About

Igal Szleifer is a Professor of Biomedical Engineering, Chemistry, Chemical and Biological Engineering, and Medicine at Northwestern University. His research focuses on the molecular modeling of biointerphases, aiming at a fundamental understanding of the properties of complex molecular systems that intersect medicine, biology, chemistry, physics, and materials science. His group develops and applies theoretical approaches to study systems at the molecular level, often collaborating closely with experimental researchers. The work is directed towards understanding the molecular factors that influence interactions between biological environments and synthetic systems, and using this knowledge to design optimal materials such as biocompatible materials and drug carriers. Specific systems of interest include chromatin, protein adsorption, biocompatible materials, lipid layers, model cell membranes, drug delivery systems, ligand-receptor binding, and smart responsive materials.

Research topics

• Biophysics
• Biology
• Chemistry
• Materials science
• Physical chemistry
• Nanotechnology
• Chemical physics
• Biochemical engineering
• Computational chemistry
• Genetics
• Physics
• Cell biology
• Computational biology
• Engineering

Selected publications

• One Chromatin, Many Structures: From Ensemble Contact Maps to Single-Cell 3D Organization

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-21

  articleOpen accessSenior authorCorresponding

  Understanding how chromatin folds in three dimensions remains challenging because most experimental assays capture low-dimensional projections of an underlying, highly heterogeneous polymer. Here we present an ensemble-based interpretive framework built on the previously introduced Self-Returning Excluded Volume (SR-EV) model, a minimal generator of nucleosome-resolution chromatin conformations based on stochastic return rules and excluded-volume geometry. Despite its simplicity, SR-EV reproduces key experimental signatures across scales: heterogeneous nanoscale packing domains resembling ChromEMT and ChromSTEM observations, sparse and highly variable single-configuration contact patterns analogous to single-cell chromosome conformation capture (Hi-C), and robust ensemble-level contact enrichment consistent with topologically associating domains (TADs). In this framework, Hi-C loop and TAD signatures are interpreted as ensemble-level statistical enrichments rather than invariant features of single-cell conformations. SR-EV is explicitly designed to generate large ensembles of complete three-dimensional chromatin configurations that can be projected consistently onto two-dimensional contact maps and one-dimensional genomic profiles. By introducing architectural-protein effects only through ensemble selection rather than explicit forces, SR-EV supports a separation between intrinsic polymer geometry and regulatory bias and suggests that TAD-like features can emerge as statistical enrichments rather than deterministic three-dimensional structures. Coordination number and probe-based accessibility computed directly from SR-EV provide a unified link between three-dimensional packing, two-dimensional contact maps, and one-dimensional genomic profiles. Together, these results establish SR-EV as a minimal and physically grounded reference framework for interpreting how heterogeneous chromatin ensembles give rise to multimodal experimental observables, while remaining consistent with the fact that chromatin organization is realized in individual cells. SIGNIFICANCE Chromatin domains, boundaries, and contact enrichments are often interpreted as fixed structural entities, even though most experimental measurements average over large and heterogeneous cell populations. The SR-EV framework shows that many of these features can be understood as emerging from minimal geometric rules combined with ensemble-level bias, without requiring explicit molecular interactions or deterministic folding mechanisms. By distinguishing single-configuration heterogeneity from ensemble-level statistical organization – including the emergence of packing domains– SR-EV supports an interpretation in which chromatin organization is realized in individual cells but must be analyzed through ensembles. This perspective clarifies the probabilistic nature of genome architecture and provides a tractable reference framework for interpreting multimodal genomic and imaging data.

  PublisherDOI

• Geometrically Encoded Positioning of Introns, Intergenic Segments, and Exons in the Human Genome (Adv. Sci. 6/2026)

  Advanced Science · 2026-01-01

  articleOpen access
  PublisherOA PDFDOI

• A self-returning excluded volume polymer model to validate 3D spectroscopic SMLM images of histone modifications

  2025-01-23

  article

  Super-resolution microscopy is widely used to quantify the spatial distribution of histone modifications. However, many features of nucleosome organization exist close to or below the resolution limit of super-resolution, and measurements made directly from super-resolution images are prone to biases from repeated blinking of individual fluorophores and the length of the probe used. To address these limitations, we have developed a simulated ground truth chromatin model upon which we simulate probe binding, fluorophore blinking dynamics, noise, and image reconstruction. This model can be used to investigate the effects of biases and to validate histone quantification techniques.

