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Poster Session H (+Lunch and Office Hours)

Session Information

Jun 10, 2021 03:05 PM - 03:35 PM(America/Detroit)
Venue : Posters
20210610T1505 20210610T1535 America/Detroit Poster Session H (+Lunch and Office Hours) Posters NIH Common Fund's 2021 High-Risk, High-Reward Research Symposium becky.miller2@nih.gov

Presentations

Combining population genomics, single-cell sequencing, and electrophysiology to uncover the genetic basis of cognitive evolution

High-Throughput and Integrative Biology 03:05 PM - 03:35 PM (America/Detroit) 2021/06/10 19:05:00 UTC - 2021/06/10 19:35:00 UTC
How do novel behaviors evolve? What aspects of DNA are changed to influence neural circuits and behavior? We have been investigating these questions in a unique model organism - the northern paper wasp. These wasps have recently evolved individual facial recognition which they use to mediate conflict on their nests. Using a combination of population genomics, single cell sequencing, and electrophysiology we are honing in on the changes that have allowed this impressive behavior in a tiny insect brain. This poster provides details on our genomics work and an overview of ongoing work on electrophysiology. Through this work, we aim to uncover basic principles about how the brain and behavior evolve.

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Presenters
MS
Michael Sheehan
Cornell University

High speed multi-channel imaging of neural activity

Instrumentation and Engineering 03:05 PM - 03:35 PM (America/Detroit) 2021/06/10 19:05:00 UTC - 2021/06/10 19:35:00 UTC
Understanding the interaction between the activity from different types of neurons requires a tool to simultaneously record the dynamics of multiple genetically targeted cell types. We have developed multiple components of a multi-channel voltage imaging platform. We have developed a red-fluorescent genetically encoded voltage indicator to complement existing green-fluorescent voltage indicators. These indicators could enable spectrally separable recordings of multiple neuron populations simultaneously. We have developed a temporal-multiplexed multi-channel fiber photometry system. This system can independently measure multiple channels of fluorescence indicators with high temporal resolution. We evaluate the fidelity of recordings using these components by comparing the imaging noise structure to the shot-noise limited noise structure.

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Presenters
YG
Yiyang Gong
Duke University

Cell-to-cell transfer of mitochondria from adipocytes to macrophages regulates white adipose tissue homeostasis and is impaired in obesity

Infectious Diseases and Immunology 03:05 PM - 03:35 PM (America/Detroit) 2021/06/10 19:05:00 UTC - 2021/06/10 19:35:00 UTC
Obesity is characterized by white adipose tissue (WAT) hypertrophy, chronic inflammation, and mitochondrial dysfunction. Macrophages in WAT regulate metabolism by promoting glucose utilization, regulating lipid storage, and increasing energy expenditure. These beneficial immunometabolic processes become dysregulated in obesity through unclear mechanisms. Recent studies suggest that mitochondria can be transferred between cells in the contexts of stroke and cancer to support the survival and proliferation of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in WAT or regulates metabolic homeostasis in vivo remains unknown. Here, we employ bone marrow transplants and adipocyte-specific mitochondria reporter (MitoFat) mice to demonstrate that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen in a BV2 myeloid cell line revealed that mitochondria uptake depends on the heparan sulfate (HS) biosynthetic pathway, including the gene Exostosin 1 (Ext1),which has been linked to the regulation of lipid metabolism in mice and humans. We found that high fat diet (HFD)-induced obese mice exhibit lower levels of HS on WAT macrophages and markedly decreased intercellular mitochondria transfer from adipocytes to macrophages. Although interferon (IFN)-γ and lipopolysaccharide (LPS) increase the ability of BV2 cells to perform phagocytosis, they substantially decrease mitochondria uptake and downregulate expression of HS biosynthesis genes. Deletion of Ext1 in myeloid cells reduces WAT macrophage HS levels, deceases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, these findings suggest that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and that is impaired in murine obesity.

