About

Andrew J. Spakowitz is a professor whose research focuses on the theory and computation of biological processes and soft materials. His work involves developing models and computational techniques to understand complex biological and soft matter systems, contributing to the fundamental understanding of these areas. The page does not provide additional biographical details or specific research projects related to his personal background or academic contributions.

Research topics

• Cell biology
• Chemistry
• Biology
• Genetics
• Evolutionary biology
• Computer Science
• Materials science
• Physics
• Polymer chemistry
• Biochemistry
• Optics
• Computational biology
• Mathematical analysis
• Physical chemistry
• Organic chemistry
• Composite material
• Quantum mechanics
• Nanotechnology
• Mathematics
• Combinatorial chemistry
• Classical mechanics

Selected publications

• Polymer field theoretic studies of heterogeneous binding in chromosomal DNA and soft materials

  Stanford Digital Repository · 2026-03-16

  dissertationOpen access
  PublisherDOI

• MACRO-MOLECULAR CROWDING FAVORS WRITHE IN UNWOUND DNA

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-05

  articleOpen access

  ABSTRACT Genomic DNA is subject to forces and torsion. Some arise mechanically, while others can be entropic, such as those due to crowding within the nuclear environment. Indeed, about 30-40% of the cell is occupied by molecules other than water, and of these, the vast majority are macromolecules. Here, we explore both experimentally and theoretically the interplay between tension, torsion, and macromolecular crowding. Using pharmaceutically relevant crowders of different molecular weights, Dextran 70, and polyethylene glycol (PEG), we observed that macromolecular crowding of unwound, stretched DNA effectively opposed the tension and promoted the formation of plectonemes. A theoretical model representing the equilibrium between B - and L -form DNA fit to the experimental measurements indicates the contractile tension produced by macromolecular crowding of DNA. SIGNIFICANCE STATEMENT Distinct DNA conformers are involved in different cellular processes. Genomic DNA is both stretched and unwound by enzymes in a crowded intracellular medium. This can induce conformational changes between extended, twisted and more compact, plectonemic forms. This study explores the effect of macro-molecular crowding on the conformations of DNA subject to tension and torque. Fitting experimental data to a model for the right-to-left-handed DNA transition, we show that macromolecular crowding induces a contractile force that favors DNA writhe and that such force depends both on the concentration and molecular weight of the crowder.

  PublisherDOI

• Nucleosome placement and polymer mechanics explain genomic contacts on 100 kb scales

  Nucleic Acids Research · 2025-07-19

  articleOpen access

  The 3D organization of the genome-in particular, which two regions of DNA are in contact with each other-plays a role in regulating gene expression. Several factors influence genome 3D organization. Nucleosomes (where ∼100 base pairs of DNA wrap around histone proteins) bend, twist, and compactify chromosomal DNA, altering its polymer mechanics. How much does the positioning of nucleosomes between gene loci influence contacts between those gene loci? And to what extent are polymer mechanics responsible for this? To address this question, we combine a stochastic polymer mechanics model of chromosomal DNA including twists and wrapping induced by nucleosomes with two data-driven pipelines. The first estimates nucleosome positioning from ATAC-seq data in regions of high accessibility. Most of the genome is low accessibility, so we combine this with a novel image analysis method that estimates the distribution of nucleosome spacing from electron microscopy data. There are no fit parameters in the biophysical model. We apply this method to IL-6, IL-15, CXCL9, and CXCL10, inflammatory marker genes in macrophages, before and after inflammatory stimulation, and compare the predictions with contacts measured by conformation capture experiments (4C-seq). We find that within a 500-kb genomic region, polymer mechanics with nucleosomes can explain 71% of close contacts. These results suggest that, while genome contacts on 100 kb scales are multifactorial, they may be amenable to mechanistic, physical explanation. Our work also highlights the role of nucleosomes, not just at the loci of interest, but between them, and not just the total number of nucleosomes, but their specific placement. The method generalizes to other genes, and can be used to address whether a contact is under active regulation by the cell (e.g. a macrophage during inflammatory stimulation).

