Kitra Lily Cates

All Publications

• A subcellular map of translational machinery composition and regulation at the single-molecule level. Science (New York, N.Y.) Zhang, Z., Xu, A., Bai, Y., Chen, Y., Cates, K., Kerr, C., Bermudez, A., Susanto, T. T., Wysong, K., García Marqués, F. J., Nolan, G. P., Pitteri, S., Barna, M. 2025; 387 (6738): eadn2623

  Abstract

  Millions of ribosomes are packed within mammalian cells, yet we lack tools to visualize them in toto and characterize their subcellular composition. In this study, we present ribosome expansion microscopy (RiboExM) to visualize individual ribosomes and an optogenetic proximity-labeling technique (ALIBi) to probe their composition. We generated a super-resolution ribosomal map, revealing subcellular translational hotspots and enrichment of 60S subunits near polysomes at the endoplasmic reticulum (ER). We found that Lsg1 tethers 60S to the ER and regulates translation of select proteins. Additionally, we discovered ribosome heterogeneity at mitochondria guiding translation of metabolism-related transcripts. Lastly, we visualized ribosomes in neurons, revealing a dynamic switch between monosomes and polysomes in neuronal translation. Together, these approaches enable exploration of ribosomal localization and composition at unprecedented resolution.

  View details for DOI 10.1126/science.adn2623

  View details for PubMedID 40048539

• Ribosome-associated proteins: unwRAPping ribosome heterogeneity in the twenty-first century. Philosophical transactions of the Royal Society of London. Series B, Biological sciences Cates, K., Hung, V., Barna, M. 2025; 380 (1921): 20230378

  Abstract

  The definition of the ribosome as the monolithic machinery in cells that synthesizes all proteins in the cell has persisted for the better part of a century. Yet, research has increasingly revealed that ribosomes are dynamic, multimodal complexes capable of fine-tuning gene expression. This translation regulation may be achieved by ribosome-associated proteins (RAPs), which play key roles as modular trans-acting factors that are dynamic across different cellular contexts and can mediate the recruitment of specific transcripts or the modification of RNA or ribosomal proteins. As a result, RAPs have the potential to rapidly regulate translation within specific subcellular regions, across different cell or tissue types, in response to signalling, or in disease states. In this article, we probe the definition of the eukaryotic ribosome and review the major layers of additional proteins that expand the definition of ribosomes in the twenty-first century. We pose RAPs as key modulators that impart ribosome function in cellular processes, development and disease.This article is part of the discussion meeting issue 'Ribosome diversity and its impact on protein synthesis, development and disease'.

  View details for DOI 10.1098/rstb.2023.0378

  View details for PubMedID 40045784

• Fate erasure logic of gene networks underlying direct neuronal conversion of somatic cells by microRNAs. Cell reports Cates, K., Yuan, L., Yang, Y., Yoo, A. S. 2025; 44 (1): 115153

  Abstract

  Neurogenic microRNAs 9/9 and 124 (miR-9/9-124) drive the direct reprogramming of human fibroblasts into neurons with the initiation of the fate erasure of fibroblasts. However, whether the miR-9/9-124 fate erasure logic extends to the neuronal conversion of other somatic cell types remains unknown. Here, we uncover that miR-9/9-124 induces neuronal conversion of multiple cell types: dura fibroblasts, astrocytes, smooth muscle cells, and pericytes. We reveal the cell-type-specific and pan-somatic gene network erasure induced by miR-9/9-124, including cell cycle, morphology, and proteostasis gene networks. Leveraging these pan-somatic gene networks, we predict upstream regulators that may antagonize somatic fate erasure. Among the predicted regulators, we identify TP53 (p53), whose inhibition is sufficient to enhance neuronal conversion even in post-mitotic cells. This study extends miR-9/9-124 reprogramming to alternate somatic cells, reveals the pan-somatic gene network fate erasure logic of miR-9/9-124, and shows a neurogenic role for p53 inhibition in the miR-9/9-124 signaling cascade.

