Biology subjects

Schmok, J. C.

Publications and source records attributed to Schmok, J. C..

4 recordsLinked to original sources

bioRxiv2025

Genome-Wide Interrogation of SARS-CoV-2 RNA-Protein Interactions Uncovers Hidden Regulatory Sites

The global impact of the COVID-19 pandemic underscores the critical need for a comprehensive understanding of SARS-CoV-2 replication mechanisms. While the central roles of the RNA dependent RNA polymerase (NSP12), primase protein (NSP8), and nucleocapsid protein (N) in the virus life cycle are extensively studied, the precise nature of their interactions with the full-length viral RNA genome remain incompletely characterized. In this study, we sought to address this knowledge gap by employing enhanced crosslinking and immunoprecipitation (eCLIP) to map the binding sites of NSP8, NSP12, and N proteins across the SARS-CoV-2 genome at early stages of viral RNA and protein synthesis and late stages of virion assembly. Our findings revealed interactions of NSP8 and NSP12 to the 5 and 3 untranslated regions (UTRs) of both positive and negative sense RNA, regions known to regulate viral replication, transcription, and translation. We identified a surprising and essential NSP12 binding site within the RNA sequence encoding the conserved Y1 domain of NSP3, which regulates RNA abundance upstream of the site. Additionally, we found that N protein interacts with the 5 UTR and influences translation efficiency. Finally, we report a novel regulatory function of N protein in modulating ribosomal frameshifting proximal to the frameshift element, a crucial process for maintaining viral protein stoichiometry. Our results provide a detailed molecular map of SARS-CoV-2 protein-RNA interactions, revealing potential therapeutic targets for attenuating viral fitness and informing the development of next-generation antiviral strategies.

molecular biology↗

bioRxiv2025

Genome modeling and design across all domains of life with Evo 2

All of life encodes information with DNA. While tools for sequencing, synthesis, and editing of genomic code have transformed biological research, intelligently composing new biological systems would also require a deep understanding of the immense complexity encoded by genomes. We introduce Evo 2, a biological foundation model trained on 9.3 trillion DNA base pairs from a highly curated genomic atlas spanning all domains of life. We train Evo 2 with 7B and 40B parameters to have an unprecedented 1 million token context window with single-nucleotide resolution. Evo 2 learns from DNA sequence alone to accurately predict the functional impacts of genetic variation--from noncoding pathogenic mutations to clinically significant BRCA1 variants--without task-specific finetuning. Applying mechanistic interpretability analyses, we reveal that Evo 2 autonomously learns a breadth of biological features, including exon-intron boundaries, transcription factor binding sites, protein structural elements, and prophage genomic regions. Beyond its predictive capabilities, Evo 2 generates mitochondrial, prokaryotic, and eukaryotic sequences at genome scale with greater naturalness and coherence than previous methods. Guiding Evo 2 via inference-time search enables controllable generation of epigenomic structure, for which we demonstrate the first inference-time scaling results in biology. We make Evo 2 fully open, including model parameters, training code, inference code, and the OpenGenome2 dataset, to accelerate the exploration and design of biological complexity.

genomics↗

bioRxiv2022

Discovery and functional interrogation of SARS-CoV-2 protein-RNA interactions

The COVID-19 pandemic is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The betacoronvirus has a positive sense RNA genome which encodes for several RNA binding proteins. Here, we use enhanced crosslinking and immunoprecipitation to investigate SARS-CoV-2 protein interactions with viral and host RNAs in authentic virus-infected cells. SARS-CoV-2 proteins, NSP8, NSP12, and nucleocapsid display distinct preferences to specific regions in the RNA viral genome, providing evidence for their shared and separate roles in replication, transcription, and viral packaging. SARS-CoV-2 proteins expressed in human lung epithelial cells bind to 4773 unique host coding RNAs. Nine SARS-CoV-2 proteins upregulate target gene expression, including NSP12 and ORF9c, whose RNA substrates are associated with pathways in protein N-linked glycosylation ER processing and mitochondrial processes. Furthermore, siRNA knockdown of host genes targeted by viral proteins in human lung organoid cells identify potential antiviral host targets across different SARS-CoV-2 variants. Conversely, NSP9 inhibits host gene expression by blocking mRNA export and dampens cytokine productions, including interleukin-1/{beta}. Our viral protein-RNA interactome provides a catalog of potential therapeutic targets and offers insight into the etiology of COVID-19 as a safeguard against future pandemics.

molecular biology↗

bioRxiv2021

A remote lecture series roadmap to equity, diversity, and inclusion in STEM

Disparities for women and minorities in science, technology, engineering, and math (STEM) careers have continued even amidst mounting evidence for the superior performance of diverse workforces. In response, we launched the Diversity and Science Lecture series, a cross-institutional platform where junior life scientists present their research and comment on equity, diversity, and inclusion in STEM. We characterize speaker representation from 79 profiles and investigate topic noteworthiness via quantitative content analysis of talk transcripts. Nearly every speaker discussed interpersonal support, and three-fifths of speakers commented on race or ethnicity. Other topics, such as sexual and gender minority identity, were less frequently addressed but highly salient to the speakers who mentioned them. We found that significantly co-occurring topics reflected not only conceptual similarity, such as terms for racial identities, but also intersectional significance, such as identifying as a Latina/Hispanic woman or Asian immigrant, and interactions between priorities and identities, including the heightened value of friendship to the LGBTQ community, which we reproduce using transcripts from an independent seminar series. Our approach to scholar profiles and talk transcripts serves as an example for transmuting hundreds of hours of scholarly discourse into rich datasets that can power computational audits of speaker diversity and illuminate speakers personal and professional priorities.

scientific communication and education↗