The Danwei Huangfu Lab: Research Overview

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We apply both precision gene editing and large-scale CRISPR screening in human pluripotent stem cells (hPSCs) to explore mechanisms underlying human development. Specifically, we are interrogating the protein-coding regulators of pancreatic development and β cell function. The pathways that regulate these processes can be exploited for therapeutics to prevent and reverse diseases such as type 1 and type 2 diabetes. In a second, closely related area, we are developing approaches to discover developmental enhancers, and to understand the epigenetic regulation of noncoding regulatory elements with a focus on DNA methylation.
Human pluripotent stem cells (hPSCs), including embryonic and induced pluripotent stem cells (hESCs and hiPSCs), can self-renew indefinitely while maintaining the ability to differentiate into all somatic cell lineages. The human-cell context also supports the use of hPSCs as a genetic model to bridge the gap between non-human model organism studies and clinical investigations.

In recent years, we established methods for efficient genome editing in hPSCs, which formed the foundation for genetic interrogations in hPSCs. Utilizing these genetic tools, we have been working on two interconnected areas of developmental biology.

  1. We have a long-standing interest in protein-coding regulators of pancreatic differentiation. We have combined targeted gene editing with directed differentiation to understand how to generate pancreatic β cells through sequential lineage decisions in development. One important area of ongoing and future work is the use of unbiased genome-scale screening to uncover novel developmental regulators. We are also expanding our work to cancer genetics by developing new hPSC-based pancreatic cancer models.
  2. Another area of interest is the noncoding or epigenetic regulation of development. We are developing methods to uncover the underlying regulatory DNA sequences by focusing on developmental enhancers. A number of newly discovered human enhancers are being validated in mouse and zebrafish models. In parallel to this effort, we are investigating the epigenetic regulation of noncoding regulatory elements with a focus on DNA methylation. In particular, we are utilizing unbiased genome-scale screening to discover novel regulators of DNA methylation.