Digital Commons Network^™

Young Krab-Zinc Finger Gene Clusters Are Highly Dynamic Incubators Of Erv-Driven Genetic Heterogeneity In Mice., Melania Bruno, Sharaf M Farhana, Apratim Mitra, Kevin Costello, Dawn E Watkins-Chow, Glennis A Logsdon, Craig W Gambogi, Beth L Dumont, Ben E Black, Thomas M Keane, Anne C Ferguson-Smith, Ryan K Dale, Todd S Macfarlan

Faculty Research 2025

KRAB-zinc finger proteins (KZFPs) comprise the largest family of mammalian transcription factors, rapidly evolving within and between species. Most KZFPs in human and mice have been found to repress endogenous retroviruses (ERVs) and other retrotransposons, with KZFP gene numbers correlating with the ERV load across species, suggesting coevolution. Whether new KZFPs emerge in response to ERV invasions is currently unknown. Using a combination of long-read sequencing technologies and genome assembly, we present a detailed comparative analysis of young KZFP gene clusters in the mouse lineage, which has undergone recent KZFP gene expansion and ERV infiltration. Detailed annotation of KZFP genes …

Cd7 Regulates The Persistence Of Terminally Exhausted Cd8 T Cells During Chronic Infection, Sean Hyslop, Colby J Hofferek, Maria V Stegantseva, Emerald Kan, Kelli A Mccord, Victor M Alvarez, Amanda Y Xia, Jacob P Conarty, Andreas Wieland, William H Hudson

Faculty, Staff and Students Publications

CD8+ T cell exhaustion limits immune responses during cancer and chronic infection. We identify CD7 as a tissue-specific regulator of terminally exhausted CD8+ T cells during chronic infection. CD7 expression progressively increases during exhaustion, reaching its highest levels on a subset of CD101+Tim3low terminally exhausted cells that arise in the liver. Transcriptomic analysis revealed that CD7-deficient terminally exhausted cells display altered expression of co-stimulatory, translational, and effector genes, correlating with markedly reduced persistence and increased apoptotic susceptibility. Importantly, CD7 is preferentially upregulated on PD-1+CD39+ tumor-infiltrating lymphocytes (TILs) in human head and neck squamous cell carcinoma (HNSCC), suggesting CD7 may play …

Setdb1 Is Critically Required For Uveal Melanoma Growth And Represents A Promising Therapeutic Target, Imène Krossa, Céline Pisibon, Yann Cheli, Karine Bille, Mélanie Dalmasso, Sabah Hamadat, Chrystel Husser, Marie Irondelle, Julien Cherfils-Vicini, Frédéric Soysouvanh, Sacha Nahon-Esteve, Arnaud Martel, Sandra Lassalle, Jean-Pierre Caujolle, Célia Maschi, Stéphanie Baillif, Dan Hasson, Saul Carcamo, Andrerw E. Aplin, Irwin Davidson, Emily Bernstein, Valeria Naim, Robert Ballotti, Corine Bertolotto, Thomas Strub

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Metastatic uveal melanomas are highly resistant to all existing treatments. To identify actionable vulnerabilities, we conducted a CRISPR-Cas9 knockout screen using a library composed of chromatin regulators. We revealed that the lysine methyltransferase, SETDB1, plays a critical role in metastatic uveal melanoma cell proliferation and survival. Functionally, SETDB1 deficiency induces a DNA damage response, senescence-like state and growth arrest. Knockdown of SETDB1 is associated with a decreased expression of genes related to replication and cell cycle. Moreover, deficiency in CDC6, an essential regulator of DNA replication, phenocopies SETDB1 inhibition. Using a pre-clinical model, we further demonstrated that anti-SETDB1 therapy impairs …

