About

Dr. Charles Danko is an Associate Professor in the Department of Biomedical and Translational Sciences at Cornell University College of Veterinary Medicine, working within the Baker Institute for Animal Health. His research focuses on understanding how cells read and interpret DNA to regulate life processes, exploring how these mechanisms are altered in diseases such as cancer. He investigates the roles of gene enhancers in evolution, studying how they influence gene transcription across different species, including humans, chimps, rhesus macaques, mice, and rats. Additionally, Dr. Danko's team studies how cancer cells, particularly glioblastoma, utilize genes differently, aiming to identify proteins called transcription factors that drive uncontrolled cell growth, which can inform the development of targeted cancer therapies. Dr. Danko holds a PhD in Bioinformatics from SUNY Upstate Medical University and completed a postdoctoral fellowship at Cornell University in Biological Statistics & Computational Biology. His academic background includes a BS in Biomedical Engineering from Johns Hopkins University. Throughout his career, he has received several awards, including the Bausch & Lomb Honorary Science Award and fellowships from the PhRMA Foundation and other institutions. His professional experience encompasses research assistantship, graduate studies, software development, and postdoctoral research, culminating in his current faculty position where he continues to advance the understanding of gene regulation and its implications for health and disease.

Research topics

• Genetics
• Computer Science
• Biology
• Anthropology
• Data science
• Evolutionary biology
• Computational biology
• Cell biology

Selected publications

• Meiotic prophase I disruption as a strategy for nonhormonal male contraception using small-molecule inhibitor JQ1

  Proceedings of the National Academy of Sciences · 2026-04-07

  articleOpen access

  Developing safe, reversible, and nonhormonal male contraceptives has been hindered by the lack of defined biological windows that can be transiently interrupted without compromising long-term fertility. Here, we tested whether meiotic prophase I can serve as such a window by pharmacologically inhibiting the testis-specific chromatin reader BRDT using the small-molecule bromodomain inhibitor (+)-JQ1 as proof-of-principle. Short-term JQ1 administration (3 wk) selectively disrupted the pachytene transcriptional program, depleted postmeiotic germ cells, and induced a reversible arrest in spermatogenesis. Upon drug withdrawal, prophase I cytological markers normalized within 6 wk, accompanied by restoration of testis architecture and germ-cell composition. Crossover metrics and transcriptional programs recovered more gradually, reaching full normalization by 30 wk alongside complete restoration of fertility and fecundity. These results demonstrate that meiotic prophase I can be transiently inhibited to suppress spermatogenesis reversibly without inducing lasting genomic or reproductive defects, defining a stage-specific framework for the rational design of nonhormonal male contraceptives.

  PublisherDOI

• Functional and computational interrogation of juvenile idiopathic arthritis risk loci in CD4+ T cells

  Human Genetics and Genomics Advances · 2026-05-01

  articleOpen access

  Genome-wide association studies (GWASs) have identified multiple genetic regions that confer risk for juvenile idiopathic arthritis (JIA). However, identifying the single-nucleotide polymorphisms (SNPs) that drive disease risk has been impeded by the fact that the SNPs used to identify risk loci are in linkage disequilibrium (LD) with hundreds of other SNPs. Since the causal SNPs remain unknown, it is difficult to identify target genes and thus use genetic information to elucidate disease biology and inform patient care. We next used existing genotyping data from 3,939 children with JIA and 14,412 healthy controls to identify SNPs on JIA-risk haplotypes that present within open chromatin in multiple immune cell types and are more common in children with JIA than the controls (p < 0.05) in the genotyping datasets. We identified SNPs within cis-regulatory regions (cis-regulatory elements [CREs]) using precision run-on sequencing data and identified likely target genes using MicroC in both resting and activated CD4+ T cells. We identified 138 SNPs within the PROseq-identified CREs and n = 41 genes with which these CREs physically interacted. Data from Genotype-Tissue Expression (GTEx) and the Database of Immune Cell Expression Quantitative Trait Loci (DICE) corroborated these analyses by showing allelic effects for SNPs within the CREs in the ERAP2/LNPEP and locus. We further corroborated IRF1 allelic effects using a luciferase reporter assay. Our findings significantly reduce the genomic search space for risk-driving variants and target genes and support the roles of IRF1, ERAP2, and LNPEP in driving risk for JIA.

