Digital Commons Network^™

Apoptosis Of Hematopoietic Stem Cells Contributes To Bone Marrow Suppression Following Chimeric Antigen Receptor T Cell Therapy, Jay A Read, Rayne H Rouce, Feiyan Mo, Maksim Mamonkin, Katherine Y King

Faculty, Staff and Students Publications

Background: CAR-T therapy represents a revolutionary treatment for patients with relapsed/refractory hematologic malignancies. However, its use can result in significant toxicities, including cytokine release syndrome (CRS), a potentially life-threatening clinical syndrome resulting from release of pro-inflammatory cytokines upon T cell activation. In addition, patients who develop CRS often experience prolonged cytopenias and those with the most severe CRS also have the greatest delay in full marrow recovery. While an association between CRS and delayed bone marrow recovery has been established, the precise mechanism underlying this phenomenon remains unknown.

Objective: To test our hypothesis that delayed bone marrow recovery following CAR-T …

Long-Chain Polyunsaturated Lipids Associated With Responsiveness To Anti-Pd-1 Therapy Are Colocalized With Immune Infiltrates In The Tumor Microenvironment, Mary E King, Robert Yuan, Jeremy Chen, Komal Pradhan, Isabel Sariol, Shirley Li, Ashish Chakraborty, Oscar Ekpenyong, Jennifer H Yearley, Janica C Wong, Luis Zúñiga, Daniela Tomazela, Maribel Beaumont, Jin-Hwan Han, Livia S Eberlin

Faculty, Staff and Students Publications

The programmed cell death protein-1 (PD-1) is highly expressed on the surface of antigen-specific exhausted T cells and, upon interaction with its ligand PD-L1, can result in inhibition of the immune response. Anti-PD-1 treatment has been shown to extend survival and result in durable responses in several cancers, yet only a subset of patients benefit from this therapy. Despite the implication of metabolic alteration following cancer immunotherapy, mechanistic associations between antitumor responses and metabolic changes remain unclear. Here, we used desorption electrospray ionization mass spectrometry imaging to examine the lipid profiles of tumor tissue from three syngeneic murine models with …

Cmpk2 Is A Host Restriction Factor That Inhibits Infection Of Multiple Coronaviruses In A Cell-Intrinsic Manner, Mingjun Zhu, Jiahuang Lv, Wei Wang, Rongli Guo, Chunyan Zhong, Avan Antia, Qiru Zeng, Jizong Li, Qingtao Liu, Jinzhu Zhou, Xuejiao Zhu, Baochao Fan, Siyuan Ding, Bin Li

2020-Current year OA Pubs

Coronaviruses (CoVs) comprise a group of important human and animal pathogens. Despite extensive research in the past 3 years, the host innate immune defense mechanisms against CoVs remain incompletely understood, limiting the development of effective antivirals and non-antibody-based therapeutics. Here, we performed an integrated transcriptomic analysis of porcine jejunal epithelial cells infected with porcine epidemic diarrhea virus (PEDV) and identified cytidine/uridine monophosphate kinase 2 (CMPK2) as a potential host restriction factor. CMPK2 exhibited modest antiviral activity against PEDV infection in multiple cell types. CMPK2 transcription was regulated by interferon-dependent and interferon regulatory factor 1 (IRF1)-dependent pathways post-PEDV infection. We demonstrated …

Cnih3 Deletion Dysregulates Dorsal Hippocampal Transcription Across The Estrous Cycle, Bernard Mulvey, Hannah E. Frye, Tania Lintz, Stuart Fass, Eric Tycksen, Elliot C. Nelson, Jose A. Morón, Joseph D. Dougherty

2020-Current year OA Pubs

In females, the hippocampus, a critical brain region for coordination of learning, memory, and behavior, displays altered physiology and behavioral output across the estrous or menstrual cycle. However, the molecular effectors and cell types underlying these observed cyclic changes have only been partially characterized to date. Recently, profiling of mice null for the AMPA receptor trafficking gene

Targeted Deletion Of Fgf9 In Tendon Disrupts Mineralization Of The Developing Enthesis, Elahe Ganji, Connor Leek, William Duncan, Debabrata Patra, David M Ornitz, Megan L Killian