Whole-Genome Sequencing Reveals Individual And Cohort Level Insights Into Chromosome 9p Syndromes, Yingxi Wang, Eleanor I Sams, Rachel Slaugh, Sandra Crocker, Emily Cordova Hurtado, Sophia Tracy, Ying-Chen Claire Hou, Christopher Markovic, Kostandin Valle, Victoria Tate, Khadija Belhassan, Elizabeth Appelbaum, Titilope Akinwe, Rodrigo T Starosta, Yang Cao, Amber Neilson, Yu Liu, Nathaniel Jensen, Reza Ghasemi, Tina Lindsay, Juana Manuel, Sophia Couteranis, Milinn Kremitzki, Jack Ustanik, Thomas Antonacci, Jeffrey K Ng, Andrew Emory, Laura Metz, Tracie Deluca, Katherine N Lyons, Toni Sinnwell, Brianne Thomeczek, Kymme Wang, Nick Sisneros, Megha Muraleedharan, Anantha Kethireddy, Marco Corbo, Harsha Gowda, Katherine A King, Christina A Gurnett, Susan K Dutcher, Catherine Gooch, Yang E Li, Matthew W Mitchell, Kevin A Peterson, Amjad Horani, Jill A Rosenfeld, Weimin Bi, Pawel Stankiewicz, Hsiao-Tuan Chao, Jennifer E Posey, Christopher M Grochowski, Zain Dardas, Erik G Puffenberger, Christopher E Pearson, Frank Kooy, Dale Annear, A Micheil Innes, Michael Heinz, Richard Head, Robert Fulton, Stephan Toutain, 9p-Arch, Lucinda Antonacci-Fulton, Xiaoxia Cui, Robi D Mitra, F Sessions Cole, Julie Neidich, Patricia I Dickson, Jeffrey Milbrandt, Tychele N Turner

Faculty, Staff and Students Publications

Background: Previous genomic efforts on chromosome 9p deletion and duplication syndromes have utilized low-resolution strategies (i.e., karyotypes, chromosome microarrays). These studies have provided important initial insights into these syndromes. This current study is the first large-scale whole-genome sequencing (WGS) study of 100 individuals from families with chromosome 9p syndromes.

Methods: Through the newly formed 9P-ARCH (Advanced Research in Chromosomal Health: Genomic, Phenotypic, and Functional Aspects of 9p-Related syndromes) research network, we assembled a cohort of individuals from families with chromosome 9p syndromes. WGS was applied to 100 individuals, and other genomic technologies were applied to a subset of individuals. To …

Positron Emission Tomography Reveals Increased Myocardial Glucose Uptake In A Subset Of Friedreich Ataxia Patients, R Mark Payne, Thomas M O'Connell, P Melanie Pride, Gregg R Wagner, George J Eckert, Tiffany R Johnson, Weinian Shou, Gary D Hutchins

Faculty, Staff and Student Publications

Why some but not all patients with the rare disease Friedreich ataxia (FRDA) are at increased risk of poor cardiovascular outcome and death is unclear and unpredictable. We investigated the hypothesis that mitochondrial dysfunction in FRDA leads to altered patterns of myocardial metabolic substrate utilization. We recruited 5 healthy controls (Ctl) and 11 FRDA participants. All underwent fasting myocardial positron emission tomography (PET scan) with 15O–H2O, 18F-FDG, and 11C-Palmitate. We conducted cardiac transcriptomics on mice with ablation of the Frda gene in heart to explore mechanisms of fuel substrate utilization. Five (45%) FRDA participants had an LV mass index (LVMi) …

Leptin As A Key Driver For Organ Fibrogenesis, Xue-Nan Sun, Shiuhwei Chen, Shangang Zhao, Jan-Bernd Funcke, Megan Virostek, Line Pedersen, Chao Li, Chanmin Joung, Qian Lin, Yan Li, Ayanna Cobb, May-Yun Wang, Kyounghee Min, Lisandro Maya-Ramos, Giovanna Degasperi, Junquan Liu, Ningyan Zhang, Zhiqiang An, Diana R Tomchick, R Max Wynn, Da Young Oh, Philipp E Scherer

Faculty, Staff and Student Publications

Leptin, a hormone primarily secreted by adipocytes, regulates energy balance and systemic metabolism through its interaction with the leptin receptor (LEPR). Beyond these functions, leptin signaling has been implicated in the pathogenesis of tissue fibrosis. Here, we report the x-ray crystal structures of a leptin-neutralizing antibody (hLep3) in the unbound and leptin-bound states. The interaction of this antibody with leptin mimics the interaction of the LEPR with leptin, providing direct insights into the mechanism by which the antibody disrupts leptin signaling. We furthermore evaluate the therapeutic potential of neutralizing leptin with this antibody across distinct mouse models of fibrosis affecting …

In Utero Rescue Of Neurological Dysfunction In A Mouse Model Of Wiedemann-Steiner Syndrome., Tinna Reynisdottir, Kimberley J Anderson, Katrin Möller, Stefán Pétursson, Andrew Brinn, Katheryn P Franklin, Juan Ouyang, Asbjorg O Snorradottir, Cathleen Lutz, Aamir Zuberi, Valerie B Deleon, Hans T Bjornsson