  View details for DOI 10.1016/j.celrep.2024.115153

  View details for PubMedID 39756035

• MICRORNA TARGETING LOGIC IN DIRECT NEURONAL REPROGRAMMING OF GLIOBLASTOMA Yuan, L., Cates, K., Kim, A., Yoo, A. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0248

  View details for Web of Science ID 001362575500014

• Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming. Science (New York, N.Y.) Sun, Z., Kwon, J., Ren, Y., Chen, S., Walker, C. K., Lu, X., Cates, K., Karahan, H., Sviben, S., Fitzpatrick, J. A., Valdez, C., Houlden, H., Karch, C. M., Bateman, R. J., Sato, C., Mennerick, S. J., Diamond, M. I., Kim, J., Tanzi, R. E., Holtzman, D. M., Yoo, A. S. 2024; 385 (6708): adl2992

  Abstract

  Late-onset Alzheimer's disease (LOAD) is the most common form of Alzheimer's disease (AD). However, modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies such as amyloid-beta (Abeta) deposition, tau tangles, and neuronal loss remains an unmet need. We demonstrate that neurons generated by microRNA (miRNA)-based direct reprogramming of fibroblasts from individuals affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional environment effectively recapitulate key neuropathological features of AD. Reprogrammed LOAD neurons exhibit Abeta-dependent neurodegeneration, and treatment with beta- or gamma-secretase inhibitors before (but not subsequent to) Abeta deposit formation mitigated neuronal death. Moreover inhibiting age-associated retrotransposable elements in LOAD neurons reduced both Abeta deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency miRNA-based neuronal reprogramming.

  View details for DOI 10.1126/science.adl2992

  View details for PubMedID 39088624

• Evaluation of an 8-week high school science communication course designed to read, write, and present scientific research ADVANCES IN PHYSIOLOGY EDUCATION Radyk, M. D., Spatz, L. B., Adkins-Threats, M. L., Cates, K., St Pierre, C. L. 2023; 47 (4): 910-918

  Abstract

  The development of science writing and presentation skills is necessary for a successful science career. Too often these skills are not included in pre- or postsecondary science, technology, engineering, and mathematics (STEM) education, leading to a disconnect between high schoolers' expectations for college preparedness and the skills needed to succeed in college. The Young Scientist Program Summer Focus recruits high school students from historically marginalized backgrounds to participate in 8-week summer internships at Washington University in St. Louis. Students conduct hands-on biomedical research projects under the mentorship of Washington University scientists (graduate students, postdoctorates, lab staff). Here, we present the curriculum for a science communication course that accompanies this early research experience. The course is designed to strengthen students' communication skills (critical reading, writing, presenting, and peer review) through a combination of weekly lectures and active learning methods. It prepares students for the capstone of their summer internship: writing a scientific paper and presenting their results at a closing symposium. We administered pre- and postprogram surveys to four Summer Focus cohorts to determine whether the course met its learning objectives. We found significant improvements in students' self-confidence in reading, interpreting, and communicating scientific data. Thus, this course provides a successful model for introducing science literacy and communication skills that are necessary for any career in STEM. We provide a detailed outline of the course structure and content so that this training can be incorporated into any undergraduate and graduate research programs.NEW & NOTEWORTHY Strong communication skills are necessary for a successful scientific career. Here, we describe the curriculum for a science communication course designed to accompany high school students participating in a summer biomedical research program. The course aims to improve their scientific literacy and communication skills. Students learn to read and understand scientific literature, write a paper about their summer research project, present their results, and provide feedback to peers. We found significant improvements in students' self-confidence in reading, interpreting, and communicating scientific data after completing the course. This successful model serves as a guide for students participating in their first research experience and provides the skills for success in future science, technology, engineering, and mathematics education and careers. The curriculum presented here can be easily adapted for any research program, including undergraduate summer research experiences and graduate student laboratory rotations.