  PublisherOA PDFDOI

• Physical models reveal indirect reader protein interactions that facilitate epigenetic crosstalk

  Proceedings of the National Academy of Sciences · 2025-11-18

  articleOpen accessSenior authorCorresponding

  The spatial organization of chromatin is governed by epigenetic factors, including epigenetic marks and the reader proteins that bind them. By dictating the accessibility of genomic loci, epigenetic factors contribute to the physical regulation of gene expression, enabling diverse cellular phenotypes to be encoded by a shared genome in an individual. Epigenetic dysregulation can lead to aberrations in chromatin architecture, contributing to diseases such as neurological disorders and cancers. Despite the known importance of chromatin organization for human health, the physical mechanisms governing chromatin folding remain underspecified. In this work, we develop a physical model of chromatin organization based on contributions from multiple epigenetic factors. Using our model, we evaluate how conditions in the nuclear environment and crosstalk between epigenetic marks affect the compartmentalization of chromatin into dense heterochromatin and loose euchromatin. Our results emphasize the role of reader protein binding in chromatin compartmentalization. We show that reader proteins interact through an indirect mechanism facilitated by the shared chromatin "scaffold" to which they bind. Under a scenario where reader proteins compete for binding sites, we find that indirect interactions affect the program adopted by the chromatin fiber. By isolating indirect modes of epigenetic crosstalk, we demonstrate how the interplay between epigenetic patterning and environmental factors influences chromatin architecture.

  PublisherDOI

• Tuning viscoelasticity of dynamic covalent hydrogels for human tissue modeling

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-17

  preprintOpen access

  Abstract The development of three-dimensional (3D) in vitro tissue culture models is critical for biomedical research. Hydrogel-based systems have become a preferred scaffold for 3D models, as they have tunable viscoelastic properties, which are well-known to influence cell morphology and function. In particular, reversible hydrogel crosslinks formed through dynamic covalent chemistry (DCC) can introduce viscoelastic behavior including stress relaxation. However, traditional strategies to increase stress-relaxation rates in DCC gels rely on faster bond kinetics, resulting in faster erosion rates that prevent their use for long-term 3D culture. As an alternative strategy, we explore the use of molecular parameters (specifically molecular weight and degree of functionalization) to independently control the stiffness and stress relaxation behavior while preventing rapid erosion. As demonstration, we develop and validate a modified theoretical model of gel viscoelasticity applied to a two-component DCC gel composed of modified hyaluronic acid and elastin-like protein. Finally, we utilize this tunable gel platform to explore the impact of scaffold viscoelasticity on encapsulated human neural progenitor cells. In summary, this work expands the molecular design space of DCC hydrogels to achieve tunable viscoelastic properties for 3D in vitro models.

  PublisherOA PDFDOI

• Parameterizing Conjugated Polymers as Ribbon-like Chains

  Macromolecules · 2025-10-29 · 1 citations

  article
  PublisherDOI

• Kinetic organization of the genome revealed by ultraresolution multiscale live imaging

  Science · 2025-09-18 · 18 citations

  articleOpen access

  Genome function requires regulated genome motion. However, tools to directly observe this motion in vivo have been limited in coverage and resolution. Here we introduce an approach to tile mammalian chromosomes with self-mapping fluorescent labels and track them at ultraresolution. We find that sequences separated by submegabase distances transition to proximity in tens of seconds. This rapid search is dependent on cohesin and is exhibited only within domains. Domain borders act as kinetic impediments to this search process, rather than structural boundaries. The genomic separation-dependent scaling of the search time for cis interactions violated predictions of diffusion, suggesting motor-driven folding. We also uncover cohesin-dependent processive motion at 2.7 kilobases per second. Together, these multiscale dynamics reveal the organization of the genome into kinetically associated domains.

  PublisherOA PDFDOI

• Leveraging inhomogeneous binding of incompatible constituents for adaptive copolymer self-assembly

  Soft Matter · 2025-01-01

  articleSenior authorCorresponding

  Using a polymer field-theoretic model, we present a system containing copolymers and two distinct chemical moieties that bind heterogeneously along the copolymer chains, enabling self-assembly of a range of periodic morphologies by tuning the concentration of binder species. Our model consists of generic "guest" species, A and B, that compete to bind "host" sites on the copolymer chains. The chemical potentials of the guests control the extent of binding, and thus determine the copolymer block size and self-assembly behavior. We apply a transfer-matrix method to calculate binding profiles along the copolymers at varying conditions. The random-phase approximation is then employed to calculate quartic-order free-energy expressions for lamellar, cylindrical, and body-centered cubic phases, which are used to generate phase diagrams. This theory predicts that our single model system can access a range of stable phases without changing the polymer sequence, allowing for polymer materials with facile control over microphase segregation.

