Department of Biology · Johns Hopkins University

Decoding the Structural Logic of the Genome

Chromatin architecture establishes the physical framework that translates the static DNA code into dynamic regulatory programs. Our laboratory investigates how this epigenetic grammar is actively written and interpreted by massive, multi-subunit machines known as chromatin remodelers and modifiers (CRMs).

Explore our research Recent publications

Scroll

By bridging high-resolution cryo-electron microscopy (cryo-EM) with real-time single-molecule biophysics and in situ cellular cryo-ET, we capture these highly dynamic epigenetic machines in action. Our goal is to watch them navigate the crowded nucleoplasm, engage their specific targets, and execute the mechanical tasks required to regulate essential cellular processes like transcription and DNA repair. Ultimately, we aim to translate these fundamental mechanistic insights into targeted therapeutic strategies for cancer, developmental disorders, and viral infections.

Research

Structural Enzymology and Regulatory Mechanisms of Chromatin Remodelers and Modifiers

Why do massive, megadalton-scale chromatin remodelers exist when their core mechanical tasks can often be performed by a single enzyme subunit? We hypothesize that these complex architectures evolved primarily for regulatability. Rather than acting as simple motors, multi-subunit CRMs operate as sophisticated signal-integration hubs that are dynamically modulated by interacting factors and nucleosome composition.

To understand how these machines function, we treat cryo-EM as a visual biochemical assay. By imaging fully assembled complexes under active turnover conditions, we resolve transient, short-lived intermediates to map the step-by-step kinetic pathways of chromatin remodeling. Coupling this structural pipeline with real-time biophysics allows us to define exactly how specific structural interfaces control enzyme activity—and how uncoupling these regulatory nodes drives disease.

Cryo-EM
Structural enzymology
Single-molecule biophysics

Opening frame of the cryo-EM sequence: a teal density map above the title
'High resolution structural characterization of chromatin remodeling machinery' — Resolving the remodeling reaction by cryo-EM — 1:24, from classification of reaction intermediates through to a reconstructed mechanism. Click to play. Accompanies Park et al., *Science Advances* 12(31):eaei7728 (2026).

Decoding the Combinatorial Logic of CRM Recruitment in Transcription and DNA Repair

How do massive chromatin remodelers navigate the sterically crowded nucleus to find specific regulatory targets among millions of bulk nucleosomes? We approach this targeting challenge as a multidimensional spatial problem. Our lab investigates how sequence-specific transcription factors synergize with local chromatin cues—such as histone modifications, nascent RNA, and DNA geometry—to recruit remodelers to specific active promoters.

We contrast this highly precise logic with the rapid mass-mobilization of remodelers during acute DNA repair. By mapping how these complexes differentially recognize, for example, active versus repressed gene regions, we are uncovering the predictive rules that connect chromatin state to specific remodeling outcomes. Deciphering how these machines “read” the genome will ultimately enable us to synthetically redirect them to correct epigenetic dysregulation.

Transcription
DNA repair
In situ cryo-ET

Structural model of the SWR1 chromatin remodeler engaging a nucleosome,
with linker DNA extending to a neighbouring nucleosome and subunits
coloured individually — Atomic-scale structural model of open promoter sensing and +1 nucleosome capture by SWR1, revealing how the remodeler integrates multidimensional spatial cues—including DNA geometry and histone PTMs—to make precise targeting decisions. From Louder et al., *Cell* 187:6849–6864 (2024).

Contact

Robert Louder · [email protected]
Department of Biology, Mudd Hall
Johns Hopkins University, 3400 N. Charles St, Baltimore, MD 21218