, and efficacious. The results suggest that PKC inhibition with darovasertib can induce clinically meaningful tumor shrinkage in patients with primary UM patients who otherwise require enucleation. Larger trials are in now progress (NCT05907954) to further quantify visual and oncological outcomes. Clinical trial information: 05187884.

  PublisherDOI

Recent grants

• Genetic and epigenetic mechanisms of developmental gene regulation

  NIH · $3.5M · 2018–2028

• NIH Grant F32GM090759

  NIH · $73k · 2011

Frequent coauthors

• Robert J. Duronio

  51 shared

• A. Gregory Matera

  University of North Carolina at Chapel Hill

  43 shared

• Giordano Caponigro

  41 shared

• Darrin D. Stuart

  Scorpion Therapeutics (United States)

  41 shared

• Emma Labrot

  33 shared

• Felipa Mapa

  Novartis (United States)

  33 shared

• Ribo Guo

  33 shared

• Paul Fordjour

  33 shared

Labs

• Genetics and Molecular Biology CurriculumPI

Education

• B.S.

  Cornell University

• Ph.D.

  Columbia University