The Stitzel Lab

Our Research Focus

The overarching goals of my lab at The Jackson Laboratory (JAX) are to determine how genetic and cellular variation contributes to human islet (dys)function and to identify new genes and pathways that may be therapeutically targeted to prevent, delay, or treat type 2 diabetes (T2D). Since the completion of the Human Genome Project and subsequent international efforts demonstrating non-coding DNA sequence roles in controlling cell fate/function and contributing to disease risk, I have been fascinated by this human genome “dark matter”. My program builds on foundational, first-in-kind integrated genome-wide maps of human isletcis­-regulatory elements (CREs) controlling gene expression I created as a postdoctoral fellow with Dr. Francis Collins at NHGRI (Cell Metabolism, 2010 PMC3026436), which revealed extensive overlap between T2D-associated variants and islet CREs and enabled identification of a generalizable “stretch enhancer” epigenomic signature marking regulatory DNA sequences controlling key cell identity/function genes (PNAS, 2013 PMC3816444).

Since joining JAX in 2013, my lab has used innovative (epi)genomic and transcriptomic profiling of human islets and islet cell models in National Institutes of Health- and Department of Defense- supported efforts to discover candidate causal DNA sequence variants (T2D SNPs) that alter islet CREs (Diabetes, 2018, PMC6198349) and identify new ‘diabetes genes’ that they target (PNAS, 2017, PMC533855), including the first variant-to-function study of the C2CD4A/B locus (AJHG, 2018, PMC5985342). Recently, we have collaborated with Dr. Ryan Tewhey at JAX using massively parallel reporter assays to comprehensively test T2D SNP effects on steady state and stress-responsive gene expression. (Nature Comms, 2021, PMC6198349). Additionally, my lab was among the first in the world to define the transcriptional repertoire of each islet cell type (Genome Research, 2017, PMC5287227), providing unexpected insights into new role(s) and function(s) of islet alpha, beta, delta, and gamma/PP cell types. In a study supported by a highly competitive American Diabetes Association Pathway to Stop Diabetes Accelerator Award, we have recently profiled >250,000 islet single cell transcriptomes from a 48-donor cohort to discover T2D islet beta cell type-specific defects in gene expression, including multiple genes that cause glucose homeostasis defects when deleted in mice (Nargund, Motakis, in preparation).

Current work in my lab is focused on: 1) understanding the genetic control of islet responses to stressors that contribute to islet failure and diabetes (e.g., inflammation, metabolic stress); 2) targeted variant-to-function analyses to understand how T2D SNPs contribute to (dys)function of islet cell organelles/sub-compartments such as the endoplasmic reticulum (ongoing NIH R01), mitochondria (BioRxiv, 2022, doi: 10.1101/2022.08.02.502357 and subject of a newly-funded NIH R01), and peroxisomes; and 3) leveraging regulatory codes and principles we have decoded from genetic and single cell genomic studies of islets to engineer more robust and resilient primary human islet cells.