Understanding Chromatin Regulation
The identity of every cell is encoded not only by its genome, but by the regulatory networks that determine which genes are active, when they are expressed, and how they respond to environmental signals. Chromatin—the dynamic protein-DNA architecture that packages the genome—plays a central role in this process by controlling the accessibility of regulatory DNA. Transcription factors and chromatin-associated proteins continuously reshape this landscape, allowing genetically identical cells to adopt remarkably diverse identities and behaviors.
Unlike mutations that directly alter protein function, changes in chromatin regulation can simultaneously influence thousands of genes, producing widespread shifts in cellular state. Understanding how individual regulatory proteins reshape chromatin therefore represents one of the central challenges in modern molecular biology.
Decoding Chromatin Dysregulation at Scale
Many diseases arise not because individual genes are mutated, but because regulatory proteins rewire the epigenetic landscape of the cell. Cancer-driving oncofusion proteins, viral transcriptional regulators, and other chromatin-associated factors frequently alter genome-wide chromatin accessibility, yet their mechanisms remain difficult to study. Traditional approaches examine one regulator at a time, making it challenging to discover common principles that govern how diverse proteins remodel chromatin.
To address this challenge, our laboratory developed PROD-ATAC, a pooled single-cell functional genomics platform that enables hundreds of regulatory proteins to be profiled simultaneously. By coupling pooled perturbation libraries with single-cell chromatin accessibility measurements, we generate large-scale maps of how protein sequence influences global chromatin architecture. These datasets allow us to move beyond individual case studies and identify shared regulatory programs that emerge across diverse classes of chromatin regulators.
Oncofusion Proteins: Discovering Common Mechanisms of Cancer
Chromosomal rearrangements frequently generate oncofusion proteins—hybrid transcriptional regulators that drive cancer by rewiring gene regulation. Thousands of oncofusions have been identified across human tumors, yet only a small fraction have been mechanistically characterized. A central question is whether these seemingly unrelated proteins act through unique pathways, or whether they converge on common mechanisms of chromatin dysregulation.
Using PROD-ATAC, we systematically profiled more than one hundred cancer-associated oncofusions in a single experiment. Rather than examining one fusion at a time, we generated a global atlas of fusion-induced chromatin remodeling, revealing that widespread chromatin dysregulation is a remarkably common feature across diverse cancers. Our analyses further demonstrated that many rare oncofusions share regulatory behaviors with more common cancer drivers, suggesting the existence of convergent mechanisms that transcend tumor type or fusion frequency. These studies begin to establish general principles by which altered transcriptional regulators reshape cellular identity during oncogenesis.
Viral Transcription Factors: Revealing Conserved Strategies of Host Reprogramming
Viruses have evolved sophisticated transcriptional regulators that manipulate host chromatin and gene expression to promote infection, persistence, and, in some cases, oncogenic transformation. Although viral genomes encode thousands of candidate regulatory proteins, the vast majority remain functionally uncharacterized.
To address this gap, we extended PROD-ATAC to systematically profile over one hundred viral transcriptional regulators in a single pooled experiment. Surprisingly, evolutionarily unrelated viral proteins frequently converged on the same host regulatory networks, including NF-κB, AP-1, p53, and Sp1/KLF signaling pathways. By integrating chromatin accessibility, transcriptomic measurements, and chemical perturbations, we identified conserved host dependencies that underlie viral epigenetic reprogramming. These studies suggest that many viruses exploit a shared set of regulatory principles despite their diverse evolutionary origins.
Toward Predictive Models of Cellular State
Our long-term goal extends beyond cataloging chromatin changes. We seek to uncover the general principles that govern how regulatory proteins reshape cellular identity. By combining pooled perturbation experiments, single-cell genomics, and machine learning, we aim to construct predictive models that connect protein sequence to chromatin remodeling, transcriptional responses, and ultimately cellular behavior.