Aman Husbands, Ph.D.

Research Interest

Despite coordinating incredible morphological complexity, developmental patterning is remarkably robust. We are interested in uncovering the properties that allow complex biological processes, like development, to occur so reproducibly. One attractive system to study these ideas is the production of flat leaf architecture. The leaves of many species emerge from the stem cell niche as radially symmetric bumps, then develop into long and wide, but very shallow, structures. Leaves have solved this difficult biological problem by using the boundary between their dorsal (adaxial or top) and ventral (abaxial or bottom) sides as a guide to orient their growth. Ensuring the dorsoventral axis is rigorously specified and maintained is thus key to the robust nature of flat leaf production. We exploit the complex, gene regulatory network underlying dorsoventral patterning to assess the determinants – and their interactions – that lead to robust developmental outcomes in multicellular organisms.

A parallel but overlapping project involves the CLASS III HOMEODOMAIN LEUCINE ZIPPER (HD-ZIPIII) proteins. This ancient family of transcription factors arose at least 700 million years ago, and was repeatedly co-opted to drive several evolutionarily-important innovations, including flat leaf production, stem cell maintenance, and vascular patterning. In addition to DNA-binding and dimerization domains, HD-ZIPIII proteins contain a StAR-related transfer (START) domain, raising the intriguing possibility that HD-ZIPIII activity may be under direct control of a lipophilic ligand. Determining how HD-ZIPIII proteins are able to function in such different developmental contexts, and identifying their putative ligands, are central goals of the lab. Given their broad and deep conservation throughout the plant kingdom, we are also considering these ideas through the lens of evolution.

Jennifer M. Kalish, M.D., Ph.D.

Attending Physician, Children’s Hospital of Philadelphia, Division of Genetics
Research Scientist, Children’s Hospital of Philadelphia, Center for Childhood Cancer Research
Director , Beckwith-Wiedemann Syndrome Clinic, Children’s Hospital of Philadelphia
Director, Program of Excellence in Beckwith-Wiedemann Syndrome, Orphan Disease Center, University of Pennsylvania

Golnaz Vahedi, Ph.D.

We have demonstrated for the first time that the epigenome of differentiated CD4 T cells is highly dynamic and extended these findings to human genetics to further our understanding of the epigenetic control in autoimmunity.
Johnson J.L. and Vahedi G.: Epigenome: a dynamic vehicle for transmitting and recording cytokine signalling. CSHL Perspectives, Cold Spring Harbor Laboratory Press 2017.
Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., Drake, A. M., Chen, Z., Sen, D., Kurachi, M., Barnitz, R. A., Bartman, C., Bengsch, B., Huang, A. C., Schenkel, J. M., Vahedi, G., Haining, W. N., Berger, S. L., Wherry, E. J.: Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 2016.
Richard AC, Peters JE, Lee JC, Vahedi G, Schäffer AA, Siegel RM, Lyons PA, Smith KG.: Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network. Genome Medicine 76(8), July 2016.
Johnson, J. L., Vahedi, G.: Exploiting Chromatin Biology to Understand Immunology. Methods Enzymol 574: 365-83, 2016.
Vahedi, G., Kanno, Y., Furumoto, Y., Jiang, K., Parker, S. C., Erdos, M. R., Davis, S. R., Roychoudhuri, R., Restifo, N. P., Gadina, M., Tang, Z., Ruan, Y., Collins, F. S., Sartorelli, V., O’Shea, J. J.: Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature April 2015.
Vahedi, G., Kanno, Y., Sartorelli, V., O’Shea, J. J.: Transcription factors and CD4 T cells seeking identity: masters, minions, setters and spikers. Immunology 139(3): 294-8, 2013.
Vahedi, G., C. Poholek A, Hand, T. W., Laurence, A., Kanno, Y., O’Shea, J. J., Hirahara, K.: Helper T-cell identity and evolution of differential transcriptomes and epigenomes. Immunol Rev 252(1): 24-40, 2013.
Roychoudhuri, R., Hirahara, K., Mousavi, K., Clever, D., Klebanoff, C. A., Bonelli, M., Sciume, G., Zare, H., Vahedi, G., … , O’Shea, J. J., Restifo, N. P.: BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. Nature 498(7455): 506-10, 2013.
Vahedi, G., Takahashi, H., Nakayamada, S., Sun, H. W., Sartorelli, V., Kanno, Y., O’Shea, J. J.: STATs shape the active enhancer landscape of T cell populations. Cell 151(5): 981-93, 2012.
Vahedi, G., Faryabi, B., Chamberland, J. F., Datta, A., Dougherty, E. R.: Intervention in gene regulatory networks via a stationary mean-first-passage-time control policy. IEEE Trans Biomed Eng 55(10): 2319-31, 2008.

Research Interest

The Vahedi laboratory is multidisciplinary, integrating computational and experimental approaches to develop a single to collective cell understanding of gene regulation in immune cells in health and disease.
We exploit the epigenomics mapping of immune cells to understand the biological circuits that underlie immune responses and uncover the molecular basis of major inherited diseases mediated by these cells. Immune-mediated disorders such as psoriasis and type 1 diabetes result from a complex interplay of genetic and environmental factors. By mapping the epigenomic alterations associated with immune-mediated diseases, we aim to further our understanding of the role of environment in triggering autoimmunity.
Information encoded in DNA is interpreted, modified, and propagated as chromatin. The diversity of inputs encountered by immune cells demands a matching capacity for transcriptional outcomes provided by the combinatorial and dynamic nature of epigenetic processes. Advances in genome editing and genome-wide analyses have revealed unprecedented complexity of chromatin pathways involved in the immune response, offering explanations to long-standing questions and presenting new challenges.
We blend epigenomics, human genetics, immunology, and computational biology to pursue a new understanding of human immunology. We generate genome-wide maps of chromatin in relevant immune cells mostly T cells. We are interested in regulators of T cell development and also T cell engagement in autoimmune disorders such as psoriasis and type 1 diabetes. We use population-based assays with strong signal-to-noise ratios such as ChIP-seq, ATAC-seq, and RNA-seq in addition to cutting-edge single-cell assays such as single-cell (sc)ATAC-seq and scRNA-seq. 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.

E. John Wherry, Ph.D.

Richard and Barbara Schiffrin President’s Distinguished Professor
Director, Institute for Immunology

Colin Conine, Ph.D.

Research Interest

The functions of small RNAs in fertility, inheritance, and development.

Kavitha Sarma, Ph.D.

Research Interest

The Sarma laboratory is interested in the mechanisms of epigenetic gene regulation, or how the dynamic modifications of the architecture of chromatin, the complex of DNA, RNA, and proteins within the nucleus of our cells, impacts gene expression and cellular function. The lab investigates consequences of epigenetic alterations in neuronal cancers and neurodegenerative diseases using a combination of biochemistry, cell and molecular biology, and functional genomics approaches to gain mechanistic insight into how chromatin architecture is modified in disease. Our goal is to identify new pathways and interactions that can be targeted to correct these epigenetic perturbations.

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