Faculty Research 2025

Wiedemann-Steiner syndrome (WDSTS) is a rare genetic cause of intellectual disability that is primarily caused by heterozygous loss-of-function variants in the gene encoding the histone lysine methyltransferase 2A (KMT2A). Prior studies have shown successful postnatal amelioration of disease phenotypes for Rett, Rubinstein-Taybi, and Kabuki syndromes, which are related Mendelian disorders of the epigenetic machinery. To explore whether the neurological phenotype in WDSTS is treatable in utero, we created a mouse model carrying a loss-of-function variant placed between 2 loxP sites. Kmt2a+/LSL mice demonstrated core features of WDSTS including growth retardation, craniofacial abnormalities, and hypertrichosis as well as hippocampal memory defects. …

Rtx-303, An Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates Parp Inhibitors In Brca Mutant Tumors, Gurushankar Chandramouly, William Fried, John Gordon, Douglas Ralph, Channita Keuk, Sangeeta Kumari, Mercy Ramanjulu, William Auerbacher, Leonid Minakhin, Taylor Tredinnick, Bernadette Tiberi, George Morton, Robert Betsch, Kathy Q. Cai, Umeshkumar M Vekariya, Mrityunjay Tyagi, Tomasz Skorski, Sergey Karakashev, Neil Johnson, Wayne E. Childers, Xiaojiang S. Chen, Richard T. Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

DNA polymerase θ (Polθ) is a polymerase-helicase fusion protein that is synthetically lethal with homologous recombination (HR) factors, such as BRCA1/2, and confers resistance to PARP inhibitors (PARPi) and other genotoxic cancer therapies. Previously developed Polθ polymerase (Polθ-pol) inhibitors (Polθi) exhibited limited pharmacological activity and metabolic stability, warranting the development of a Polθi with improved drug-like properties. Here, we developed RTx-303, a selective allosteric small-molecule Polθ-pol inhibitor that exhibits 5.1 nM IC50, 88% oral bioavailability, and a prolonged half-life along with its equipotent metabolite. X-ray crystallography highlights the development of a solvent-exposed side-chain that is essential for the optimal drug-like …

Mir147 Promotes Mucosal Integrity And Healing In Intestinal Inflammation, Agnieszka K Czopik, Arash Dabiri, Chia-Hao Tung, Victoria Vaughn, Xiangsheng Huang, Jinlian Wang, Hui Li, Nicolas F Moreno, Natalia V Piwko, Katherine Figarella, Hongfang Liu, Zhongming Zhao, Xiaoyi Yuan, Holger K Eltzschig

Faculty, Staff and Student Publications

The intestinal mucosal epithelium forms a barrier between luminal contents and the body. MicroRNAs (miRNAs) regulate mucosal homeostasis by controlling inflammatory responses and structural integrity. Here, we discovered a protective role for miR147 in intestinal inflammation using a miR147tdTomato reporter mouse. miR147 was enriched in the intestines, with the highest expression in the colonic epithelial cells at the luminal surface, with prominent expression in differentiated enterocytes. Mice with general or intestinal epithelial deletion of miR147 showed increased intestinal inflammation and diminished mucosal healing during colitis. RNA sequencing of miR147-deficient cells showed dysregulated immune signaling, with upregulated proinflammatory cytokine pathways and …

Apoa1 Binding Protein Promotes Lymphatic Cell Fate And Lymphangiogenesis By Relieving Caveolae-Mediated Inhibition Of Vegfr3 Signaling, Jun-Dae Kim, Surbhi Chaudhary, Weiqing Chen, Jonathan Astin, Philip S Crosier, Pengchun Yu, John P Cooke, Henry J Pownall, Hugo J Bellen, Nhat-Tu Le, Daniel L Kiss, Guangyu Wang, Stanley G Rockson, Hong Chen, Longhou Fang

Faculty, Staff and Students Publications

The lymphatic system maintains tissue fluid balance, and its dysfunction can result in lymphedema. Although cholesterol is essential for cellular function, its role in lymphatic development has remained unknown. Here, we identify APOA1 binding protein (AIBP) as a key regulator that promotes lymphatic endothelial cell fate specification and lymphangiogenesis. Mechanistically, AIBP reduces plasma membrane cholesterol content, thereby enhancing VEGFR3 signaling by disrupting caveolae—small plasma membrane invaginations formed by the scaffolding protein caveolin-1 (CAV-1)—and relieving CAV-1–mediated inhibition. In zebrafish and mice, AIBP loss impairs VEGFR3 signaling and lymphatic development, defects that can be rescued by CAV-1 deletion or by a VEGFR3 …