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Presenters Jonathan Brestoff
Department Of Pathology And Immunology, Washington University School Of Medicine, St. Louis, MO, USA
Co-Authors
CW
Craig Wilen
Department Of Laboratory Medicine And Department Of Immunobiology, Yale University School Of Medicine, New Haven, CT, USA
JM
John Moley
Department Of Pathology And Immunology, Washington University School Of Medicine, St. Louis, MO, USA
YL
Yongjia Li
Department Of Medicine, Washington University School Of Medicine, St. Louis, MO, USA
WZ
Wei Zou
Department Of Medicine, Washington University School Of Medicine, St. Louis, MO, USA
MR
Marina Rowen
Department Of Pathology And Immunology, Washington University School Of Medicine, St. Louis, MO, USA
NR
Nidhi Rohatgi
Department Of Medicine, Washington University School Of Medicine, St. Louis, MO, USA
AG
Andrew Gelman
Department Of Surgery, Washington University School Of Medicine, St. Louis, MO, USA
ST
Steven Teitelbaum
Department Of Pathology And Immunology, Department Of Medicine, Washington University School Of Medicine, St. Louis, MO, USA

Bidirectional communication between nucleus and mitochondria drives cancer progression

Molecular and Cellular Biology 03:05 PM - 03:35 PM (America/Detroit) 2021/06/10 19:05:00 UTC - 2021/06/10 19:35:00 UTC
Cancer cells have acquired the ability to sense and adapt to varying conditions of nutrient supply. Mitochondria lay at the core of cellular metabolism, whereas nucleus integrates cellular and environmental signals to activate gene transcription. However how mitochondrial enzymes and nuclear factors communicate to modulate gene transcription in response to bioenergetic stress is poorly understood. Biochemical screening identified mitochondrial aconitase (ACO2) enzyme activity is crucial for de novo lipogenesis in tumors. Proteomics studies identified a single acetylation mark lysine258 on ACO2 functioning as a regulatory motif, and the acetylation deficient Lys258Arg-mutant was enzymatically inactive. Acetylation of ACO2 was reversibly regulated by SIRT3, which was predominantly repressed in many tumors including prostate cancer. Mechanistic studies revealed that transcriptional repression of SIRT3 by androgen receptor and coactivator SRC-2 facilitates enhanced ACO2 activity to drive de novo lipogenesis. This genetic regulation was sufficient to drive prostate cancer colonization in the bone microenvironment. Next to investigate the mitochondrial control on gene transcription, we found that a set of enzymes regulating citrate synthesis, the precursor molecule generating acetyl CoA are found in the nucleus. As we know, acetyl CoA availability in the nucleus is critical for acetylation of histone tail for greater chromatin accessibility to the transcription factors. However, acetyl CoA is predominantly synthesized in the mitochondria and remains impermeable to mitochondrial membranes. We found that genetic ablation of ACO2 affects specific histone marks, and genome-wide chromatin accessibility using ATAC-seq showed that depletion of ACO2 resulted in loss of 16626 peaks compared to wildtype (WT) cells, suggesting overall closing of chromatin with ACO2 depletion. To conclude, our study identified novel functions of mitochondrial enzymes in the nucleus and a bi-directional inter-organelle communication system regulating tumor progression. 

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Presenters
SD
Subhamoy Dasgupta
Roswell Park Comprehensive Cancer Center
Co-Authors
AS
Abhisha Sawant Dessai
Roswell Park Comprehensive Cancer Center
MP
Mayrel Palestino Dominguez
Roswell Park Comprehensive Cancer Center