  View details for DOI 10.1152/advan.00085.2022

  View details for Web of Science ID 001127097700001

  View details for PubMedID 37769043

  View details for PubMedCentralID PMC10854798

• Age-related Huntington's disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy. Nature neuroscience Oh, Y. M., Lee, S. W., Kim, W. K., Chen, S., Church, V. A., Cates, K., Li, T., Zhang, B., Dolle, R. E., Dahiya, S., Pak, S. C., Silverman, G. A., Perlmutter, D. H., Yoo, A. S. 2022; 25 (11): 1420-1433

  Abstract

  Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of neurodegeneration in patients with HD remains unclear. In this study we examined striatal medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of patients with HD to model the age-dependent onset of pathology. We found that pronounced neuronal death occurred selectively in reprogrammed MSNs from symptomatic patients with HD (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and control MSNs from age-matched healthy individuals. We observed age-associated alterations in chromatin accessibility between HD-MSNs and pre-HD-MSNs and identified miR-29b-3p, whose age-associated upregulation promotes HD-MSN degeneration by impairing autophagic function through human-specific targeting of the STAT3 3' untranslated region. Reducing miR-29b-3p or chemically promoting autophagy increased the resilience of HD-MSNs against neurodegeneration. Our results demonstrate miRNA upregulation with aging in HD as a detrimental process driving MSN degeneration and potential approaches for enhancing autophagy and resilience of HD-MSNs.

  View details for DOI 10.1038/s41593-022-01185-4

  View details for PubMedID 36303071

  View details for PubMedCentralID PMC10162007

• Generation of Human Neurons by microRNA-Mediated Direct Conversion of Dermal Fibroblasts. Methods in molecular biology (Clifton, N.J.) Church, V. A., Cates, K., Capano, L., Aryal, S., Kim, W. K., Yoo, A. S. 2021; 2239: 77-100

  Abstract

  MicroRNAs (miRNAs), miR-9/9*, and miR-124 (miR-9/9*-124) display fate-reprogramming activities when ectopically expressed in human fibroblasts by erasing the fibroblast identity and evoking a pan-neuronal state. In contrast to induced pluripotent stem cell-derived neurons, miRNA-induced neurons (miNs) retain the biological age of the starting fibroblasts through direct fate conversion and thus provide a human neuron-based platform to study cellular properties inherent in aged neurons and model adult-onset neurodegenerative disorders using patient-derived cells. Furthermore, expression of neuronal subtype-specific transcription factors in conjunction with miR-9/9*-124 guides the miNs to distinct neuronal fates, a feature critical for modeling disorders that affect specific neuronal subtypes. Here, we describe the miR-9/9*-124-based neuronal reprogramming protocols for the generation of several disease-relevant neuronal subtypes: striatal medium spiny neurons, cortical neurons, and spinal cord motor neurons.

  View details for DOI 10.1007/978-1-0716-1084-8_6

  View details for PubMedID 33226614

• Comparison of differential accessibility analysis strategies for ATAC-seq data SCIENTIFIC REPORTS Gontarz, P., Fu, S., Xing, X., Liu, S., Miao, B., Bazylianska, V., Sharma, A., Madden, P., Cates, K., Yoo, A., Moszczynska, A., Wang, T., Zhang, B. 2020; 10 (1): 10150

  Abstract

  ATAC-seq is widely used to measure chromatin accessibility and identify open chromatin regions (OCRs). OCRs usually indicate active regulatory elements in the genome and are directly associated with the gene regulatory network. The identification of differential accessibility regions (DARs) between different biological conditions is critical in determining the differential activity of regulatory elements. Differential analysis of ATAC-seq shares many similarities with differential expression analysis of RNA-seq data. However, the distribution of ATAC-seq signal intensity is different from that of RNA-seq data, and higher sensitivity is required for DARs identification. Many different tools can be used to perform differential analysis of ATAC-seq data, but a comprehensive comparison and benchmarking of these methods is still lacking. Here, we used simulated datasets to systematically measure the sensitivity and specificity of six different methods. We further discussed the statistical and signal density cut-offs in the differential analysis of ATAC-seq by applying them to real data. Batch effects are very common in high-throughput sequencing experiments. We illustrated that batch-effect correction can dramatically improve sensitivity in the differential analysis of ATAC-seq data. Finally, we developed a user-friendly package, BeCorrect, to perform batch effect correction and visualization of corrected ATAC-seq signals in a genome browser.

