Bio

I was born and raised in Syracuse, New York. I first attended Onondaga Community College, where I developed a fascination with the development of complex biological systems, and then transferred to Syracuse University where I completed my B.S. in biochemistry. I next attended the University of Michigan MD/PhD program, where I used in-vitro models of human neurodevelopment to study to role of epigenetic marks in guiding neurogenesis. While at Michigan, I became interested in the prospect of harnessing in-vitro differentiation to cultivate functional tissues that can be transplanted to replace what is lost in degenerative conditions. Ophthalmology, with its microsurgical access to functionally critical cell layers, is well-positioned to capitalize on this emerging field of science to treat degenerative conditions. I am humbled and incredibly thankful to have the opportunity to pursue this aim as a SOAR resident at Stanford.

Additional Info

All Publications

  • Safety and tolerability of RPESC-RPE transplantation in patients with dry age-related macular degeneration: Low-dose clinical outcomes. Cell stem cell Rao, R. C., Arduini, B. L., Borden, S., Sareen, D., Svendsen, C., Lee, P., Ryan, C., Kodati, S., Nyaiburi, C., Wolsieffer, K., Oh, E., Park, S., Ford, G., Dionne, K., Temple, S., Stern, J. 2025

    Abstract

    Retinal pigment epithelium (RPE) cell atrophy in dry age-related macular degeneration (AMD) compromises photoreceptor cell function, leading to vision loss. Stem cell-based RPE replacement therapy aims to reverse disease progression and restore vision. RPESC-RPE-4W, a post-mitotic adult RPE stem cell-derived RPE (RPESC-RPE) progenitor cell product, exhibits consistent safety and efficacy in preclinical studies. The first-in-human clinical trial of RPESC-RPE-4W completed low-dose cohort 1 interventions (NCT04627428). Six subjects received a subretinal suspension of 50,000 RPESC-RPE-4W cells. No significant inflammation, tumor, or product-related serious adverse events were observed. Best-corrected visual acuity in the three worse-seeing group A subjects improved by an average of +21.67 letters from baseline at 12 months. Three better-seeing group B subjects improved by an average of +3.0 letters at 6 months. The positive safety and tolerability outcomes for low-dose cohort 1 enabled dose escalation to mid-dose RPESC-RPE-4W therapy for dry AMD.

    View details for DOI 10.1016/j.stem.2025.08.012

    View details for PubMedID 40961946

    View details for PubMedCentralID PMC12533590

  • RNF2 Missense Variants Disrupt Polycomb Repression and Enable Ectopic Mesenchymal Lineage Conversion During Human Neural Differentiation. Research square Ryan, C. W., Regan, S. L., Sheingold, J. B., Goswami, A., Mulhern, M., Ploeger, J., Huang, S., Hartill, V., Rippert, A., Bhoj, E., Chung, W. K., Bain, J., Srivastava, K. R., Bielas, S. L. 2025

    Abstract

    Polycomb Repressive Complex 1 (PRC1) catalyzes H2AK119ub1 to facilitate transcriptional repression during development. De novo dominant missense variants in RNF2, the principal E3 ligase of PRC1, are the genetic basis of Luo-Schoch-Yamamoto syndrome. To investigate the developmental impact of catalytically impaired RNF2 alleles, we engineered hESC lines harboring homozygous hypomorphic RNF2 missense alleles (RNF2 MS/MS ) that stably expresses RNF2 but results in reduced H2AK119ub1. Upon directed neural differentiation, RNF2 MS/MS cells exhibited asynchronous neural differentiation and ectopic emergence of mesenchymal fated lineages. Single-cell transcriptomic analyses revealed a fate bifurcation characterized by derepression of TWIST1 and other epithelial-to-mesenchymal transition (EMT) gene-network components, coinciding with focal loss of H2AK119ub1 and H3K27me3. These findings demonstrate that RNF2-mediated H2AK119ub1 is required to constrain lineage fidelity by repressing context-inappropriate developmental programs during early human neural differentiation and reveal a shared chromatin-based mechanism linking RNF2 missense variants to both neurodevelopmental pathology and oncogenic plasticity.

    View details for DOI 10.21203/rs.3.rs-7143352/v1

    View details for PubMedID 40831499

    View details for PubMedCentralID PMC12363927

  • Bilateral acute macular neuroretinopathy following influenza A infection IDCASES Ryan, C. W., Rao, R. C. 2025; 39: e02173

    Abstract

    A previously healthy 18-year-old female presented with bilateral cecocentral scotomas two-days after onset of confirmed Influenza A infection, consistent with a post-viral acute macular neuroretinopathy (AMN). Fundoscopy revealed bilateral small petaloid lightening in the nasal macula, and optical coherence tomography revealed thinning of the interdigitation zone, ellipsoid zone, and outer nuclear layer bilaterally. Scotomas and associated imaging findings showed partial improvement in the weeks following diagnosis. This case demonstrates that AMN may be triggered Influenza A infection, and that resulting scotomas and retinal thinning may improve in the weeks following the initial insult.

