Description:

The Department of Biochemistry and Molecular Genetics presents:

Kenneth Zaret, Joseph Leidy Professor, Cell and Developmental Biology

University of Pennsylvania, Perelman School of Medicine

Title: "Overcoming Chromatin Barriers for Changes in Cell Fate"

Abstract: The revelation of signals and regulatory transcription factors that induce embryonic tissues has provided guidance for generating new cells and tissues from embryonic stem cells and, via reprogramming, from somatic cells. Yet neither the developmental nor the reprogramming approach yields cells that provide long-term reconstitution in transplantation contexts, demonstrating insufficient differentiation.

Our lab takes two approaches to this problem: First, we investigate how pioneer transcription factors engage silent chromatin and perturb the underlying nucleosome, to enable nucleosome remodelers and other components to activate target genes. Reconstituting linker histone-compacted chromatin in vitro and analyzing the binding by different pioneer factors is informing about the multiple steps and types of chromatin opening involved.

Second, we found that H3K9me3-heterochromatin is a barrier to gene activation during development and during cellular reprogramming.  We have used a functional protein screen to understand how different heterochromatin proteins target different classes of liver genes in non-liver cells. Our work suggests that a transient heterochromatin protein knockdown may improve differentiation from stem cells and a combination of ectopic transcription factors and transient heterochromatin protein knockdown may generate higher fidelity cells with genetic reprogramming approaches.