Novel Cryo-EM Methods and Applications for Macromolecular Structural Biology

Molecular and Cellular Biology 03:05 PM - 03:35 PM (America/Detroit) 2021/06/10 19:05:00 UTC - 2021/06/10 19:35:00 UTC
Recent advances in cryo-electron microscopy (cryo-EM) have enabled routine structural biology applications. However, there is a persistent problem of "preferred specimen orientation" – when only one or a few views of the protein sample is evident within the data. This problem is ubiquitous and affects most cryo-EM specimens prepared using current vitrification technologies, leading to resolution anisotropy, limiting achievable resolution, and often stifling structural biology efforts entirely. We proposed a generalizable experimental strategy to tackle the preferred orientation problem by tilting the stage during data acquisition, which is now frequently utilized by cryo-EM practitioners. We also established quantitative validation procedures to analyze the resolution of cryo-EM reconstructions, which are now incorporated into cryo-EM software packages and available to the community. We are currently developing novel computational tools to visualize distinct effects caused by preferred specimen orientation and to highlight improvements when the stage is tilted in the electron microscope. The ideas provide a general framework for understanding cryo-EM resolution, with specific experimental recommendations for data acquisition and analysis. We are applying these tools to all our cryo-EM datasets collected in the lab. One principal area of investigation is understanding the structural bases of HIV integration into host chromatin and its inhibition by modern antiretroviral therapeutics. Using tilted data collection strategies, we determined high-resolution cryo-EM structures of HIV integration nucleoprotein assemblies bound to the latest generation clinically approved and developmental drugs. Our structures highlight how small changes in the enzyme active site can have notable implications for drug binding and design and provide mechanistic insights into why a leading drug retains efficacy against a broad spectrum of drug-resistant variants. The structural biology findings have implications for expanding effective treatments available for HIV-infected individuals.

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Presenters
DL
Dmitry Lyumkis
The Salk Institute For Biological Studies

Stress-induced RNA-chromatin interactions promote endothelial dysfunction

Molecular and Cellular Biology 03:05 PM - 03:35 PM (America/Detroit) 2021/06/10 19:05:00 UTC - 2021/06/10 19:35:00 UTC
Chromatin-associated RNA (caRNA) has been proposed as a type of epigenomic modifier. Here, we test whether environmental stress can induce cellular dysfunction through modulating RNA-chromatin interactions. We induce endothelial cell (EC) dysfunction with high glucose and TNFα (H + T), that mimic the common stress in diabetes mellitus. We characterize the H + T-induced changes in gene expression by single cell (sc)RNA-seq, DNA interactions by Hi-C, and RNA-chromatin interactions by iMARGI. H + T induce inter-chromosomal RNA-chromatin interactions, particularly among the super enhancers. To test the causal relationship between H + T-induced RNA-chromatin interactions and the expression of EC dysfunction-related genes, we suppress the LINC00607 RNA. This suppression attenuates the expression of SERPINE1, a critical pro-inflammatory and pro-fibrotic gene. Furthermore, the changes of the co-expression gene network between diabetic and healthy donor-derived ECs corroborate the H + T-induced RNA-chromatin interactions. Taken together, caRNA-mediated dysregulation of gene expression modulates EC dysfunction, a crucial mechanism underlying numerous diseases.

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Presenters Sheng Zhong
University Of California San Diego
Co-Authors
RC
Riccardo Calandrelli
University Of California San Diego
LX
Lixia Xu
City Of Hope
YL
Yingjun Luo
City Of Hope
WW
Weixin Wu
University Of California San Diego
XF
Xiaochen Fan
University Of California San Diego
TN
Tri Nguyen
University Of California San Diego
CC
Chien-Ju Chen
University Of California San Diego
KS
Kiran Sriram
City Of Hope
RN
Rama Natarajan
City Of Hope
ZC
Zhen Chen
City Of Hope
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Duke University
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
Roswell Park Comprehensive Cancer Center
The Salk Institute for Biological Studies
Cornell University
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Duke University
NCI/NIH
University of Washington
 Andrew Stergachis
University of Washington
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Slides

1623087456ShengZhong-Stress-inducedRNA-chromatin-1.png
Stress-induced RNA-chromatin interact...
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Submitted by Sheng Zhong
1623087602SubhamoyDasgupta-Bidirectionalcommunication-1.png
Bidirectional communication between n...
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Submitted by Subhamoy Dasgupta
1623097327JonathanBrestoff-Cell-to-celltransferofmitochondria-1.png
Cell-to-cell transfer of mitochondria...
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Submitted by Jonathan Brestoff
1623087697YiyangGong-Highspeedmulti-channelimaging.png
High speed multi-channel imaging of n...
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Submitted by Yiyang Gong
1623097501MichaelSheehan-Combiningpopulationgenomics-1.png
Combining population genomics, single...
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Submitted by Michael Sheehan

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