    View details for DOI 10.1016/j.idcr.2025.e02173

    View details for Web of Science ID 001423360600001

    View details for PubMedID 39989950

    View details for PubMedCentralID PMC11847514

  • Ophthalmology at the Veterans Health Administration: How Sex and Other Factors Affect Salary Journal of Academic Ophthalmology Carman, T. J., Parkinson, D. H., Habib, N. B., Ryan, C. W., DuPuis, D. T., Rosenthal, J. M., Kim, D. S., John, D. A., Maiz, A. M., Rao, R. C. 2025; 17 (3)

    View details for DOI 10.62199/2475-4757.1310

  • A novel interaction between RNA m<SUP>6</SUP>A methyltransferase METTL3 and RREB1 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Xu, J., Sivakumar, C., Ryan, C. W., Rao, R. C. 2024; 733: 150668

    Abstract

    Regulation of gene expression is achieved through the modulation of regulatory inputs both pre- and post-transcriptionally. Methyltransferase-like 3 (METTL3) is a key player in pre-mRNA processing, actively catalyzing N6-methyladenosine (m6A). Among the most enriched mRNA targets of METTL3 is the Ras Responsive Element Binding Protein 1 (RREB1), a transcription factor which functions to govern cell fate, proliferation and DNA repair. Here, we show a novel interaction between METTL3 and RREB1. Further examination of this interaction indicates that METTL3's N-terminus is the primary interacting domain. Our findings uncover a novel interacting partner of METTL3, providing further insights into METTL3's regulatory network.

    View details for DOI 10.1016/j.bbrc.2024.150668

    View details for Web of Science ID 001317653200001

    View details for PubMedID 39278095

  • <i>RING1</i> missense variants reveal sensitivity of DNA damage repair to H2A monoubiquitination dosage during neurogenesis NATURE COMMUNICATIONS Ryan, C. W., Regan, S. L., Mills, E. F., McGrath, B. T., Gong, E., Lai, Y. T., Sheingold, J. B., Patel, K., Horowitz, T., Moccia, A., Tsan, Y. C., Srivastava, A., Bielas, S. L. 2024; 15 (1): 7931

    Abstract

    Polycomb repressive complex 1 (PRC1) modifies chromatin through catalysis of histone H2A lysine 119 monoubiquitination (H2AK119ub1). RING1 and RNF2 interchangeably serve as the catalytic subunit within PRC1. Pathogenic missense variants in PRC1 core components reveal functions of these proteins that are obscured in knockout models. While Ring1a knockout models remain healthy, the microcephaly and neuropsychiatric phenotypes associated with a pathogenic RING1 missense variant implicate unappreciated functions. Using an in vitro model of neurodevelopment, we observe that RING1 contributes to the broad placement of H2AK119ub1, and that its targets overlap with those of RNF2. PRC1 complexes harboring hypomorphic RING1 bind target loci but do not catalyze H2AK119ub1, reducing H2AK119ub1 by preventing catalytically active complexes from accessing the locus. This results in delayed DNA damage repair and cell cycle progression in neural progenitor cells (NPCs). Conversely, reduced H2AK119ub1 due to hypomorphic RING1 does not generate differential expression that impacts NPC differentiation. In contrast, hypomorphic RNF2 generates a greater reduction in H2AK119ub1 that results in both delayed DNA repair and widespread transcriptional changes. These findings suggest that the DNA damage response is more sensitive to H2AK119ub1 dosage change than is regulation of gene expression.

    View details for DOI 10.1038/s41467-024-52292-8

    View details for Web of Science ID 001335554500012

    View details for PubMedID 39256363

    View details for PubMedCentralID PMC11387726

  • H2A monoubiquitination: insights from human genetics and animal models HUMAN GENETICS Ryan, C. W., Peirent, E. R., Regan, S. L., Guxholli, A., Bielas, S. L. 2024; 143 (4): 511-527

    Abstract

    Metazoan development arises from spatiotemporal control of gene expression, which depends on epigenetic regulators like the polycomb group proteins (PcG) that govern the chromatin landscape. PcG proteins facilitate the addition and removal of histone 2A monoubiquitination at lysine 119 (H2AK119ub1), which regulates gene expression, cell fate decisions, cell cycle progression, and DNA damage repair. Regulation of these processes by PcG proteins is necessary for proper development, as pathogenic variants in these genes are increasingly recognized to underly developmental disorders. Overlapping features of developmental syndromes associated with pathogenic variants in specific PcG genes suggest disruption of central developmental mechanisms; however, unique clinical features observed in each syndrome suggest additional non-redundant functions for each PcG gene. In this review, we describe the clinical manifestations of pathogenic PcG gene variants, review what is known about the molecular functions of these gene products during development, and interpret the clinical data to summarize the current evidence toward an understanding of the genetic and molecular mechanism.