  PublisherDOI

• Leveraging chromatin packing domains to target chemoevasion in vivo

  Proceedings of the National Academy of Sciences · 2025-07-22 · 3 citations

  articleOpen access

  Cancer cells exhibit a remarkable resilience to cytotoxic stress, often adapting through transcriptional changes linked to alterations in chromatin structure. In several types of cancer, these adaptations involve epigenetic modifications and restructuring of topologically associating domains. However, the underlying principles by which chromatin architecture facilitates such adaptability across different cancers remain poorly understood. To investigate the role of chromatin in this process, we developed a physics-based model that connects chromatin organization to cell fate decisions, such as survival following chemotherapy. Our model builds on the observation that chromatin forms packing domains, which influence transcriptional activity through macromolecular crowding. The model accurately predicts chemoevasion in vitro, suggesting that changes in packing domains affect the likelihood of survival. Consistent results across diverse cancer types indicate that the model captures fundamental principles of chromatin-mediated adaptation, independent of the specific cancer or chemotherapy mechanisms involved. Based on these insights, we hypothesized that compounds capable of modulating packing domains, termed Transcriptional Plasticity Regulators (TPRs), could prevent cellular adaptation to chemotherapy. We conducted a proof-of-concept compound screen using live-cell chromatin imaging to identify several TPRs that synergistically enhanced chemotherapy-induced cell death. The most effective TPR significantly improved therapeutic outcomes in a patient-derived xenograft model of ovarian cancer. These findings underscore the central role of chromatin in cellular adaptation to cytotoxic stress and present a framework for enhancing cancer therapies, with broad potential across multiple cancer types.

  PublisherOA PDFDOI

• Geometrically Encoded Positioning of Introns, Intergenic Segments, and Exons in the Human Genome

  Advanced Science · 2025-10-27 · 2 citations

  articleOpen accessCorresponding

  Human tissues require a mechanism to generate durable, yet modifiable, transcriptional memories to sustain cell function across a lifetime. Previously, it was demonstrated that nanoscale packing domains couple heterochromatin (cores) and euchromatin (outer zone) into unified reaction volumes that can generate transcriptional memory. In prior work, this framework demonstrates that RNA synthesis occurred within the ideal zone (intermediate density) portions of the domain. Naturally, this creates a question of where genes are positioned in relation to the packing domain architecture and which genetic material fills the domain core to sustain transcription. Here, it is proposed that this can be solved by the encoded positioning of introns, intergenic segments, and exons as a projection of the functional packing layers of domains. This suggests that introns and intergenic segments are coupled to adjacent exons to generate coherent packing domain volumes. How this organization will reconcile contradictions in epigenetic patterns, non-randomness in oncogenic mutations, and produce durable transcriptional memory is illustrated. The study concludes by showing that this genome geometry may have coincided with the rapid evolution of body-plan complexity, suggesting that chromatin geometry could be fundamental to metazoan evolution.

  PublisherOA PDFDOI

• Mature chromatin packing domains persist after RAD21 depletion in 3D

  Science Advances · 2025-01-24 · 16 citations

  articleOpen access

  Understanding chromatin organization requires integrating measurements of genome connectivity and physical structure. It is well established that cohesin is essential for TAD and loop connectivity features in Hi-C, but the corresponding change in physical structure has not been studied using electron microscopy. Pairing chromatin scanning transmission electron tomography with multiomic analysis and single-molecule localization microscopy, we study the role of cohesin in regulating the conformationally defined chromatin nanoscopic packing domains. Our results indicate that packing domains are not physical manifestation of TADs. Using electron microscopy, we found that only 20% of packing domains are lost upon RAD21 depletion. The effect of RAD21 depletion is restricted to small, poorly packed (nascent) packing domains. In addition, we present evidence that cohesin-mediated loop extrusion generates nascent domains that undergo maturation through nucleosome posttranslational modifications. Our results demonstrate that a 3D genomic structure, composed of packing domains, is generated through cohesin activity and nucleosome modifications.

