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Postbac Seminar Series: June 18, 2019

Series: Science Skills; Speaking

Jun 18, 2019

This event is recommended for: Postbacs.

Science isn't complete until the results have been shared with others, and talking about your results is one of the important ways of making them public. The Postbac Seminar Series provides a unique opportunity for two Postbacs each month to present their research to a diverse audience of their peers.  The atmosphere is relatively informal and non-threatening.  The series allows Postbacs who attend to learn about the different types of biomedical research being conducted at the NIH while meeting other postbacs.  Read more about the seminar series.

This month's presenters are:

Sadie Signorella (NIAMS)

Title: The role of CTCF in cytokine gene expression

Summary:  Innate and adaptive lymphoid cells tightly regulate their cytokine production to defeat pathogen invasion without introducing autoimmunity. Interestingly, a pro-inflammatory cytokine that combats intracellular pathogens, interferon-gamma (IFNγ), evolutionarily resides in close genomic proximity of Interleukin-22 (IL-22), a cytokine against extracellular bacteria. However, how these cytokines are differentially regulated in distinct lineages remains unclear. Recently, the importance of DNA architecture has emerged as an element of transcriptional control, with the protein CCCTC binding factor (CTCF) serving as a mediator of some structural loops. We propose that CTCF-mediated DNA looping serves as a control of gene expression by assisting in the formation of higher-order chromatin structure to prevent these proximal genes from cross interacting. To prove this, we deleted the CTCF site residing between Ifng and Il22 using a CRISPR strategy to understand the role of CTCF-dependent loops in lymphocyte maturation and function.

Bio:  Sadie graduated from Dickinson College with honors in Biochemistry and Molecular Biology. She completed her thesis in the lab of Dr. Kristen Guss, exploring Yorkie expression in the growth regulatory Hippo pathway during Drosophila embryogenesis. Currently, Sadie works with Dr. Han-Yu Shih and Dr. John O’Shea exploring the regulation of cytokine expression through three-dimensional chromatin organization.


Xinghao Wang (NIAMS)

Title: Gasdermin D serves a protective role in murine lupus

Summary:  Gasdermin D (GSDMD) has been described as the executioner of pyroptosis, a proinflammatory form of lytic cell death. However, it has also recently been implicated in another form of cell death – NETosis, in which neutrophils released decondensed chromatin and granule proteins into the extracellular space. Given the role of both mechanisms in the pathogenesis of systemic lupus erythematosus (SLE), we induced a lupus model in GSDMD D KO mice to assess its role. Surprisingly, the KO mice developed the worse disease, marked by higher renal inflammation, expansion of circulating immune cells, as well as higher autoantibody titers. In fact, GSDMD KO mice had elevated serum NETs, suggesting the role of neutrophils in the development of SLE.

Bio:  Xinghao graduated from the University of Michigan in 2018 with a B.S. in Biomolecular science. There, he worked with Dr. Yanzhuang Wang to investigate the mechanism of Golgi fragmentation in contributing to amyloid plaque deposition in Alzheimer’s disease. Xinghao joined the Systemic Autoimmunity Branch led by Dr. Mariana J. Kaplan in May 2018, where he also handles clinical trials. He is applying to MD/PhD programs in Immunology for Fall 2020.

 

Sukriti Bagchi (NCI)

Title: Lineage specific transcription factor SOX11 drives cell growth and SOX4 induces differentiation in neuroblastoma

Summary:  Neuroblastoma (NB) arises from the persistence of undifferentiated neural crest cells and is the most common extracranial solid tumor of childhood. Despite multimodal therapies, patients with high risk disease have <50% survival. Retinoic acid (RA), induces growth arrest and differentiation in NB cells. Using this model, we aimed to identify the transcription factors (TFs) required for reprogramming NB cells from a growing or self-renewal program to a differentiation program. Using ChIP-seq for H3K27ac, we identified dynamic changes in the super enhancer (SE) landscape, notably and SE linked to SOX11 which is lost with RA treatment and SEs linked to SOX4 which are gained. Furthermore, literature has shown that sequential expression of first SOX11 then SOX4 is required for normal sympathetic nervous system development. We aimed to first validate the bioinformatically identified SEs, then probe the roles of these TFs. To this end, long-range SE and promoter interactions were validated by 4C-seq. Effect on SEs on gene expression was evaluated by silencing SEs with sgRNAs using a CRISPR-dCas9-KRAB system. Finally, the TFs were genetically silenced using siRNA/shRNA and their functions were assessed in NB cell lines. The data suggest that SOX11 plays an important role in maintaining the self-renewal, proliferative state of NB while SOX4 is critical for implementing a differentiation program. For the first time, our study identifies involvement of lineage specific transcription factors in NB differentiation, and thus provides novel targets that can be explored or therapeutically intervened. Additionally, our work demonstrates the use of novel techniques to validate the roles of epigenetic mechanisms and regulatory regions in cancer progression.

Bio:  Sukriti Bagchi joined the NIH in September 2017 after graduating from UNC-Chapel Hill with a double major in Chemistry and Biology. Her background is in cancer biology, researching first at the Translational Genomics Institute in Phoenix, AZ on the effects of a potential chemotherapeutic Triptolide on the pancreatic cancer and fibroblast secretomes. At UNC, her undergraduate research explored the effects of Rab27a mediated exosome secretion on the immune microenvironment in distant organs, priming them for metastases from primary pancreatic cancer. Here at the NIH, she works in the Pediatric Oncology Branch under Dr. Carol Thiele on pediatric neuroblastoma, which she will speak about today. Sukriti will be leaving the NIH next week to go back to Phoenix to begin her MD/PhD at the University of Arizona and hopes to continue in this field. In her spare time you can usually find her climbing or checking out the DC food scene. Let’s talk about food!!