2020-Current year OA Pubs

The enthesis is a transitional tissue between tendon and bone that matures postnatally. The development and maturation of the enthesis involve cellular processes likened to an arrested growth plate. In this study, we explored the role of fibroblast growth factor 9 (Fgf9), a known regulator of chondrogenesis and vascularization during bone development, on the structure and function of the postnatal enthesis. First, we confirmed spatial expression of Fgf9 in the tendon and enthesis using in situ hybridization. We then used Cre-lox recombinase to conditionally knockout Fgf9 in mouse tendon and enthesis (Scx-Cre) and characterized enthesis morphology as well as mechanical …

Hiv Increases The Risk Of Cigarette Smoke-Induced Emphysema Through Mmp-9, Bashar S. Staitieh, Simran Malik, Sara C. Auld, Gregory W. Wigger, Xian Fan, Andrew T. Roth, Tanima Chatterjee, Itika Arora, S. Vamsee Raju, Sonya Heath, Saurabh Aggrawal

2020-Current year OA Pubs

BACKGROUND: HIV is associated with an increased risk for emphysema. Matrix metalloproteinase 9 (MMP-9) is a lung tissue remodeling enzyme associated with emphysema. We previously found MMP-9 activity increases with increases in oxidative stress and that HIV increases alveolar oxidative stress. We hypothesized that HIV proteins would increase the risk of cigarette smoke-induced emphysema due to MMP-9.

METHODS: HIV-1 transgenic rats and wild-type littermates were exposed to cigarette smoke or sham for 8 weeks. Lung compliance and histology were assessed. Bronchoalveolar lavage (BAL), primary alveolar macrophages (AM), and serum samples were obtained. A rat alveolar macrophage cell line was exposed …

Single Cell Preparations Of Mycobacterium Tuberculosis Damage The Mycobacterial Envelope And Disrupt Macrophage Interactions, Ekansh Mittal, Andrew T Roth, Anushree Seth, Srikanth Singamaneni, Wandy Beatty, Jennifer A Philips

2020-Current year OA Pubs

For decades, investigators have studied the interaction of

The Er Protein Translocation Channel Subunit Sbh1 Controls Virulence Of Cryptococcus Neoformans, Felipe H. Santiago-Tirado, Thomas Hurtaux, Jennifer Geddes-Mcalister, Duy Nguyen, Volkhard Helms, Tamara L Doering, Karin Römisch

2020-Current year OA Pubs

The fungal pathogen Cryptococcus neoformans is distinguished by a cell-wall-anchored polysaccharide capsule that is critical for virulence. Biogenesis of both cell wall and capsule relies on the secretory pathway. Protein secretion begins with polypeptide translocation across the endoplasmic reticulum (ER) membrane through a highly conserved channel formed by three proteins: Sec61, Sbh1, and Sss1. Sbh1, the most divergent, contains multiple phosphorylation sites, which may allow it to regulate entry into the secretory pathway in a species- and protein-specific manner. Absence of

Allosteric Autoregulation Of Dna Binding Via A Dna-Mimicking Protein Domain: A Biophysical Study Of Znf410-Dna Interaction Using Small Angle X-Ray Scattering, Gundeep Kaur, Ren Ren, Michal Hammel, John R Horton, Jie Yang, Yu Cao, Chenxi He, Fei Lan, Xianjiang Lan, Gerd A Blobel, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

ZNF410 is a highly-conserved transcription factor, remarkable in that it recognizes a 15-base pair DNA element but has just a single responsive target gene in mammalian erythroid cells. ZNF410 includes a tandem array of five zinc-fingers (ZFs), surrounded by uncharacterized N- and C-terminal regions. Unexpectedly, full-length ZNF410 has reduced DNA binding affinity, compared to that of the isolated DNA binding ZF array, both in vitro and in cells. AlphaFold predicts a partially-folded N-terminal subdomain that includes a 30-residue long helix, preceded by a hairpin loop rich in acidic (aspartate/glutamate) and serine/threonine residues. This hairpin loop is predicted by AlphaFold to …