Sperm And Offspring Production In A Nonobstructive Azoospermia Mouse Model Via Testicular Mrna Delivery Using Lipid Nanoparticles, Daisuke Mashiko, Chihiro Emori, Yuki Hatanaka, Daisuke Motooka, Chen Pan, Yuki Kaneda, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Microsurgical testicular sperm extraction (microTESE) with intracytoplasmic sperm injection (ICSI) represents the current standard treatment for nonobstructive azoospermia (NOA). However, cures remain unavailable for NOA patients lacking retrievable haploid cells. mRNA supplementation could be a potential treatment for genetic defects leading to impaired spermatogenesis. Lipid nanoparticles (LNPs) have emerged as mRNA delivery vehicles with minimal risk of genome integration; however, their ability to selectively deliver mRNA to specific cell types remains limited. To overcome this, microRNA (miRNA) target sequences were incorporated into mRNA constructs to restrict expression specifically to germ cells. Using pyruvate dehydrogenase E1 subunit alpha 2 (PDHA2) knockout …

Injectable Microparticle-Nanoliposome Hydrogel For Extended Release Of Small Hydrophilic Molecules, Gil Aizik, Wonmin Choi, Claire A Ostertag-Hill, Matthew Torre, Daniel S Kohane

Duncan NRI Faculty and Staff Publications

Achieving sustained local release of small hydrophilic drugs is challenging and is particularly important when the drugs are toxic. To address these challenges, we developed a hybrid system comprising drug-containing microparticles embedded within a nanoliposomal hydrogel matrix. This system forms through salt-induced gelation using physiologically relevant sodium chloride concentrations (0.9%), allowing for microparticle encapsulation without harsh chemical processes. In vitro, the hybrid system exhibited a slower release of encapsulated cargo compared to microparticles or hydrogel alone. In vivo proof of principle was provided with tetrodotoxin (TTX), a small hydrophilic and ultrapotent local anesthetic, which can cause systemic toxicity if the …

A Machine Learning Framework For Classifying Lipids In Untargeted Metabolomics Using Mass-To-Charge Ratios And Retention Times., Christelle Colin-Leitzinger, Yonatan Ayalew Mekonnen, Isis Narvaez-Bandera, Vanessa Y. Rubio, Dalia Ercan, Eric A. Welsh, Lancia N F Darville, Min Liu, Hayley D. Ackerman, Julian Avila-Pacheco, Clary B. Clish, Kevin Hicks, John M. Koomen, Nancy Gillis, Brooke L. Fridley, Elsa R. Flores, Oana A. Zeleznik, Paul A. Stewart

Manuscripts, Articles, Book Chapters and Other Papers

INTRODUCTION: The identification of unknown metabolites remains a major challenge in untargeted metabolomics using liquid chromatography-mass spectrometry (LC-MS). This process typically depends on comparing mass spectral or chromatographic data to reference databases or deciphering complex fragmentation in tandem mass spectra. While current machine learning methods can predict metabolite structures using MS/MS (MS2) data, no approaches, to our knowledge, use only mass-to-charge ratio (m/z) and retention time (RT) from LC-MS data.

OBJECTIVE: To explore the potential of using the mass-to-charge ratio (m/z) and retention time (RT) from LC-MS data as standalone predictors for metabolite classification and propose a modeling framework which …

Hydralazine Inhibits Cysteamine Dioxygenase To Treat Preeclampsia And Senesce Glioblastoma, Kyosuke Shishikura, Jiasong Li, Yiming Chen, Nate R. Mcknight, Thomas P. Keeley, Katelyn A. Bustin, Eric W. Barr, Snehil R. Chilkamari, Mahaa Ayub, Sun Woo Kim, Zongtao Lin, Ren-Ming Hu, Kelly Hicks, Xie Wang, Donald M. O'Rourke, J. Martin Bollinger, Zev A. Binder, William H. Parsons, Kirill A. Martemyanov, Aimin Liu, Megan L. Matthews