  PublisherDOI

• Modeling DNA methyltransferase function to predict epigenetic correlation patterns in healthy and cancer cells

  Proceedings of the National Academy of Sciences · 2025-01-10 · 1 citations

  articleOpen accessSenior authorCorresponding

  DNA methylation is a crucial epigenetic modification that orchestrates chromatin remodelers that suppress transcription, and aberrations in DNA methylation result in a variety of conditions such as cancers and developmental disorders. While it is understood that methylation occurs at CpG-rich DNA regions, it is less understood how distinct methylation profiles are established within various cell types. In this work, we develop a molecular-transport model that depicts the genomic exploration of DNA methyltransferase within a multiscale DNA environment, incorporating biologically relevant factors like methylation rate and CpG density to predict how patterns are established. Our model predicts DNA methylation-state correlation distributions arising from the transport and kinetic properties that are crucial for the establishment of unique methylation profiles. We model the methylation correlation distributions of nine cancerous human cell types to determine how these properties affect the epigenetic profile. Our theory is capable of recapitulating experimental methylation patterns, suggesting the importance of DNA methyltransferase transport in epigenetic regulation. Through this work, we propose a mechanistic description for the establishment of methylation profiles, capturing the key behavioral characteristics of methyltransferase that lead to aberrant methylation.

  PublisherDOI

• Kinetic organization of the genome revealed by ultra-resolution, multiscale live imaging

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-01 · 5 citations

  preprintOpen access

  Abstract In the last decade, sequencing methods like Hi-C have made it clear the genome is intricately folded, and that this organization contributes significantly to the control of gene expression and thence cell fate and behavior. Single-cell DNA tracing microscopy and polymer physics-based simulations of genome folding have proposed these population-scale patterns arise from motor- driven, heterogeneous movement, rather than stable 3D genomic architecture, implying that motion, rather than structure, is key to understanding genome function. However, tools to directly observe this motion in vivo have been limited in coverage and resolution. Here we describe TRansposon Assisted Chromatin Kinetic Imaging Technology (TRACK-IT), which combines a suite of imaging and labeling improvements to achieve ultra-resolution in space and time, with self-mapping transposons to distribute labels across the chromosome, uncovering dynamic behaviors across four orders of magnitude of genomic separation. We find that sequences separated by sub-megabase distances, typically 200-500 nm of nanometers apart, can transition to close proximity in tens of seconds - faster than previously hypothesized. This rapid motion is dependent upon cohesin and is exhibited only within certain genomic domains. Domain borders act as kinetic impediments to this search process, substantially slowing the rate and frequency of the transition to proximity. The genomic separation-dependent scaling of the search time for cis-interactions within a domain violates predictions of diffusion, suggesting motor driven folding. This distinctive scaling is lost following cohesin depletion, replaced with a behavior consistent with diffusion. Finally, we found cohesin containing cells exhibited rare, processive movements, not seen in cohesin depleted cells. These processive trajectories exhibit extrusion rates of ∼2.7 kb/s across three distinct genomic intervals, faster than recent in vitro measurements and prior estimates from in vivo data. Taken together, these results reveal a genome in motion across multiple genomic and temporal scales, where motor-dependent extrusion divides the sequence, not into spatially separate domains, but into kinetically separated domains that experience accelerated local search.

  PublisherDOI

Recent grants

• Polymer Physics Across Scales: Bridging Atomistic and Coarse-Grained Polymer Models

  NSF · $384k · 2019–2023

• CAREER: Target-Site Search of DNA-Binding Proteins

  NSF · $579k · 2009–2014

• UNS: Microstructural determinants of ion transport in ion exchange fuel cell membranes

  NSF · $370k · 2015–2018

• Theoretical Modeling of Protein-Driven Chromosomal Dynamics and Biological Function

  NSF · $455k · 2017–2021

• Revealing the Physical Principles Underlying Epigenetic Regulation Using Theory, Simulation, and Experiment

  NSF · $381k · 2013–2017

Frequent coauthors

• Elena F. Koslover

  University of California, San Diego

  27 shared

• Sarah C. Heilshorn

  25 shared

• Nicholas Cordella

  Stanford University

  19 shared

• Quinn MacPherson

  Stanford University

  19 shared

• Shafigh Mehraeen

  University of Illinois Chicago

  16 shared

• Brad A. Krajina

  Stanford University

  15 shared

• Julie A. Theriot

  Howard Hughes Medical Institute

  14 shared

• Alberto Salleo

  11 shared

Labs

• Spakowitz Research GroupPI

  Theory and Computation of Biological Processes and Soft Materials

Education

• Ph.D., Physics

  Stanford University

  1994

• B.S., Physics

  University of California, Berkeley

  1989