Jonathan Jude Perera

All Publications

• Whole-genome 3D architectural screen reveals modulators of brain DNA structure. bioRxiv : the preprint server for biology Parasar, B., Venkatesh, A. R., Perera, J., Sosnick, L., Moghadami, S., Seo, Y., Shi, J., Chan, L., Takenawa, S., Akiyama, T., Sianto, O., Uenaka, T., Hadjipanayis, A., Wernig, M., Gitler, A. D., Tan, L. 2026

  Abstract

  Three-dimensional (3D) genome architecture is the foundation of gene regulation, and plays a critical role in normal physiology and disease. However, our understanding of its biochemical determinants has long been limited by technology: imaging-based screens only profile a small number of loci, while sequencing-based studies rarely exceed 100 samples or conditions. Here we present "in-plate chromosome conformation capture" (Plate-C), a high-throughput, cost-effective platform that profiles thousands of whole-genome architectures in a day. Plate-C enabled the first chemical screen for whole-genome structural changes-profiling 2,956 samples from 834 conditions across 5 neuronal and glial types, accompanied by 6,081 single cells using "easy diploid chromosome conformation capture" (Easy Dip-C) and 200,893 single-cell transcriptomes. We discovered that diverse, dose/time-dependent, and cell type/species-specific modes of DNA structural changes can be rapidly induced by manipulating epigenetic (HDAC, BET), metabolic (mTOR), proteostatic (UPR), developmental (GSK3/Wnt, Hedgehog), immune (cGAS/STING), and neurotransmission pathways. To validate our finding in vivo, we demonstrated in newborn mice that HDAC inhibition drives brain-wide genome rewiring within hours, highly correlated with changes in vitro and inducing a latent structural and transcriptional state orthogonal to normal differentiation. By enabling massively parallel profiling of whole-genome structures, Plate-C paves the way for systematic discovery of DNA folding principles to better understand and engineer the human genome in 3D.

  View details for DOI 10.64898/2026.04.15.718501

  View details for PubMedID 42039500

  View details for PubMedCentralID PMC13104906

• Sialylated CD43 forms a glyco-immune barrier that restrains antileukemic immunity. Science (New York, N.Y.) Chung, J., Vallurupalli, M., Noel, S., Schor, G., Mrowka, S., Scapozza, I., Demere, Z., Kammula, S. V., Hu, M., Kim, S. Y., Liu, Y., Nobrega, C., Perera, J. J., Wrona, E., Cheruiyot, C. K., Lin, Y., Wu, D. W., Saberi, M., Cruickshank, A., Woods, E. C., Chuong, C. L., Birocchi, F., Kammula, A. V., Avila, O. I., Knudsen, N., Kocak, M., Doench, J. G., Procter, D., Thornton, L., Brunner, A. M., Winer, E., DeAngelo, D. J., Garcia, J. S., Stone, R. M., Jenkins, R. W., Maus, M. V., Graubert, T. A., Yates, K. B., Golub, T. R., Manguso, R. T. 2026; 392 (6794): eady5196

  Abstract

  Macrophages exert antitumorigenic activity through phagocytosis, but phagocytosis-enhancing therapeutics have not improved acute myeloid leukemia (AML) outcomes. To identify phagocytosis regulators, we performed CRISPR knockout screens in human AML cells cocultured with human macrophages. We found that the "don't eat me" signal CD47 inhibited mouse but not human macrophage phagocytosis. However, O-linked glycosylation and sialylation were strong negative regulators of phagocytosis. In AML, the cell surface mucin-like glycoprotein CD43 was the major effector of these pathways. Inhibition of phagocytosis by CD43 was dependent on the length of its ectodomain and independent of the macrophage sialic acid receptors SIGLEC-1, SIGLEC-7, and SIGLEC-9. The inhibitory effects of CD43 extended beyond human macrophages to natural killer and T cells. Thus, CD43 forms a glyco-immune barrier that restrains both innate and adaptive antileukemic immunity.

  View details for DOI 10.1126/science.ady5196

  View details for PubMedID 41955354

• In vivo CRISPR screening in head and neck cancer reveals Uchl5 as an immunotherapy target. Nature communications Fu, C., Saddawi-Konefka, R., Chinai, J. M., Kim, S. Y., Kammula, A. V., Perera, J. J., Jiang, A., Tiwari, P., Kistler, E. N., Tang, S., Luna, S. M., Colvin, K. J., Dubrot, J., Anderson, S., Fetterman, R. A., Chuong, C. L., Lane-Reticker, S. K., Cheruiyot, C. K., Muscato, A. J., Alipour, Z., Adkins, D. R., Griffin, G. K., Bernstein, B. E., Egloff, A. M., Yates, K. B., Chernock, R. D., Gutkind, J. S., Uppaluri, R., Manguso, R. T. 2025; 16 (1): 8572

  Abstract

  Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a significant unmet need for enhancing immunotherapy response given current modest efficacy. Here, we perform an in vivo CRISPR screen in an HNSCC mouse model to identify immune evasion genes. We identify several regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increases CD8+ T cell infiltration and improved ICB responses. Uchl5 deficiency attenuates extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional programs, which contribute to stromal desmoplasia, a histologic finding we describe as associated with reduced anti-PD1 response in human HNSCCs. COL17A1, a collagen highly and specifically expressed in HNSCC, mediates in part Uchl5-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.