Jaml Immunotherapy Targets Recently Activated Tumor-Infiltrating Cd8+ T Cells, Simon Eschweiler, Alice Wang, Ciro Ramírez-Suástegui, Adrian Von Witzleben, Yingcong Li, Serena J Chee, Hayley Simon, Monalisa Mondal, Matthew Ellis, Gareth J Thomas, Vivek Chandra, Christian H Ottensmeier, Pandurangan Vijayanand

Faculty, Staff and Student Publications

Junctional adhesion molecule-like protein (JAML) serves as a co-stimulatory molecule in γδ T cells. While it has recently been described as a cancer immunotherapy target in mice, its potential to cause toxicity, specific mode of action with regard to its cellular targets, and whether it can be targeted in humans remain unknown. Here, we show that JAML is induced by T cell receptor engagement, reveal that this induction is linked to cis-regulatory interactions between the CD3D and JAML gene loci. When compared with other immunotherapy targets plagued by low target specificity and end-organ toxicity, we find JAML to be mostly …

Apical Secretory Glycoprotein Complex Contributes To Cell Attachment And Entry By Cryptosporidium Parvum, Marianna E. Akey, Rui Xu, Soumya Ravindran, Lisa Funkhouser-Jones, L. David Sibley

2020-Current year OA Pubs

Cryptosporidium parvum is an enteric pathogen that invades epithelial cells in the intestine, where it resides at the apical surface in a unique epicellular location. Compared with those of related apicomplexan parasites, the processes of host cell attachment and invasion by C. parvum are poorly understood. The streamlined C. parvum genome contains numerous mucin-like glycoproteins, several of which have previously been shown to mediate cell attachment, although the majority are unstudied. Here, we identified the antigens recognized by monoclonal antibody (MAb) 1A5, which stains the apical end of sporozoites and mature merozoites. Immunoprecipitation with MAb 1A5 followed by mass spectrometry …

Trpv1-Mediated Sonogenetic Neuromodulation Of Motor Cortex In Freely Moving Mice, Kevin Xu, Yaoheng Yang, Zhongtao Hu, Yimei Yue, Yan Gong, Jianmin Cui, Joseph P Culver, Michael R Bruchas, Hong Chen

2020-Current year OA Pubs

No abstract provided.

Uncovering Novel Regulators Of Memory Using C Elegans Genetic And Genomic Analysis, Katie L Brandel-Ankrapp, Rachel N Arey

Faculty, Staff and Students Publications

How organisms learn and encode memory is an outstanding question in neuroscience research. Specifically, how memories are acquired and consolidated at the level of molecular and gene pathways remains unclear. In addition, memory is disrupted in a wide variety of neurological disorders; therefore, discovering molecular regulators of memory may reveal therapeutic targets for these disorders. C. elegans are an excellent model to uncover molecular and genetic regulators of memory. Indeed, the nematode's invariant neuronal lineage, fully mapped genome, and conserved associative behaviors have allowed the development of a breadth of genetic and genomic tools to examine learning and memory. In …

Mecp2 Regulates Gdf11, A Dosage-Sensitive Gene Critical For Neurological Function, Sameer S Bajikar, Ashley G Anderson, Jian Zhou, Mark A Durham, Alexander J Trostle, Ying-Wooi Wan, Zhandong Liu, Huda Y Zoghbi

Faculty, Staff and Students Publications

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, but identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we revealed that MeCP2 finely regulates growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and, conversely, up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral …

Orthodenticle Homeobox 2 Is Transported To Lysosomes By Nuclear Budding Vesicles, Jun Woo Park, Eun Jung Lee, Eunyoung Moon, Hong-Lim Kim, In-Beom Kim, Didier Hodzic, Namsuk Kim, Hee-Seok Kweon, Jin Woo Kim

2020-Current year OA Pubs

Transcription factors (TFs) are transported from the cytoplasm to the nucleus and disappear from the nucleus after they regulate gene expression. Here, we discover an unconventional nuclear export of the TF, orthodenticle homeobox 2 (OTX2), in nuclear budding vesicles, which transport OTX2 to the lysosome. We further find that torsin1a (Tor1a) is responsible for scission of the inner nuclear vesicle, which captures OTX2 using the LINC complex. Consistent with this, in cells expressing an ATPase-inactive Tor1aΔE mutant and the LINC (linker of nucleoskeleton and cytoskeleton) breaker KASH2, OTX2 accumulated and formed aggregates in the nucleus. Consequently, in the mice expressing …