SKMC Student Presentations and Publications

Hydralazine (HYZ), a treatment for preeclampsia and hypertensive crisis, is listed by the World Health Organization as an essential medicine. Its mode of action has remained unknown through its seven decades of clinical use. Here, we identify 2-aminoethanethiol dioxygenase (ADO), a key mediator of targeted protein degradation, as a selective HYZ target. The drug chelates ADO's metallocofactor and can alkylate one of its ligands. The resultant inactivation stabilizes regulators of G protein signaling (RGS4 and RGS5) that ADO normally marks for proteolysis, explaining the drug's vasodilatory activity and comporting with observations of diminished RGS levels in both clinical preeclampsia and …

Estrogen-Related Receptor Alpha Promotes Skeletal Muscle Regeneration And Mitigates Muscular Dystrophy, Thi Thu Hao Nguyen, Ya Xiang Huang, Svitlana Poliakova, Citu Citu, Eira Mann, Danesh H Sopariwala, Zhongming Zhao, Ashok Kumar, Vihang A Narkar

The Brown Foundation: Institute of Molecular Medicine

Skeletal muscle regeneration in chronic muscle diseases such as Duchenne Muscular Dystrophy (DMD) has remained clinically unsurmountable. Estrogen‐related receptor alpha (ERRα) plays a critical role in adult skeletal muscle metabolism and exercise fitness. Whether ERRα activation can drive muscle regeneration and mitigate dystrophy in DMD is not known. We have investigated ERRα signaling in pre‐clinical models of acute muscle injury and DMD. ERRα is induced in differentiating C2C12 myoblast and regenerating muscle. ERRα silencing suppressed proliferation and differentiation in C2C12 myoblasts. RNA sequencing revealed that angiogenic factor and proliferation genes were downregulated by ERRα knockdown in proliferating cells, whereas oxidative …

Resilience And Vulnerabilities Of Tumor Cells Under Purine Shortage Stress, Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael A Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel J George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang

Faculty, Staff and Students Publications

Purpose: Purine metabolism is a promising therapeutic target in cancer; however, how cancer cells respond to purine shortage, particularly their adaptation and vulnerabilities, remains unclear.

Experimental design: Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated the responses in prostate, lung, and glioma cancer models.

Results: We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multiprotein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. Although this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the …

Tng260 Is A Small-Molecule Corest Inhibitor That Sensitizes Stk11-Mutant Tumors To Anti-Pd-1 Immunotherapy, Leanne G Ahronian, Soumyadip Sahu, Minjie Zhang, Ayushi S Patel, Ke Geng, Reshmee Bhattacharya, Gerald S Falchook, Jonathan W Goldman, Alexander I Spira, Salman R Punekar, David R Spigel, Judy S Wang, Ferdinandos Skoulidis, Janaye Stephens, Mary Meynardie, Jaylen M Powell, Alfonso Lopez, Michela Ranieri, Magdalena A Ploszaj, Yi Jer Tan, Yeuan Ting Lee, Yi Yu, Jiehui Deng, Ting Chen, Patrick Mccarren, Alice Tsai, Suleman S Hussain, Brian Doyon, Kenjie Amemiya, Jacques Ermolieff, Preksha Shahagadkar, Nikitha M Das, Lauren R Flynn, Julie A Shields, Laney Danielczyk, Brian J Mcmillan, Andre Mignault, Samuel R Meier, Hsin-Jung Wu, David J Guerin, Douglas A Whittington, Chengyin Min, Iga Sienczylo, John P Maxwell, Heather J Dibenedetto, Hideo Watanabe, Brian B Haines, Alan Huang, Adam Crystal, Jannik N Andersen, Xinyuan Wu, Kwok-Kin Wong

Faculty, Staff and Student Publications

Patients with non–small cell lung cancer (NSCLC) with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti–PD-1. In this study, we conducted an in vivo CRISPR screen that identified histone deacetylase 1 as a target to reverse anti–PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti–PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11 …

Organism-Specific Sequence Motifs Link Ribosomal Rnas To Brain Disorders, Isidore Rigoutsos, Stepan Nersisyan, Eric Londin, Iliza Nazeraj, Bonnie Dong, Anastasios Vourekas, Phillipe Loher