  View details for DOI 10.1038/s41467-025-63592-y

  View details for PubMedID 41022734

  View details for PubMedCentralID PMC12480505

• Fantastic Bugs and Where to Find Them in AI Benchmarks NeurIPS Truong, S., Tu, Y., Reuel, A., Tang, Z., Burapacheep, J., Perera, J., Uwakwe, C., Domingue, B., Haber, N., Koyejo, S. 2025: arXiv:2511.16842
• Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint. Immunity Tsao, H. W., Anderson, S., Finn, K. J., Perera, J. J., Pass, L. F., Schneider, E. M., Jiang, A., Fetterman, R., Chuong, C. L., Kozuma, K., Stickler, M. M., Creixell, M., Klaeger, S., Phulphagar, K. M., Rachimi, S., Verzani, E. K., Olsson, N., Dubrot, J., Pech, M. F., Silkworth, W., Lane-Reticker, S. K., Allen, P. M., Ibrahim, K., Knudsen, N. H., Cheng, A. Y., Long, A. H., Ebrahimi-Nik, H., Kim, S. Y., Du, P. P., Iracheta-Vellve, A., Robitschek, E. J., Suermondt, J. S., Davis, T. G., Wolfe, C. H., Atluri, T., Olander, K. E., Rush, J. S., Sundberg, T. B., McAllister, F. E., Abelin, J. G., Firestone, A., Stokoe, D., Carr, S. A., Harding, F. A., Yates, K. B., Manguso, R. T. 2024

  Abstract

  The aminopeptidase, endoplasmic reticulum aminopeptidase 1 (ERAP1), trims peptides for loading into major histocompatibility complex class I (MHC class I), and loss of this activity has broad effects on the MHC class I peptidome. Here, we investigated the impact of targeting ERAP1 in immune checkpoint blockade (ICB), as MHC class I interactions mediate both activating and inhibitory functions in antitumor immunity. Loss of ERAP sensitized mouse tumor models to ICB, and this sensitivity depended on CD8+ T cells and natural killer (NK) cells. In vivo suppression screens revealed that Erap1 deletion inactivated the inhibitory NKG2A-HLA-E checkpoint, which requires presentation of a restricted set of invariant epitopes (VL9) on HLA-E. Loss of ERAP altered the HLA-E peptidome, preventing NKG2A engagement. In humans, ERAP1 and ERAP2 showed functional redundancy for the processing and presentation of VL9, and loss of both inactivated the NKG2A checkpoint in cancer cells. Thus, loss of ERAP phenocopies the inhibition of the NKG2A-HLA-E pathway and represents an attractive approach to inhibit this critical checkpoint.

  View details for DOI 10.1016/j.immuni.2024.10.013

  View details for PubMedID 39561763

• Emerging point-of-care autologous cellular therapy using adipose-derived stromal vascular fraction for neurodegenerative diseases. Clinical and translational medicine Al-Kharboosh, R., Perera, J. J., Bechtle, A., Bu, G., Quinones-Hinojosa, A. 2022; 12 (12): e1093

  Abstract

  Neurodegenerative disorders are characterized by the gradual decline and irreversible loss of cognitive functions and CNS structures. As therapeutic recourse stagnates, neurodegenerative diseases will cost over a trillion dollars by 2050. A dearth of preventive and regenerative measures to hinder regression and enhance recovery has forced patients to settle for traditional therapeutics designed to manage symptoms, leaving little hope for a cure. In the last decade, pre-clinical animal models and clinical investigations in humans have demonstrated the safety and promise of an emerging cellular product from subcutaneous fat. The adipose-derived stromal vascular fraction (SVF) is an early intervention and late-stage novel 'at point' of care cellular treatment, demonstrating improvements in clinical applications for Multiple Sclerosis, Alzheimer's disease, and Parkinson's disease. SVF is a heterogeneous fraction of cells forming a robust cellular ecosystem and serving as a novel and valuable source of point-of-care autologous cell therapy, providing an easy-to-access population that we hypothesize can mediate repair through 'bi-directional' communication in response to pathological cues. We provide the first comprehensive review of all pre-clinical and clinical findings available to date and highlight major challenges and future directions. There is a greater medical and economic urgency to innovate and develop novel cellular therapy solutions that enable the repair and regeneration of neuronal tissue that has undergone irreversible and permanent damage.

  View details for DOI 10.1002/ctm2.1093

  View details for PubMedID 36495120

  View details for PubMedCentralID PMC9736801

• Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma. Nature communications Tomaszewski, W. H., Waibl-Polania, J., Chakraborty, M., Perera, J., Ratiu, J., Miggelbrink, A., McDonnell, D. P., Khasraw, M., Ashley, D. M., Fecci, P. E., Racioppi, L., Sanchez-Perez, L., Gunn, M. D., Sampson, J. H. 2022; 13 (1): 6483

  Abstract

  Glioblastoma (GBM) is notorious for its immunosuppressive tumor microenvironment (TME) and is refractory to immune checkpoint blockade (ICB). Here, we identify calmodulin-dependent kinase kinase 2 (CaMKK2) as a driver of ICB resistance. CaMKK2 is highly expressed in pro-tumor cells and is associated with worsened survival in patients with GBM. Host CaMKK2, specifically, reduces survival and promotes ICB resistance. Multimodal profiling of the TME reveals that CaMKK2 is associated with several ICB resistance-associated immune phenotypes. CaMKK2 promotes exhaustion in CD8+ T cells and reduces the expansion of effector CD4+ T cells, additionally limiting their tumor penetrance. CaMKK2 also maintains myeloid cells in a disease-associated microglia-like phenotype. Lastly, neuronal CaMKK2 is required for maintaining the ICB resistance-associated myeloid phenotype, is deleterious to survival, and promotes ICB resistance. Our findings reveal CaMKK2 as a contributor to ICB resistance and identify neurons as a driver of immunotherapeutic resistance in GBM.

  View details for DOI 10.1038/s41467-022-34175-y

  View details for PubMedID 36309495

  View details for PubMedCentralID PMC9617949