Golnaz Vahedi

Golnaz Vahedi 

Assistant Professor of Genetics
Institute for Immunology
Core member of the Epigenetics Institute
Perelman School of Medicine
University of Pennsylvania
Room 310 BRB II/III, 421 Curie Boulevard
Philadelphia, PA 19104-6160
Email: vahedi at pennmedicine.upenn.edu

The Vahedi Laboratory

Our laboratory is multidisciplinary, integrating computational and cutting-edge experimental approaches to develop a single to collective cell understanding of gene regulation in T cells.

What is the goal of our research?

In every single cell in the human body, the six feet of DNA is compacted in the micrometer space of the nucleus by wrapping around spools called nucleosomes in addition to extraordinary three-dimensional folding of DNA inside the nucleus. Tissue-specific decoding of the genetic information from this extreme compression is orchestrated by specialized proteins capable of binding DNA in a sequence-specific manner. Locally, a number of proteins called lineage-determining transcription factors can access their binding sites even if they are partially occluded by nucleosomes, recruiting chromatin-remodeling enzymes and exposing the underlying DNA. Globally, sequence-specific proteins such as CTCF act as structural regulators of spatial genome organization. Considering that every two human genomes contain more than 6 million nucleotide differences and the fact that genetics is a major determinant of susceptibility to common diseases, it is essential to understand how the packaging of DNA inside the nucleus becomes resilient or susceptible to diseases due to large numbers of sequence variation. The overarching goal of my laboratory is to understand the molecular mechanisms through which genomic information in our immune cells is interpreted in normal development and further dissect how common genetic variation can lead to misinterpretation of the genetic material in immune-mediated diseases, particularly autoimmune disorders. The multidisciplinary nature of our laboratory allows us to exploit computational and cutting-edge experimental approaches and generate unbiased maps of genome organization in primary immune cells in humans and mice. We further follow our hypothesis-generating yet unbiased efforts with experiments dissecting the mechanisms of our predictions using genome editing in mice or cell lines which provides us with an unparalleled opportunity to rigorously define the link between genetics and chromatin organization in complex diseases such as autoimmunity.

How do we do research?

We measure epigenomic modifications of the linear genome using bulk assays such as ChIP-seq and ATAC-seq. The three-dimensional (3D) organization of the genome also plays a crucial role in carrying out the instructions encoded in its linear sequence. We create high-resolution maps of 3D genome interactions in primary T cells using HiChiP which only requires hundred thousand cells. Our lab invested in single-cell technology and we were the first to publish maps of chromatin accessibility at individual T cells. We take advantage of natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on transcription factor binding, 3D genome organization, and transcriptional outcomes in primary T cells. As a result of our computational expertise, we also harvest the vast troves of big data that immunologists and other researchers are pouring into public repositories. Our data integrations rely on available computational pipelines. Furthermore, we develop novel computational techniques to fully understand the complexity of multidimensional epigenomics datasets in T cells.

What is our training goal?

Biology in the 21st century is arguably the most data-rich science of the most intricately regulated dynamical systems that any discipline has to offer. We view quantitative and computational biology as intrinsic parts of the biological discipline.

List of Projects 2019-2020 (Rotation, Thesis, Postdoc)

This article very nicely summarizes our lab's philosophy and the kind of projects available for trainees.

1) What is the underlying mechanism through which the lineage-restricted 3D genome organization is established in T cells?

2) How do endogenous retroelements control gene regulation in T cells?

3) How can common genetic variations associated with type 1 diabetes change the 3D genome organization of T cells?

4) How does the chimeric antigen receptor (CAR) integration change the linear and 3D genome organization of T cells?

5) What are the epigenetic mechanisms through which the transcription factor TCF-1 creates accessible chromatin in T cells? (PMID: 29466756)

7) Exploiting natural genetic variations in multiple mouse strains to decipher transcription factor grammar in T cell development.


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