Research Overview

Thirty years after starting the Human Genome Project, we now live in an era of widespread human genome sequencing. Yet, most functions encoded in the human genome remain mysterious and relating individual genetic variations to health still poses challenges. Human induced pluripotent stem (iPS) cells represent a powerful approach to functional genomics, given their broad capacity for differentiation. The Woltjen Lab develops genome and epigenome editing tools in human iPS cells to create isogenic disease models, with applications in regenerative medicine.

The Woltjen Lab develops various gene editing methods using reprogrammable nucleases such as TALEN and CRISPR-Cas9. Targeting the most common, yet subtle, variants known as single nucleotide polymorphisms (SNPs), we developed methods to bias DNA repair outcomes and achieve precise, single-nucleotide editing. For the second most common class of variants, insertions and deletions (indels), we characterized the sequence features of natural variants and published a database enabling efficient CRISPR editing. As a complementary approach to gene editing, we are developing CRISPR interference (CRISPRi) and activation (CRISPRa) systems that target the epigenome and do not damage DNA. Controlling gene expression through the epigenome helps understand quantitative traits and develop novel therapies.

Amongst our technical successes, the Woltjen Lab has applied gene and epigenome editing to create models of X-linked dominant protoporphyria and muscular dystrophy, repair genes that cause metabolic diseases such as diabetes, elucidate mechanisms of early embryonic development, evade allogenic immune responses, and explore the role of genetic variants underlying genome stability and cancer. Unique in CiRA, we are developing protocols for skin cell differentiation from iPS cells in order to study genodermatoses (hereditary skin diseases).

Through our approach we aim to gain "total control" of the human genome, guiding iPS cell differentiation, phenotypes, and future regenerative medicine applications.