  PublisherDOI

• An end-to-end generalizable deep learning framework to comprehensively analyze transcriptional regulation

  Nature Communications · 2026-04-01

  articleOpen access

  Genome annotation currently requires performing dozens of molecular assays in hundreds of cell and tissue samples, an expensive endeavor which is impractical to replicate across all species and conditions of interest. Here, we introduce BioSeq2Seq, a deep learning framework that infers cell-line-specific molecular assays widely used for genome annotation by leveraging a tri-modal input: evolutionarily conserved DNA sequence features, together with cell-line-specific transcriptional activity and directionality captured by a single run-on sequencing assay. BioSeq2Seq enables flexible genome annotation tasks through parameterized configurations of input features and output targets, combined with gradient-guided architectural refinement for specific biological objectives. Our model demonstrates high accuracy across four downstream tasks, showing improvements of 14.27% in histone modification prediction, 2.50% in functional element identification, and 2.90% in gene expression prediction compared to state-of-the-art methods. In transcription factor binding site (TFBS) prediction, it maintains performance comparable to that of leading existing approaches. By achieving competitive performance across tasks with single-cell-line input data, BioSeq2Seq provides an efficient and low-cost alternative for genome annotation. Genome annotation typically requires costly experimental assays across diverse cell types, limiting its scalability. Here, authors introduce BioSeq2Seq, a deep learning framework that leverages DNA sequence and run-on sequencing (RO-seq) data to accurately predict histone modifications, functional elements, gene expression, and transcription factor binding sites.

  PublisherDOI

• Transcriptomic and chromatin accessibility profiling unveils new regulators of heat hormesis in Caenorhabditis elegans

  PLoS Biology · 2026-02-20

  articleOpen access

  Heat hormesis describes the beneficial adaptations resulting from transient exposure to mild heat stress, which enhances stress resilience and promotes healthy aging. While heat hormesis is widely observed, much remains to be learned about its molecular basis. This study bridges a critical knowledge gap through a comprehensive multiomic analysis, providing key insights into the transcriptomic and chromatin accessibility landscapes throughout a heat hormesis regimen in Caenorhabditis elegans. We uncover highly dynamic, dose-dependent molecular responses to heat stress and reveal that while most initial molecular changes induced by mild stress revert to baseline, key differences emerge in response to subsequent heat shock challenge that likely contribute to physiological benefits. We further demonstrate that heat hormesis extends life span specifically in wild-type animals, but not in germline-less mutants, likely due to transient disruption of germline activities during mild heat exposure, which appears sufficient to trigger pro-longevity mechanisms. This finding points to tissue-specific responses in mediating the physiological outcomes of heat hormesis. Importantly, we identify several highly conserved regulators of heat hormesis that likely orchestrate gene expression to enhance stress resilience. Among these regulators, some (MARS-1/MARS1, SNPC-4/SNAPc, FOS-1/c-Fos) are broadly required for heat-hormesis-induced benefits, whereas others (ELT-2/GATA4, DPY-27/SMC4) are uniquely important in specific genetic backgrounds. This study advances our understanding of stress resilience mechanisms, points to multiple new avenues for future investigations, and provides a molecular framework for promoting healthy aging through strategic mid-life stress management.

  PublisherDOI

• An end-to-end generalizable deep learning framework to comprehensively analyze transcriptional regulation

  Research Square · 2025-08-18

  preprintOpen access
  PublisherOA PDFDOI

• Revisiting models of enhancer–promoter communication in gene regulation

  Genome Research · 2025-06-01

  reviewOpen accessSenior author

  Enhancer-promoter communication is fundamental to gene regulation in metazoans, yet the mechanisms underlying these interactions remain debated. Two primary models have been proposed: the structural bridge model, in which enhancers and promoters come into close proximity through stable, protein-mediated interactions, and the hub model, in which dynamic clusters of transcription-associated proteins facilitate communication over variable distances. Emerging evidence suggests that although enhancer-promoter pairs do come into close proximity during transcriptional activation, these interactions are highly transient, and the precise distances remain challenging to measure. Moving forward, resolving the distinctions between these models will require novel techniques to more precisely measure the spatial and temporal dynamics of enhancer-promoter interactions. Understanding how enhancers interact with promoters will deepen our understanding of the regulation of gene expression and the molecular underpinnings of transcriptional control.

  PublisherOA PDFDOI

• Evolution of promoter-proximal pausing enabled a new layer of transcription control

  Nature Structural & Molecular Biology · 2025-12-15 · 5 citations

  articleSenior authorCorresponding
  PublisherDOI

• Accurate <i>de novo</i> transcription unit annotation from run-on and sequencing data

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-17

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Functional element annotations are critical tools used to provide insight into the molecular processes governing cell development, differentiation, and disease. Run-on and sequencing assays measure the production of nascent RNAs and can provide an effective data source for discovering functional elements. However, the accurate inference of functional elements from run-on sequencing data remains an open problem because the signal is noisy and challenging to model. Here we investigated computational approaches that convert run-on and sequencing data into annotations representing transcription units, including genes and non-coding RNAs. We developed a convolutional neural network, called c onvolutional discovery of g ene a natomy using P RO-seq (CGAP), trained to identify different anatomical features of a transcription unit, which were then stitched together into transcript annotations using a hidden Markov model (HMM). Comparison with existing methods showed a significant performance improvement using our novel CGAP-HMM approach. We developed a voting system that ensembles the top three annotation strategies, resulting in large and significant improvements in transcription unit annotation accuracy over the best performing individual method. Finally, we also report a conditional generative adversarial network (cGAN) as a generative approach to transcription unit annotation that shows promise for further development. Collectively our work provides novel tools for de novo transcription unit annotation from run-on and sequencing data that are accurate enough to be useful in many applications.

