Research

Mammalian development relies on a complex interplay between genetic and epigenetic factors to create trillions of highly specialized cells from the same genetic blueprint. This process is orchestrated by gene regulatory sequences encoded in DNA, which in turn are influenced by epigenetic properties including DNA methylation, DNA packaging, and modifications of DNA packaging proteins. Mammalian genomes contain hundreds of epigenetic regulators — collectively referred to as the epigenetic machinery — which are responsible for reading, writing, and erasing this epigenetic information. Our research seeks to understand how the epigenetic machinery works, and how its malfunction contributes to disease.

Current directions

Current work in the lab addresses three key questions about the epigenetic machinery:

1. Regulatory targets. What are the specific regulatory sequences and target genes influenced by components of the epigenetic machinery, and in what cell types and contexts?
2. Recruitment. How are components of the epigenetic machinery recruited to specific regions of the genome — for example, to regulatory sequences — in specific cellular contexts?
3. Disease mechanisms. By what mechanisms do disease-causing mutations in components of the epigenetic machinery give rise to phenotypes at the molecular, cellular, and organismal levels?

Approach

To answer these questions, we use a variety of tools including:

• Epigenomics — ChIP-seq, ATAC-seq, Hi-C, and related assays applied to bulk and single-cell samples.
• Genome editing — CRISPR/Cas9 knockouts, base editing, and enhancer perturbations.
• Single-cell genomics — snATAC-seq, snRNA-seq, and multi-omic profiling.
• Computational biology — computational approaches to model regulatory sequence and predict variant impact.

We work in both mouse developmental models and human cell culture models, and collaborate broadly with clinical geneticists on disease-focused projects (e.g., ASD, Coffin-Siris syndrome, and other epigenetic-machinery disorders).