  PublisherDOI

• Chromatin conformation, gene transcription, and nucleosome remodeling as an emergent system

  Science Advances · 2025-01-10 · 29 citations

  articleOpen accessCorresponding

  In single cells, variably sized nanoscale chromatin structures are observed, but it is unknown whether these form a cohesive framework that regulates RNA transcription. Here, we demonstrate that the human genome is an emergent, self-assembling, reinforcement learning system. Conformationally defined heterogeneous, nanoscopic packing domains form by the interplay of transcription, nucleosome remodeling, and loop extrusion. We show that packing domains are not topologically associated domains. Instead, packing domains exist across a structure-function life cycle that couples heterochromatin and transcription in situ, explaining how heterochromatin enzyme inhibition can produce a paradoxical decrease in transcription by destabilizing domain cores. Applied to development and aging, we show the pairing of heterochromatin and transcription at myogenic genes that could be disrupted by nuclear swelling. In sum, packing domains represent a foundation to explore the interactions of chromatin and transcription at the single-cell level in human health.

  PublisherDOI

• RN-SDEs: Limited-Angle CT Reconstruction with Residual Null-Space Diffusion Stochastic Differential Equations

  SSRN Electronic Journal · 2025-01-01 · 1 citations

  preprintOpen access
  PublisherDOI

• Geometrically encoded positioning of introns, intergenic segments, and exons in the human genome

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-29

  preprintOpen access

  Human tissues require a mechanism to generate durable, yet modifiable, transcriptional memories to sustain cell function across a lifetime. Previously, we demonstrated that nanoscale packing domains couple heterochromatin (cores) and euchromatin (outer zone) into unified reaction volumes that can generate transcriptional memory. In prior work, this framework demonstrated that RNA synthesis occurred within the ideal zone (intermediate density) portions of the domain. Naturally, this creates a question of where genes are positioned in relation to the packing domain architecture and which genetic material fills the domain core to sustain transcription. Here we propose that this could be solved by the encoded positioning of introns, intergenic segments, and exons as a projection of the functional packing layers of domains. This suggests that introns and intergenic segments are coupled to adjacent exons to generate coherent packing domain volumes. We illustrate how this organization would reconcile contradictions in epigenetic patterns, non-randomness in oncogenic mutations, and produce durable transcriptional memory. We conclude by showing that this genome geometry might have coincided with the rapid evolution of body-plan complexity, suggesting that chromatin geometry could be fundamental to metazoan evolution.

  PublisherOA PDFDOI

• Author response: Local Volume Concentration, Packing Domains and Scaling Properties of Chromatin

  2024-08-28

  peer-reviewOpen accessSenior author

  We propose the Self Returning Excluded Volume (SR-EV) model for the structure of chromatin based on stochastic rules and physical interactions. The SR-EV rules of return generate conformationally-defined domains observed by single cell imaging techniques. From nucleosome to chromosome scales, the model captures the overall chromatin organization as a corrugated system, with dense and dilute regions alternating in a manner that resembles the mixing of two disordered bi-continuous phases. This particular organizational topology is a consequence of the multiplicity of interactions and processes occurring in the nuclei, and mimicked by the proposed return rules. Single configuration properties and ensemble averages show a robust agreement between theoretical and experimental results including chromatin volume concentration, contact probability, packing domain identification and size characterization, and packing scaling behavior. Model and experimental results suggest that there is an inherent chromatin organization regardless of the cell character and resistant to an external forcing such as Rad21 degradation.

  PublisherDOI

Recent grants

• Responsive Tethered Polymer Layers: Protein Adsorption, Phase Transition and Interactions

  NSF · $300k · 2003–2007

• Molecular Organization and Transport in Synthetic and Biological Nanopores

  NSF · $386k · 2014–2018

• Collaborative Research: Molecular basis for protein sorption in polymer-modified chromatographic media

  NSF · $225k · 2013–2016

• NIH Grant R01EB005772

  NIH · $2.8M · 2018

• Reducing Cancer Transcriptional Heterogeneity through Regulation of Chromatin Structure

  NIH · $3.2M · 2018–2025

Frequent coauthors

• Mario Tagliazucchi

  Fundación Ciencias Exactas y Naturales

  90 shared

• Marcelo A. Carignano

  62 shared

• Rikkert J. Nap

  57 shared

• Vadim Backman

  Northwestern University

  51 shared

• Luay M. Almassalha

  Northwestern University

  41 shared

• Gabriel S. Longo

  Consejo Nacional de Investigaciones Científicas y Técnicas

  39 shared

• Omar Azzaroni

  Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas

  38 shared

• Horacio R. Corti

  Fundación Ciencias Exactas y Naturales

  29 shared

Labs

• Igal Szleifer Research GroupPI

Education

• PhD

  Hebrew University of Jerusalem

  1989

• B.Sc,

  Hebrew University of Jerusalem

  1984