  View details for DOI 10.1038/s41598-020-66998-4

  View details for Web of Science ID 000543993000027

  View details for PubMedID 32576878

  View details for PubMedCentralID PMC7311460

• Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs. Cell stem cell Cates, K. n., McCoy, M. J., Kwon, J. S., Liu, Y. n., Abernathy, D. G., Zhang, B. n., Liu, S. n., Gontarz, P. n., Kim, W. K., Chen, S. n., Kong, W. n., Ho, J. N., Burbach, K. F., Gabel, H. W., Morris, S. A., Yoo, A. S. 2020

  Abstract

  Cell-fate conversion generally requires reprogramming effectors to both introduce fate programs of the target cell type and erase the identity of starting cell population. Here, we reveal insights into the activity of microRNAs miR-9/9∗ and miR-124 (miR-9/9∗-124) as reprogramming agents that orchestrate direct conversion of human fibroblasts into motor neurons by first eradicating fibroblast identity and promoting uniform transition to a neuronal state in sequence. We identify KLF-family transcription factors as direct target genes for miR-9/9∗-124 and show their repression is critical for erasing fibroblast fate. Subsequent gain of neuronal identity requires upregulation of a small nuclear RNA, RN7SK, which induces accessibilities of chromatin regions and neuronal gene activation to push cells to a neuronal state. Our study defines deterministic components in the microRNA-mediated reprogramming cascade.

  View details for DOI 10.1016/j.stem.2020.08.015

  View details for PubMedID 32961143

• An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia. The Journal of biological chemistry Cherian, M. A., Olson, S., Sundaramoorthi, H., Cates, K., Cheng, X., Harding, J., Martens, A., Challen, G. A., Tyagi, M., Ratner, L., Rauch, D. 2018; 293 (18): 6844-6858

  Abstract

  The human T-cell leukemia virus-1 (HTLV-1) oncoprotein Tax drives cell proliferation and resistance to apoptosis early in the pathogenesis of adult T-cell leukemia (ATL). Subsequently, probably as a result of specific immunoediting, Tax expression is down-regulated and functionally replaced by somatic driver mutations of the host genome. Both amplification and point mutations of interferon regulatory factor 4 (IRF4) have been previously detected in ATL., K59R is the most common single-nucleotide variation of IRF4 and is found exclusively in ATL. High-throughput whole-exome sequencing revealed recurrent activating genetic alterations in the T-cell receptor, CD28, and NF-κB pathways. We found that IRF4, which is transcriptionally activated downstream of these pathways, is frequently mutated in ATL. IRF4 RNA, protein, and IRF4 transcriptional targets are uniformly elevated in HTLV-1-transformed cells and ATL cell lines, and IRF4 was bound to genomic regulatory DNA of many of these transcriptional targets in HTLV-1-transformed cell lines. We further noted that the K59R IRF4 mutant is expressed at higher levels in the nucleus than WT IRF4 and is transcriptionally more active. Expression of both WT and the K59R mutant of IRF4 from a constitutive promoter in retrovirally transduced murine bone marrow cells increased the abundance of T lymphocytes but not myeloid cells or B lymphocytes in mice. IRF4 may represent a therapeutic target in ATL because ATL cells select for a mutant of IRF4 with higher nuclear expression and transcriptional activity, and overexpression of IRF4 induces the expansion of T lymphocytes in vivo.

  View details for DOI 10.1074/jbc.RA117.000164

  View details for PubMedID 29540473

  View details for PubMedCentralID PMC5936815