Microrna Profiles In Intestinal Epithelial Cells In A Mouse Model Of Sepsis, Siqingaowa Caidengbate, Yuichi Akama, Anik Banerjee, Khwanchanok Mokmued, Eiji Kawamoto, Arong Gaowa, Louise D Mccullough, Motomu Shimaoka, Juneyoung Lee, Eun Jeong Park

Faculty, Staff and Student Publications

Sepsis is a systemic inflammatory disorder that leads to the dysfunction of multiple organs. In the intestine, the deregulation of the epithelial barrier contributes to the development of sepsis by triggering continuous exposure to harmful factors. However, sepsis-induced epigenetic changes in gene-regulation networks within intestinal epithelial cells (IECs) remain unexplored. In this study, we analyzed the expression profile of microRNAs (miRNAs) in IECs isolated from a mouse model of sepsis generated via cecal slurry injection. Among 239 miRNAs, 14 miRNAs were upregulated, and 9 miRNAs were downregulated in the IECs by sepsis. Upregulated miRNAs in IECs from septic mice, particularly …

Feasibility Of [18f]Fspg Pet For Early Response Assessment To Combined Blockade Of Egfr And Glutamine Metabolism In Wild-Type Kras Colorectal Cancer, Seong-Woo Bae, Jianbo Wang, Dimitra K Georgiou, Xiaoxia Wen, Allison S Cohen, Ling Geng, Mohammed Noor Tantawy, H Charles Manning

Faculty, Staff and Student Publications

Early response assessment is critical for personalizing cancer therapy. Emerging therapeutic regimens with encouraging results in the wild-type (WT) KRAS colorectal cancer (CRC) setting include inhibitors of epidermal growth factor receptor (EGFR) and glutaminolysis. Towards predicting clinical outcome, this preclinical study evaluated non-invasive positron emission tomography (PET) with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) in treatment-sensitive and treatment-resistant WT KRAS CRC patient-derived xenografts (PDXs). Tumor-bearing mice were imaged with [18F]FSPG PET before and one week following the initiation of treatment with either EGFR-targeted monoclonal antibody (mAb) therapy, glutaminase inhibitor therapy, or the combination. Imaging was correlated with tumor volume and histology. In PDX …

Mitochondrial Phosphatidylethanolamine Modulates Ucp1 To Promote Brown Adipose Thermogenesis, Jordan M Johnson, Irfan J Lodhi, Et Al.

2020-Current year OA Pubs

Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of adenosine triphosphate (ATP) synthase. Here, we provide evidence that phosphatidylethanolamine (PE) modulates UCP1-dependent proton conductance across the IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen …

Macroh2a Histone Variants Modulate Enhancer Activity To Repress Oncogenic Programs And Cellular Reprogramming, Wazim Mohammed Ismail, Amelia Mazzone, Flavia G Ghiraldini, Jagneet Kaur, Manvir Bains, Amik Munankarmy, Monique S Bagwell, Stephanie L Safgren, John Moore-Weiss, Marina Buciuc, Lynzie Shimp, Kelsey A Leach, Luis F Duarte, Chandandeep S Nagi, Saul Carcamo, Chi-Yeh Chung, Dan Hasson, Neda Dadgar, Jian Zhong, Jeong-Heon Lee, Fergus J Couch, Alexander Revzin, Tamas Ordog, Emily Bernstein, Alexandre Gaspar-Maia

Faculty, Staff and Students Publications

Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined 'macro-Bound Enhancers', that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at …

Dpc29 Promotes Post-Initiation Mitochondrial Translation In Saccharomyces Cerevisiae, Kyle A. Hubble, Michael F. Henry

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Mitochondrial ribosomes synthesize essential components of the oxidative phosphorylation (OXPHOS) system in a tightly regulated process. In the yeast Saccharomyces cerevisiae, mitochondrial mRNAs require specific translational activators, which orchestrate protein synthesis by recognition of their target gene's 5'-untranslated region (UTR). Most of these yeast genes lack orthologues in mammals, and only one such gene-specific translational activator has been proposed in humans-TACO1. The mechanism by which TACO1 acts is unclear because mammalian mitochondrial mRNAs do not have significant 5'-UTRs, and therefore must promote translation by alternative mechanisms. In this study, we examined the role of the TACO1 orthologue in yeast. We …