    View details for DOI 10.1007/s00439-023-02557-x

    View details for Web of Science ID 000973359200002

    View details for PubMedID 37086328

    View details for PubMedCentralID 3832937

  • Identifying the Gene Regulatory Network of the Starvation-Induced Transcriptional Activator Nla28 JOURNAL OF BACTERIOLOGY Ma, M., Garza, A. G., Lemon, D. J., Caro, E. A., Ritchie, L., Ryan, C., Spearing, V. M., Murphy, K. A., Welch, R. D. 2022; 204 (12): e0026522

    Abstract

    Myxococcus xanthus copes with starvation by producing fruiting bodies filled with dormant and stress-resistant spores. Here, we aimed to better define the gene regulatory network associated with Nla28, a transcriptional activator/enhancer binding protein (EBP) and a key regulator of the early starvation response. Previous work showed that Nla28 directly regulates EBP genes that are important for fruiting body development. However, the Nla28 regulatory network is likely to be much larger because hundreds of starvation-induced genes are downregulated in a nla28 mutant strain. To identify candidates for direct Nla28-mediated transcription, we analyzed the downregulated genes using a bioinformatics approach. Nine potential Nla28 target promoters (29 genes) were discovered. The results of in vitro promoter binding assays, coupled with in vitro and in vivo mutational analyses, suggested that the nine promoters along with three previously identified EBP gene promoters were indeed in vivo targets of Nla28. These results also suggested that Nla28 used tandem, imperfect repeats of an 8-bp sequence for promoter binding. Interestingly, eight of the new Nla28 target promoters were predicted to be intragenic. Based on mutational analyses, the newly identified Nla28 target loci contained at least one gene that was important for starvation-induced development. Most of these loci contained genes predicted to be involved in metabolic or defense-related functions. Using the consensus Nla28 binding sequence, bioinformatics, and expression profiling, 58 additional promoters and 102 genes were tagged as potential Nla28 targets. Among these putative Nla28 targets, functions, such as regulatory, metabolic, and cell envelope biogenesis, were assigned to many genes. IMPORTANCE In bacteria, starvation leads to profound changes in behavior and physiology. Some of these changes have economic and health implications because the starvation response has been linked to the formation of biofilms, virulence, and antibiotic resistance. To better understand how starvation contributes to changes in bacterial physiology and resistance, we identified the putative starvation-induced gene regulatory network associated with Nla28, a transcriptional activator from the bacterium Myxoccocus xanthus. We determined the mechanism by which starvation-responsive genes were activated by Nla28 and showed that several of the genes were important for the formation of a highly resistant cell type.

    View details for DOI 10.1128/jb.00265-22

    View details for Web of Science ID 000901494400017

    View details for PubMedID 36448789

    View details for PubMedCentralID PMC9765219

  • Deciphering multi-way interactions in the human genome NATURE COMMUNICATIONS Dotson, G. A., Chen, C., Lindsly, S., Cicalo, A., Dilworth, S., Ryan, C., Jeyarajan, S., Meixner, W., Stansbury, C., Pickard, J., Beckloff, N., Surana, A., Wicha, M., Muir, L. A., Rajapakse, I. 2022; 13 (1): 5498

    Abstract

    Chromatin architecture, a key regulator of gene expression, can be inferred using chromatin contact data from chromosome conformation capture, or Hi-C. However, classical Hi-C does not preserve multi-way contacts. Here we use long sequencing reads to map genome-wide multi-way contacts and investigate higher order chromatin organization in the human genome. We use hypergraph theory for data representation and analysis, and quantify higher order structures in neonatal fibroblasts, biopsied adult fibroblasts, and B lymphocytes. By integrating multi-way contacts with chromatin accessibility, gene expression, and transcription factor binding, we introduce a data-driven method to identify cell type-specific transcription clusters. We provide transcription factor-mediated functional building blocks for cell identity that serve as a global signature for cell types.

