About

Seychelle M. Vos is an Associate Professor of Biology at MIT and a Howard Hughes Medical Institute Freeman Hrabowski Scholar. Her research investigates how genome organization and gene expression are physically coupled across molecular scales. Her work focuses on understanding how large molecular machineries involved in genome organization and gene transcription regulate each other's function to ultimately determine cell fate and identity. She employs a broad range of approaches including single-particle cryo-electron microscopy (cryo-EM), X-ray crystallography, biochemistry, and genetics to mechanistically understand how these molecular assemblies regulate each other across molecular scales.

Research topics

• Genetics
• Bioinformatics
• Biology
• Cancer research
• Computational biology
• Medicine

Selected publications

• BPS2026 – Dynamic CTCF conformations control cohesin barrier function

  Biophysical Journal · 2026-02-01

  article
  PublisherDOI

• A Modular Framework for Automated Segmentation and Analysis of AFM Imaging of Chromatin Organization

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-07

  articleOpen access

  ABSTRACT Chromatin organization underlies essential genome functions, but its nanoscale organization remains challenging to capture and quantify with precision. Atomic force microscopy (AFM) offers direct structural readouts of DNA and chromatin, yet translating these rich images into reproducible biological metrics has been limited by the lack of standardized, scalable analysis tools. Here we present DNAsight, an automated analysis framework that integrates machine learning (ML)-based segmentation with modular, base-pair-calibrated quantification of DNA spatial organization, looping, nucleosome spacing, and protein clustering. Applied across diverse chromatin-associated proteins, DNAsight reveals protein-specific organizational signatures, including topology-dependent compaction by integration host factor (IHF), condition-dependent changes in loop-like DNA structures in cohesin-CTCF-precocious dissociation of sisters 5A (PDS5A) reactions, and promoter-driven multimerization of GAGA factor (GAF) clusters. The framework further enables direct extraction of nucleosome spacing distributions from raw AFM images, providing a label-free route to investigate chromatin fiber architecture. Together, these advances establish DNAsight as a generalizable and scalable approach for converting AFM measurements into quantitative insights into the physical principles of chromatin organization. Abstract Figure

  PublisherDOI

• Structural basis for CTCF-mediated chromatin organization

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-08 · 1 citations

  articleOpen accessSenior authorCorresponding

  Eukaryotic DNA is organized across multiple scales to support genome compaction, appropriate gene expression, and DNA recombination. A central player in these roles is the CCCTC binding factor (CTCF), which defines specific chromatin loop structures and insulates enhancer elements from promoters. Chromatin is organized in a distinct pattern around CTCF-bound sites, however, the role of this patterning remains unclear. Here, we report cryo-electron microscopy structures of reconstituted CTCF-nucleosome complexes, revealing that CTCF dimerization promotes the oligomerization of nucleosomes into defined higher-order assemblies involving specific histone-histone and CTCF-CTCF interactions. Notably, CTCF does not oligomerize efficiently on non-chromatinized DNA substrates. Disruption of CTCF-CTCF interaction interfaces in cells results in a marked decrease in chromatin looping and impairs cellular differentiation. These results indicate that chromatin structure at CTCF sites plays an important role in supporting higher-order interactions between distal regions of the genome and that these interactions are important for supporting cell-type-specific gene expression.

  PublisherOA PDFDOI

• A sequence‑encoded promoter proximal super pause stabilizes an offline RNA polymerase II state

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-18

  articleOpen accessSenior authorCorresponding

  Promoter proximal pausing by RNA polymerase II is critical for regulating gene expression in multicellular eukaryotes. How nucleic acid sequence and protein factors contribute to pausing remains incompletely understood. We developed Gene-specific Analysis of Transcriptional Output (GATO)-seq, which for the first time enables massively parallel, temporally resolved, reconstituted transcription in an assay that uses direct RNA sequencing to map 3'ends of nascent transcripts from a library of human genes. GATO-seq identified a "super pause" sequence that potently induces RNA polymerase II pausing and is not relieved by rescue factor Transcription Factor (TF) IIS. Cryogenic-electron microscopy (cryo-EM) structures of RNA polymerase II on the super pause sequence reveal a previously unobserved, reversible single-nucleotide backtracked state ("sidetracked"), stabilized by a threonine-lined pocket that limits further backtracking. We introduce a powerful in vitro technique that can be employed to study transcription regulation and through its use show that nucleic acid sequence encodes pausing propensity and traps sequence specific offline states, linking sequence to pausing control.

