Linus Tsai, MD, PhD

Institution: Beth Israel Deaconess Medical Center
Research: Defining Cell type and gene networks underlying obesity and type 2 Diabetes
Grants & Publications: Harvard Catalyst
Categories: BIDMC

Broadly, my laboratory seeks to utilize next generation sequencing technologies and analysis to better understand the genetic, epigenetic, and tissue/cell type bases of metabolic disease. In particular, we study the biological and neural circuits and gene regulatory networks underlying obesity and type 2 Diabetes in the hypothalamus and adipose tissue of human and rodent models. Research areas include:

1. Molecular taxonomy of hypothalamic neurons. With Brad Lowell and John Campbell groups, we are systematically defining the hypothalamic neuron types underlying weight regulation, insulin resistance, and glucose homeostasis using single cell transcriptional profiling of key hypothalamic regions involved in energy balance. Starting with unbiased single cell profiling, we define a “parts” list of each region’s constituent neuron types and the genetic markers that specify each. We integrate these profiles with human GWAS data to suggest function and validate hypotheses using specific recombinase lines (many engineered from above profiling) to monitor or manipulate each’s activity and connectivity using genetic, optogenetic or pharmacogenetic approaches. My initial work on the arcuate nucleus was supported by a BADERC P&F award (2016) and resulted in publication of a seminal manuscript in the field (PMC5323293). Similar manuscripts on DMV, PVH, and LPBN have or will be submitted within the year.

2. Role of median eminence cell types in barrier function and energy balance. The arcuate-median eminence ooccupies a unique anatomical position at the nexus between the peripheral circulation, CSF of the third ventricle, and the brain parenchyma. Using single cell transcriptional profiling, we have molecularly characterized the cell types regulating communication between these compartments including: 1) specialized fenestrated endothelial cells of the ME that allow passage of signals to and from the periphery,2) β1 and β2 tanycytes that form the junction between ME, arcuate, and 3rd ventricle, and 3) neuroendocrine cells of the pars tuberalis, which lines the ME and sends signals to central brain. Using tools to induce cell-type specific activation or loss of function, we are characterizing the molecular pathways by which these cells regulate energy intake and insulin sensitivity.

3. Reconstructing the functional gene regulatory circuitry of adipocytes. In collaboration with Evan Rosen, we are systematically identifying the functional components of the human adipocyte epigenome, using histone modification ChIP-seq, ATAC-seq, RNA-seq and Hi-C to profile regulatory elements controlling gene expression across a spectrum of obesity and insulin resistance states. Bioinformatically, we reconstruct the molecular circuits underlying variation in transcription, determine adipocyte-specific eQTLS, and prioritize causal GWAS variants mediating adipocyte roles in obesity, insulin resistance, and diabetes.

4. Atlas of cell types in human and mouse adipose tissue. Adipose tissue plays a central role in the pathophysiology of obesity and diabetes, modulating satiety, glucose, and lipid homeostasis. Adipose tissue cell type content is heterogeneous, dynamic, and altered by obesity. Using single nucleus RNA-seq we assess functional cell type interactions across a variety of metabolic perturbations, including fasting, weight loss, high fat diet exposure, gastric bypass, and aging to determine how individual cell types interact to produce the adipose tissue dysfunction.