    View details for DOI 10.1038/s41467-022-32980-z

    View details for Web of Science ID 000856140700005

    View details for PubMedID 36127324

    View details for PubMedCentralID PMC9489732

  • Functional organization of the maternal and paternal human 4D Nucleome ISCIENCE Lindsly, S., Jia, W., Chen, H., Liu, S., Ronquist, S., Chen, C., Wen, X., Stansbury, C., Dotson, G. A., Ryan, C., Rehemtulla, A., Omenn, G. S., Wicha, M., Li, S., Muir, L., Rajapakse, I. 2021; 24 (12): 103452

    Abstract

    Every human somatic cell inherits a maternal and a paternal genome, which work together to give rise to cellular phenotypes. However, the allele-specific relationship between gene expression and genome structure through the cell cycle is largely unknown. By integrating haplotype-resolved genome-wide chromosome conformation capture, mature and nascent mRNA, and protein binding data from a B lymphoblastoid cell line, we investigate this relationship both globally and locally. We introduce the maternal and paternal 4D Nucleome, enabling detailed analysis of the mechanisms and dynamics of genome structure and gene function for diploid organisms. Our analyses find significant coordination between allelic expression biases and local genome conformation, and notably absent expression bias in universally essential cell cycle and glycolysis genes. We propose a model in which coordinated biallelic expression reflects prioritized preservation of essential gene sets.

    View details for DOI 10.1016/j.isci.2021.103452

    View details for Web of Science ID 000740254100007

    View details for PubMedID 34877507

    View details for PubMedCentralID PMC8633971

  • Predicting severe outcomes in Covid-19 related illness using only patient demographics, comorbidities and symptoms AMERICAN JOURNAL OF EMERGENCY MEDICINE Ryan, C., Minc, A., Caceres, J., Balsalobre, A., Dixit, A., KaPik Ng, B., Schmitzberger, F., Syed-Abdul, S., Fung, C. 2021; 45: 378-384

    Abstract

    Development of a risk-stratification model to predict severe Covid-19 related illness, using only presenting symptoms, comorbidities and demographic data.We performed a case-control study with cases being those with severe disease, defined as ICU admission, mechanical ventilation, death or discharge to hospice, and controls being those with non-severe disease. Predictor variables included patient demographics, symptoms and past medical history. Participants were 556 patients with laboratory confirmed Covid-19 and were included consecutively after presenting to the emergency department at a tertiary care center from March 1, 2020 to April 21, 2020 RESULTS: Most common symptoms included cough (82%), dyspnea (75%), and fever/chills (77%), with 96% reporting at least one of these. Multivariable logistic regression analysis found that increasing age (adjusted odds ratio [OR], 1.05; 95% confidence interval [CI], 1.03-1.06), dyspnea (OR, 2.56; 95% CI: 1.51-4.33), male sex (OR, 1.70; 95% CI: 1.10-2.64), immunocompromised status (OR, 2.22; 95% CI: 1.17-4.16) and CKD (OR, 1.76; 95% CI: 1.01-3.06) were significant predictors of severe Covid-19 infection. Hyperlipidemia was found to be negatively associated with severe disease (OR, 0.54; 95% CI: 0.33-0.90). A predictive equation based on these variables demonstrated fair ability to discriminate severe vs non-severe outcomes using only this historical information (AUC: 0.76).Severe Covid-19 illness can be predicted using data that could be obtained from a remote screening. With validation, this model could possibly be used for remote triage to prioritize evaluation based on susceptibility to severe disease while avoiding unnecessary waiting room exposure.

    View details for DOI 10.1016/j.ajem.2020.09.017

    View details for Web of Science ID 000675408600006

    View details for PubMedID 33046294

    View details for PubMedCentralID PMC7480533

  • Cellular reprogramming: Mathematics meets medicine WIRES MECHANISMS OF DISEASE Dotson, G. A., Ryan, C. W., Chen, C., Muir, L., Rajapakse, I. 2021; 13 (4): e1515

    Abstract

    Generating needed cell types using cellular reprogramming is a promising strategy for restoring tissue function in injury or disease. A common method for reprogramming is addition of one or more transcription factors that confer a new function or identity. Advancements in transcription factor selection and delivery have culminated in successful grafting of autologous reprogrammed cells, an early demonstration of their clinical utility. Though cellular reprogramming has been successful in a number of settings, identification of appropriate transcription factors for a particular transformation has been challenging. Computational methods enable more sophisticated prediction of relevant transcription factors for reprogramming by leveraging gene expression data of initial and target cell types, and are built on mathematical frameworks ranging from information theory to control theory. This review highlights the utility and impact of these mathematical frameworks in the field of cellular reprogramming. This article is categorized under: Reproductive System Diseases > Reproductive System Diseases>Genetics/Genomics/Epigenetics Reproductive System Diseases > Reproductive System Diseases>Stem Cells and Development Reproductive System Diseases > Reproductive System Diseases>Computational Models.

    View details for DOI 10.1002/wsbm.1515

    View details for Web of Science ID 000594987800001

    View details for PubMedID 33289324

    View details for PubMedCentralID PMC8867497

https://orcid.org/0000-0001-7476-9099