Computational Medicine Center Faculty Papers

We report that in humans, mice, fruit flies, and worms, the ribosomal RNAs and the transcribed spacers of 45S are densely packed with organism-specific sequence motifs that are primarily shared with nervous system genes. The human ribosomal RNAs and 45S spacers contain 1,723 such motifs. Specific combinations of these motifs are predominantly found in 3,430 human nervous system genes, of which 1,046 are genes associated with brain disorders, including autism spectrum disorder and schizophrenia. The sequences of the 1,723 motifs and their locations in the introns and exons of nervous system genes are unique to primates. Experimental evidence indicates that …

Inhibition Of Osteosarcoma Lung Metastases By Β-Glucan And Cd40 Agonist Is Mediated By Activation Of Macrophages And Nk Cells, Pradeep Shrestha, Rejeena Shrestha, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Background: Osteosarcoma (OS) lung metastases remain a significant therapeutic challenge. Innate immune activation is a promising therapeutic approach. Innate immune agonists can modulate the tumor immune microenvironment and improve therapeutic response.

Methods: Using an experimental syngeneic OS lung metastasis BALB/c mouse model with K7M3-luc OS cells, we evaluated the antitumor effects of yeast-derived particulate β-glucan in prevention and therapeutic settings. We then assessed whether the CD40 agonist (CD40a) in combination with β-glucan increased therapeutic response in two different immune-competent mouse models of OS lung tumor burden.

Results: In the pretreatment settings, mice treated with β-glucan prior to OS cell infusion …

Ligand-Receptor Interactions Induce And Mediate Regulatory Functions Of Batf3+ B Cells, Hui Yan, Rui Wang, Suryavathi Viswanadhapalli, Christian Cervantes, Funan He, Shuai Wu, Azad Khosh, Weiwei Luo, Jingwei Wang, Maria J Fernandez, Uday P Pratap, Mustafa Khan, Karli Hinton, Sai Eashan Vankamamidi, Dariela Perez, Carlos E Rivera, Harshita B Gupta, Fushun Zhang, Zhenqing Ye, Yidong Chen, Xiao-Dong Li, Gangadhara R Sareddy, Hong Zan, Yue Li, Exing Wang, Evelien M Bunnik, Guangming Zhong, Christopher A Hunter, Ross M Kedl, Zhinan Yin, Booki Min, Diako Ebrahimi, Siyuan Zheng, Tyler J Curiel, Yan Xiang, Ratna K Vadlamudi, Paolo Casali, Zhenming Xu

Faculty, Staff and Student Publications

B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined receptor signals, and assessed their regulatory capacities and specificities through in silico analysis of ligand-receptor interactions. Consequently, we identified a B cell subset that expressed cytokine interleukin-27 (IL-27) and chemokine CXCL10. Through the IL-27–IL-27 receptor interaction, these IL-27/CXCL10-producing B cells targeted CD40-activated B cells in vitro and, upon induction by immunization and viral infection, optimized antibody responses and antiviral immunity in vivo. Also present in breast cancer tumors and retained there through CXCL10-CXCR3 …

Polychlorinated Biphenyls Alter Estrogen Receptor Β-Mediated Epigenetic Regulation, Promoting Endometriosis, Yuri Park, Nuri Sung, Eunsu Kim, Jaeyeong Jeong, Juhee Sim, Mi Jin Park, John P Lydon, Xiaoming Guan, Sang Jun Han

Faculty, Staff and Students Publications

Endometriosis is a pathological condition characterized by the ectopic growth of endometrial cells, leading to chronic pelvic pain and infertility. Epidemiological studies have associated exposure to dioxin-like polychlorinated biphenyls, particularly PCB126, with an increased risk of endometriosis. However, the underlying mechanisms of this association remain poorly understood. We utilized a surgically induced endometriosis mouse model and human endometrial cell lines to assess the impact of PCB126 on endometriosis progression. Mice were exposed to environmentally relevant doses of PCB126. Endometriotic lesion growth, estrogen receptor signaling, receptor tyrosine kinase activity, and gene expression changes induced by PCB126-mediated elevation of DNA methyltransferase 3A …

Dual Targeting Of Orphan Nuclear Receptors Nr4a1 And Nr4a2 For Nonhormonal Endometriosis Therapy, Wai Ning Tiffany Tsui, Yuri Park, Srijana Upadhyay, Da Mi Kim, Lei Zhang, Gus Wright, Amanuel Hailemariam, Arafat Rahman Oany, Sang Jun Han, Stephen Safe