  PublisherDOI

• Transcriptomic and chromatin accessibility profiling unveils new regulators of heat hormesis in <i>Caenorhabditis elegans</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-14 · 1 citations

  preprintOpen access

  Abstract Heat hormesis describes the beneficial adaptations resulting from transient exposure to mild heat stress, which enhances stress resilience and promotes healthy aging. While heat hormesis is widely observed, much remains to be learned about its molecular basis. This study bridges a critical knowledge gap through a comprehensive multiomic analysis, providing key insights into the transcriptomic and chromatin accessibility landscapes throughout a heat hormesis regimen in C. elegans . We uncover highly dynamic, dose-dependent molecular responses to heat stress and reveal that while most initial molecular changes induced by mild stress revert to baseline, key differences emerge in response to subsequent heat shock challenge that likely contribute to physiological benefits. We further demonstrate that heat hormesis extends lifespan specifically in wild-type animals, but not in germlineless mutants, likely due to transient disruption of germline activities during mild heat exposure, which appears sufficient to trigger pro-longevity mechanisms. This finding points to tissue-specific responses in mediating the physiological outcomes of heat hormesis. Importantly, we identify several highly conserved regulators of heat hormesis that likely orchestrate gene expression to enhance stress resilience. Among these regulators, some (MARS-1/MARS1, SNPC-4/SNAPc, FOS-1/c-Fos) are broadly required for heat hormesis-induced benefits, whereas others (ELT-2/GATA4, DPY-27/SMC4) are uniquely important in specific genetic backgrounds. This study advances our understanding of stress resilience mechanisms, points to multiple new avenues for future investigations, and provides a molecular framework for promoting healthy aging through strategic mid-life stress management.

  PublisherOA PDFDOI

• Meiotic prophase I disruption as a strategy for non-hormonal male contraception using small-molecule inhibitor JQ1

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-14 · 1 citations

  preprintOpen access

  ABSTRACT Long-acting non-hormonal male contraceptives are urgently needed but developing strategies that are both effective and reversible presents significant challenges. Here, we investigated the potential of meiotic prophase I blockade as a promising and potentially reversible approach to male contraception. To do this, we utilized (+)-JQ1, a small-molecule inhibitor of the testis-specific protein, BRDT. Daily injections of (+)-JQ1 for three weeks resulted in disrupted spermatogenesis resulting in loss of spermatozoa and an inability to sire pups. While spermatogenic cells repopulated the testis within six weeks post drug cessation, full fertility restoration required a longer recovery period. We attribute this delay in full recovery to persistent issues with the pachytene transcriptional program, which is crucial for meiotic progression and spermatid development. These findings underscore the potential of pharmacological approaches to disrupt meiotic prophase I as a targeted, reversible male contraceptive strategy, providing new insights into developing effective non-hormonal contraceptive approaches.

  PublisherOA PDFDOI

Recent grants

• Mapping RNA polymerase in tissue samples with ChRO-seq.

  NIH · $1.9M · 2017–2023

Frequent coauthors

• Edward J. Rice

  Cornell University

  72 shared

• Leighton J. Core

  University of Connecticut

  38 shared

• Tinyi Chu

  Memorial Sloan Kettering Cancer Center

  38 shared

• Adam Siepel

  36 shared

• Brooke A. Marks

  34 shared

• Scott A. Coonrod

  Cornell University

  34 shared

• Lauren A. Choate

  Mayo Clinic

  30 shared

• Shao‐Pei Chou

  25 shared

Labs

• Danko LabPI

Education

• Ph.D., Department of Pharmacology

  State University of New York Upstate Medical University

  2009

• BS, Biomedical Engineering

  Johns Hopkins University

  2003

Awards & honors

• Bausch & Lomb Honorary Science Award (1999)
• Professional and Public Service Award (2008)
• Postdoctoral Fellowship. Competitive T32 in Reproductive Gen…
• Postdoctoral Fellowship. Biological Informatics, awarded by…
• Best Poster. Ranked 1 of 30, Reproductive Genomics Retreat P…