  PublisherOA PDFDOI

• MYC binding to nascent RNA suppresses innate immune signaling by R-loop-derived RNA-DNA hybrids

  Cell · 2026-01-22 · 6 citations

  articleOpen access

  In response to perturbed transcription elongation, the MYC oncoprotein multimerizes and undergoes a phase transition. Here, we demonstrate that MYC globally relocalizes from its canonical positions on DNA to nascent RNA upon accumulation of intronic RNA. Upon binding to RNA, MYC forms multimers that concentrate the nuclear exosome, an RNA exonuclease, and its targeting complexes around double-stranded RNA and R-loops. MYC harbors four RNA-binding regions (RBRI-IV). RBRIII promotes MYC multimerization and is necessary for recruiting the exosome to R-loops. RBRIII is dispensable for transcriptional activation and pancreatic tumor cell proliferation in culture, but it is indispensable for sustaining tumor growth in vivo. Via RBRIII, MYC suppresses the accumulation of R-loop-derived RNA-DNA hybrids and prevents them from activating the innate immune kinase TBK1 via the TLR3 pattern recognition receptor. Our data demonstrate that the phase transition of MYC is an RNA-driven stress response that suppresses the accumulation of immunogenic RNA-DNA hybrids.

  PublisherDOI

• Chemical crosslinking extends and complements UV crosslinking in analysis of RNA/DNA nucleic acid–protein interaction sites by mass spectrometry

  Nucleic Acids Research · 2025-07-22 · 6 citations

  articleOpen access

  Ultraviolet (UV) crosslinking with mass spectrometry (XL-MS) has been established for identifying RNA- and DNA-binding proteins along with their domains and amino acids involved. Here, we explore chemical XL-MS for RNA-protein, DNA-protein, and nucleotide-protein complexes in vitro and in vivo. We introduce a specialized nucleotide-protein-crosslink search engine, NuXL, for robust and fast identification of such crosslinks at amino acid resolution. Chemical XL-MS complements UV XL-MS by generating different crosslink species, increasing crosslinked protein yields in vivo almost four-fold, and thus it expands the structural information accessible via XL-MS. Our workflow facilitates integrative structural modelling of nucleic acid-protein complexes and adds spatial information to the described RNA-binding properties of enzymes, for which crosslinking sites are often observed close to their cofactor-binding domains. In vivo UV and chemical XL-MS data from E. coli cells analysed by NuXL establish a comprehensive nucleic acid-protein crosslink inventory with crosslink sites at amino acid level for >1500 proteins. Our new workflow combined with the dedicated NuXL search engine identified RNA crosslinks that cover most RNA-binding proteins, with DNA and RNA crosslinks detected in transcriptional repressors and activators.

  PublisherOA PDFDOI

• Cryo-EM Studies of Genome Organization and Transcription Complexes

  Structural Dynamics · 2025-09-01

  articleOpen access1st authorCorresponding

  RNA polymerase (Pol) II is regulated during all stages of transcription to ensure appropriate gene expression. This regulation involves interaction with various factors that modulate Pol II activity as it traverses across genes. I will discuss recent cryo-electron microscopy(EM) work that has uncovered how Pol II is both negatively and positively regulated by transcription elongation factors. Pol II activity is also influenced by the organization of the genome. Genome organisation is regulated at multiple levels ranging from the underlying DNA sequence to large scale interactions between chromosomes. Our recent efforts to understand how these multiple levels of genome organisation are used to regulate gene expression will be discussed.