Faculty, Staff and Students Publications

Previous studies show that orphan nuclear receptor 4A1 (NR4A1) regulates endometriotic cell growth, survival, estrogen receptor β (ERβ), mechanistic target of rapamycin signaling and fibrosis. NR4A2 is also expressed in epithelial and stromal derived endometriotic cells, and in this study the effects of 1,1-bis(3'-indolyl)-(3,5-disubstitutedphenyl)methane (DIM-3,5) dual NR4A1/nuclear receptor 4A2 (NR4A2) ligands and knockdown of NR4A1 and NR4A2 were investigated. The dual NR4A1/2 DIM-3,5 analogs inhibited previously identified proendometriotic pathways and gene products, and they also inhibited TWIST1 and multiple markers associated with epithelial-to-mesenchymal transition (EMT). The results show that both NR4A1 and NR4A2 regulate the same pathways, including endometriotic cell …

Synaptic Transmission Promotes Brain Metastatic Outgrowth In Breast Cancer, Jayanta Mondal, Patrick Nylund, Prit Benny Malgulwar, William E Johnson, Jason T Huse

Faculty, Staff and Student Publications

This work demonstrates that normal neuron-to-neuron signaling machinery is hijacked by metastasizing cancer cells during their outgrowth in the central nervous system.

Quiescent Oxphos-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend On Bcl-Xl For Survival, Slawomir Andrzejewski, Marie Winter, Leandro Encarnacao Garcia, Olusiji Akinrinmade, Francisco Madeira Marques, Emmanouil Zacharioudakis, Anna Skwarska, Julio Aguirre-Ghiso, Marina Konopleva, Guangrong Zheng, Susan A Fineberg, Daohong Zhou, Evripidis Gavathiotis, Tao Wang, Eugen Dhimolea

Faculty, Staff and Student Publications

The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, …

Hydroxyapatite Microspheres Induce Durable Pleurodesis And Are Rapidly Cleared By Pleural Osteoclasts, Yusuke Tanaka, Yuki Takahashi, Yuma Shindo, Lori B. Pitstick, Steven L. Teitelbaum, Wei Zou, Xiangning Wang, Jason C. Woods, Kathryn A. Wikenheiser-Brokamp, Francis X. Mccormack

2020-Current year OA Pubs

Talc pleurodesis is highly effective for preventing recurrence of pneumothorax and pleural effusion, but it can be complicated by dissemination, acute lung injury, lead exposure, and foreign body-induced chronic inflammation and pain. Our objective is to develop a safe, biodegradable, contaminant-free particle for pleurodesis. We used mouse models of pneumothorax and malignant pleural effusion to compare the efficacy and safety of pleurodesis with talc and hydroxyapatite microspheres (HAM). Intrapleural instillation of microspheres induced pleural adhesions, fibrosis, and symphysis as effectively as talc and resulted in more durable protection from experimental pneumothorax. HAM and talc both induced an osteoclastogenic, inflammatory, and …

Gabaergic Interneurons Contribute To The Fatal Seizure Phenotype Of Cln2 Disease Mice, Keigo Takahashi, Nicholas R. Rensing, Elizabeth M. Eultgen, Letitia L. Williams, Sophie H. Wang, Hemanth R. Nelvagal, Steven Q. Le, Marie S. Roberts, Balraj Doray, Edward B. Han, Patricia I. Dickson, Michael Wong, Mark S. Sands, Jonathan D. Cooper

2020-Current year OA Pubs

The cellular etiology of seizures in CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), remains elusive. Given that Cln2R207X/R207X mice display fatal spontaneous seizures and an early loss of several cortical GABAergic interneuron populations, we hypothesized that these 2 events might be causally related. To study the cell-autonomous effects of interneuron-specific TPP1 deficiency, we first generated transgenic mice expressing loxP-flanked lysosomal membrane-tethered TPP1 (TPP1LAMP1 mice) on the Cln2R207X/R207X genetic background, and then crossed TPP1LAMP1 mice with Vgat-Cre mice. These Vgat-Cre; TPP1LAMP1 mice accumulated storage material in cortical and striatal interneurons. Vgat-Cre; …

Genetics-Nutrition Interactions Control Diurnal Enhancer-Promoter Dynamics And Liver Lipid Metabolism, Dishu Zhou, Ying Chen, Panpan Liu, Kun Zhu, Juliet Holder-Haynes, S Julie-Ann Lloyd, Cam Mong La, Inna I Astapova, Seunghee Choa, Ying Xiong, Hosung Bae, Marlene Aguilar, Hongyuan Yang, Yu A An, Zheng Sun, Mark A Herman, Xia Gao, Liming Pei, Cholsoon Jang, Joshua D Rabinowitz, Samer G Mattar, Yongyou Zhang, Dongyin Guan