Tfeb-Mediated Lysosomal Exocytosis Alleviates High-Fat Diet-Induced Lipotoxicity In The Kidney, Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Satoshi Minami, Atsushi Takahashi, Jun Matsuda, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Isao Matsui, Takayuki Hamano, Masatomo Takahashi, Maiko Goto, Yoshihiro Izumi, Takeshi Bamba, Miwa Sasai, Masahiro Yamamoto, Taiji Matsusaka, Fumio Niimura, Motoko Yanagita, Shuhei Nakamura, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka

Duncan NRI Faculty and Staff Publications

Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in obesity-related kidney disease, in both humans and experimental animal models. However, the regulatory factors involved in countering renal lipotoxicity are largely unknown. Here, we found that palmitic acid strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB) by inhibiting the mechanistic target of rapamycin kinase complex 1 pathway in a Rag GTPase-dependent manner, though these effects gradually diminished after extended treatment. We then investigated the role of TFEB in the pathogenesis of obesity-related kidney …

Alternative Splicing Mediates The Compensatory Upregulation Of Mbnl2 Upon Mbnl1 Loss-Of-Function, Larissa Nitschke, Rong-Chi Hu, Andrew N Miller, Lathan Lucas, Thomas A Cooper

Faculty, Staff and Students Publications

Loss of gene function can be compensated by paralogs with redundant functions. An example of such compensation are the paralogs of the Muscleblind-Like (MBNL) family of RNA-binding proteins that are sequestered and lose their function in Myotonic Dystrophy Type 1 (DM1). Loss of MBNL1 increases the levels of its paralog MBNL2 in tissues where Mbnl2 expression is low, allowing MBNL2 to functionally compensate for MBNL1 loss. Here, we show that loss of MBNL1 increases the inclusion of Mbnl2 exon 6 and exon 9. We find that inclusion of Mbnl2 exon 6 increases the translocation of MBNL2 to the nucleus, while …

Setd2 Regulates Chromatin Accessibility And Transcription To Suppress Lung Tumorigenesis, Yuchen Xie, Merve Sahin, Toru Wakamatsu, Akane Inoue-Yamauchi, Wanming Zhao, Song Han, Amrita M. Nargund, Shaoyuan Yang, Yang Lyu, James J. Hsieh, Christina S. Leslie, Emily H. Cheng

2020-Current year OA Pubs

SETD2, a H3K36 trimethyltransferase, is the most frequently mutated epigenetic modifier in lung adenocarcinoma, with a mutation frequency of approximately 9%. However, how SETD2 loss of function promotes tumorigenesis remains unclear. Using conditional Setd2-KO mice, we demonstrated that Setd2 deficiency accelerated the initiation of KrasG12D-driven lung tumorigenesis, increased tumor burden, and significantly reduced mouse survival. An integrated chromatin accessibility and transcriptome analysis revealed a potentially novel tumor suppressor model of SETD2 in which SETD2 loss activates intronic enhancers to drive oncogenic transcriptional output, including the KRAS transcriptional signature and PRC2-repressed targets, through regulation of chromatin accessibility and histone chaperone recruitment. …

Lacrimal Gland Epithelial Cells Shape Immune Responses Through The Modulation Of Inflammasomes And Lipid Metabolism, Vanessa Delcroix, Olivier Mauduit, Menglu Yang, Amrita Srivastava, Takeshi Umazume, Cintia S De Paiva, Valery I Shestopalov, Darlene A Dartt, Helen P Makarenkova

Faculty, Staff and Students Publications

Lacrimal gland inflammation triggers dry eye disease through impaired tear secretion by the epithelium. As aberrant inflammasome activation occurs in autoimmune disorders including Sjögren's syndrome, we analyzed the inflammasome pathway during acute and chronic inflammation and investigated its potential regulators. Bacterial infection was mimicked by the intraglandular injection of lipopolysaccharide (LPS) and nigericin, known to activate the NLRP3 inflammasome. Acute injury of the lacrimal gland was induced by interleukin (IL)-1α injection. Chronic inflammation was studied using two Sjögren's syndrome models: diseased

Tcr-Engineered Adoptive Cell Therapy Effectively Treats Intracranial Murine Glioblastoma, Maximilian O. Schaettler, Rupen Desai, Anthony Z. Wang, Alexandra J. Livingstone, Dale K. Kobayashi, Andrew T. Coxon, Jay A. Bowman-Kirigin, Connor J. Liu, Mao Li, Diane E. Bender, Michael J. White, David M. Kranz, Tanner M. Johanns, Gavin P. Dunn

2020-Current year OA Pubs

BACKGROUND: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma.