  PublisherOA PDFDOI

• The USP11/TCEAL1 complex promotes transcription elongation to sustain oncogenic gene expression in neuroblastoma

  Genes & Development · 2025-04-18 · 2 citations

  articleOpen access

  During early transcription, RNA polymerase II (RNAPII) undergoes a series of structural transitions controlled by cyclin-dependent kinases. How protein ubiquitylation and proteasomal degradation control the function of RNAPII is less well understood. Here we show that the deubiquitinating enzyme USP11 forms a complex with TCEAL1, a member of the TFIIS (TCEA)-like protein family. TCEAL1 shares sequence homology with the RNAPII interaction domain of the elongation factor TFIIS (which controls the fate of backtracked RNAPII) and competes with TFIIS for binding to core promoters. USP11 protects TCEAL1 from proteasomal degradation, and TCEAL1 recruits USP11 to RNAPII. Both USP11 and TCEAL1 promote transcription elongation and maintain expression of RPB8, an essential subunit of all three nuclear RNA polymerases. In neuroblastoma, USP11- and TCEAL1-dependent genes define a gene expression program that is characteristic for mesenchymal tumors, which are described as able to escape from many treatments, suggesting that the USP11/TCEAL1 complex promotes transcription elongation to support a critical oncogenic gene expression program.

  PublisherDOI

• Chromatin boundary permeability is controlled by CTCF conformational ensembles

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-29 · 3 citations

  preprintOpen access

  Genomes are organized into chromatin loops through cohesin-mediated extrusion, with CTCF acting as a polar boundary element. As cohesin approaches CTCF at kilobase-per-second speeds, it must rapidly choose whether to stall or bypass. How CTCF encodes this probabilistic decision within a brief encounter window has remained unclear. Here we show that CTCF governs this probabilistic outcome by rapidly sampling a dynamic ensemble of conformations generated by spontaneous rearrangements of its DNA-binding zinc fingers. This ensemble is tuned by DNA sequence, CpG methylation, nearby nucleosomes, and the cohesin regulator PDS5A before cohesin engagement. Upon cohesin binding, PDS5A enhances loop-anchor mechanical stability, reinforcing orientation-dependent boundaries. These findings establish conformational ensemble tuning, rather than static occupancy, as a regulatory principle linking base pair-scale motions to megabase-scale genome organization.

  PublisherDOI

• Distinct negative elongation factor conformations regulate RNA polymerase II promoter-proximal pausing

  Molecular Cell · 2024-02-23 · 28 citations

  articleOpen accessSenior authorCorresponding

  Metazoan gene expression regulation involves pausing of RNA polymerase (Pol II) in the promoter-proximal region of genes and is stabilized by DSIF and NELF. Upon depletion of elongation factors, NELF appears to accompany elongating Pol II past pause sites; however, prior work indicates that NELF prevents Pol II elongation. Here, we report cryoelectron microscopy structures of Pol II-DSIF-NELF complexes with NELF in two distinct conformations corresponding to paused and poised states. The paused NELF state supports Pol II stalling, whereas the poised NELF state enables transcription elongation as it does not support a tilted RNA-DNA hybrid. Further, the poised NELF state can accommodate TFIIS binding to Pol II, allowing for Pol II reactivation at paused or backtracking sites. Finally, we observe that the NELF-A tentacle interacts with the RPB2 protrusion and is necessary for pausing. Our results define how NELF can support pausing, reactivation, and elongation by Pol II.

  PublisherDOI

Recent grants

• Towards fully reconstituting mammalian transcription in a test tube

  NIH · $2.2M · 2021–2026

Frequent coauthors

• Michael A. Cianfrocco

  University of Michigan–Ann Arbor

  23 shared

• Patrick Cramer

  Max Planck Institute for Multidisciplinary Sciences

  21 shared

• Quanfu Fan

  Amazon (Germany)

  20 shared

• Yilai Li

  20 shared

• Ziping Xu

  19 shared

• Lucy Yip

  IBM (United States)

  18 shared

• Veronique Demers

  University of Michigan–Ann Arbor

  18 shared

• Emma Rose Lee

  IBM (United States)

  18 shared

Labs

• Seychelle M. Vos LabPI

Education

• PhD, Department of Molecular and Cell Biology

  University of California Berkeley

  2013

Awards & honors

• New Innovator Award, National Institutes of Health Common Fu…