Faculty, Staff and Student Publications

The circadian clock controls 24-h rhythmic processes. However, how genetic variations outside clock genes impact peripheral diurnal rhythms remains largely unknown. Here, we find that genetic variation contributes to different diurnal patterns of hepatic gene expression in both humans and mice. Nutritional challenges alter the rhythmicity of gene expression in mouse liver in a strain-specific manner. Remarkably, genetics and nutrition interdependently control more than 80% of rhythmic gene and enhancer-promoter interactions (E-PIs), with a noncanonical clock regulator, estrogen-related receptor gamma (ESRRγ), emerging as a top transcription factor during motif mining. Knockout of Esrrγ abolishes strain-specific metabolic processes in response to …

Biliverdin Reductase A Is A Major Determinant Of Protective Nrf2 Signaling, Chirag Vasavda, Ruchita Kothari, Navneet Ammal Kaidery, Suwarna Chakraborty, Sunil Jamuna Tripathi, Ryan S Dhindsa, Cristina Ricco, Shruthi Shanmukha, Samaneh Saberi, Julia E Lefler, Priyanka Kothari, Kalyani Chaubey, Adele M Snowman, Michael C Ostrowski, Eugenio Barone, Lakshminarayan M Iyer, L Aravind, Sudarshana M Sharma, Andrew A Pieper, Bobby Thomas, Solomon H Snyder, Bindu D Paul

Duncan NRI Faculty and Staff Publications

Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a nonenzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical nonenzymatic antioxidant activity. Transcriptomic analyses further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived factor-like 2 (NRF2), a major transcriptional regulator of cellular redox signaling. ChIP-seq and RNA-seq analyses reveal that BVRA and NRF2 coordinate the expression of antioxidant genes, many of which are typically dysregulated in neurodegenerative conditions such as Alzheimer's disease. Thus, this noncanonical …

Enhanced Piezo1 Function Contributes To The Pathogenesis Of Sickle Cell Disease, Luis O Romero, Manisha Bade, Laila Elsherif, Jada D Williams, Xiangmei Kong, Adebowale Adebiyi, Kenneth I Ataga, Shang Ma, Julio F Cordero-Morales, Valeria Vásquez

Faculty, Staff and Student Publications

Sickle cell disease (SCD), an inherited blood disorder caused by a mutation in the β-globin gene, is characterized by sickle erythrocytes that are prone to hemolysis, leading to anemia and vaso-occlusion crises. In sickle erythrocytes, hemoglobin aggregation is followed by altered cation permeability and subsequent dehydration. Interventions that restore cation permeability can decrease hemolysis and ameliorate the symptoms associated with SCD. PIEZO1 is a nonselective mechanosensitive cation channel that regulates erythrocyte volume. Gain-of-function (GOF) mutations in PIEZO1 cause hemolytic anemia by increasing cation permeability, leading to erythrocyte dehydration in humans and mice. Although PIEZO1 plays a key role in erythrocyte …

Phosphorylation Of Ryr1 At Ser2902 Decreases Ca2+ Leak In Skeletal Muscle And Susceptibility To Malignant Hyperthermia And Heat Stroke, Rachel Sue Zhen Yee, Chang Seok Lee, Ting Chang, Sung Yun Jung, Omar Yousif, Courtney Cavazos, John Colyer, Filip Van Petegem, George G Rodney, Susan L Hamilton

Faculty, Staff and Students Publications

The ryanodine receptor 1 (RYR1) is the sarcoplasmic reticulum (SR) Ca2+ release channel required for both skeletal muscle contraction and Ca2+ leak. Mutations in RYR1 cause malignant hyperthermia susceptibility (MHS) and enhanced sensitivity to heat stroke (ESHS), which can result in death due to excessive skeletal muscle thermogenesis upon exposure to volatile anesthetics or heat. Here, we investigated the molecular and physiological functions of phosphorylation of RYR1 at Ser2902 by the kinase SPEG (striated muscle preferentially expressed protein). Muscle from SPEG-deficient mice expressing RYR1 with a Ser2902 →Asp2902 (S2902D) point mutation to mimic phosphorylation by SPEG showed decreased SR Ca2+ …