METHODS: We employed single-cell PCR to isolate a TCR specific for the Imp3

RESULTS: We isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a …

Exploiting Prmt5 As A Target For Combination Therapy In Mantle Cell Lymphoma Characterized By Frequent Atm And Tp53 Mutations, Yuxuan Che, Yang Liu, Yixin Yao, Holly A Hill, Yijing Li, Qingsong Cai, Fangfang Yan, Preetesh Jain, Wei Wang, Lixin Rui, Michael Wang

Faculty, Staff and Student Publications

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. …

Alternative Polyadenylation Alters Protein Dosage By Switching Between Intronic And 3’Utr Sites, Nicola De Prisco, Caitlin Ford, Nathan D Elrod, Winston Lee, Lauren C Tang, Kai-Lieh Huang, Ai Lin, Ping Ji, Venkata S Jonnakuti, Lia Boyle, Maximilian Cabaj, Salvatore Botta, Katrin Õunap, Karit Reinson, Monica H Wojcik, Jill A Rosenfeld, Weimin Bi, Kristian Tveten, Trine Prescott, Thorsten Gerstner, Audrey Schroeder, Chin-To Fong, Jaya K George-Abraham, Catherine A Buchanan, Andrea Hanson-Khan, Jonathan A Bernstein, Aikaterini A Nella, Wendy K Chung, Vicky Brandt, Marko Jovanovic, Kimara L Targoff, Hari Krishna Yalamanchili, Eric J Wagner, Vincenzo A Gennarino

Faculty, Staff and Students Publications

Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' untranslated region (3'UTR), introns, or exons. Most studies focus on APA within the 3'UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function …

Emergent Dynamics Of Adult Stem Cell Lineages From Single Nucleus And Single Cell Rna-Seq Of Drosophila Testes, Amelie A Raz, Gabriela S Vida, Sarah R Stern, Sharvani Mahadevaraju, Jaclyn M Fingerhut, Jennifer M Viveiros, Soumitra Pal, Jasmine R Grey, Mara R Grace, Cameron W Berry, Hongjie Li, Jasper Janssens, Wouter Saelens, Zhantao Shao, Chun Hu, Yukiko M Yamashita, Teresa Przytycka, Brian Oliver, Julie A Brill, Henry Krause, Erika L Matunis, Helen White-Cooper, Stephen Dinardo, Margaret T Fuller

Faculty, Staff and Students Publications

Proper differentiation of sperm from germline stem cells, essential for production of the next generation, requires dramatic changes in gene expression that drive remodeling of almost all cellular components, from chromatin to organelles to cell shape itself. Here, we provide a single nucleus and single cell RNA-seq resource covering all of spermatogenesis in Drosophila starting from in-depth analysis of adult testis single nucleus RNA-seq (snRNA-seq) data from the Fly Cell Atlas (FCA) study. With over 44,000 nuclei and 6000 cells analyzed, the data provide identification of rare cell types, mapping of intermediate steps in differentiation, and the potential to identify …

Fmr1 Mutation Alters The Early Development Of Sensory Coding And Hunting And Social Behaviors In Larval Zebrafish, Shuyu I Zhu, Michael H Mccullough, Zac Pujic, Jordan Sibberas, Biao Sun, Thomas Darveniza, Bianca Bucknall, Lilach Avitan, Geoffrey J Goodhill

2020-Current year OA Pubs

Autism spectrum disorders (ASDs) are developmental in origin; however, little is known about how they affect the early development of behavior and sensory coding. The most common inherited form of autism is Fragile X syndrome (FXS), caused by a mutation in

Intestinal Neuropod Cell Gucy2c Regulates Visceral Pain, Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting …