Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Neuronal Ablation Of Ghsr Mitigates Diet-Induced Depression And Memory Impairment Via Ampk-Autophagy Signaling-Mediated Inflammation, Hongying Wang, Zheng Shen, Chia-Shan Wu, Pengfei Ji, Ji Yeon Noh, Cédric G Geoffroy, Sunja Kim, David Threadgill, Jianrong Li, Yu Zhou, Xiaoqiu Xiao, Hui Zheng, Yuxiang Sun

Faculty, Staff and Students Publications

Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the …

Phenotypic And Functional Assessment Of Two Novel Kcnq2 Gain-Of-Function Variants Y141n And G239s And Effects Of Amitriptyline Treatment, Allan Bayat, Stefano Iavarone, Francesco Miceli, Anne V Jakobsen, Katrine M Johannesen, Marina Nikanorova, Rafal Ploski, Krystyna Szymanska, Robert Flamini, Edward C Cooper, Sarah Weckhuysen, Maurizio Taglialatela, Rikke S Møller

Faculty, Staff and Students Publications

While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n = 1) or G239S variant (n = 2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell …

Combined Bioinformatic And Splicing Analysis Of Likely Benign Intronic And Synonymous Variants Reveals Evidence For Pathogenicity, Owen R Hirschi, Stephanie A Felker, Surya P Rednam, Kelly L Vallance, D Williams Parsons, Angshumoy Roy, Gregory M Cooper, Sharon E Plon

Faculty, Staff and Students Publications

PURPOSE: Clinical variant analysis pipelines likely have poor sensitivity to the effects on splicing from variants beyond 10 to 20 bases of exon-intron boundaries. Here, we demonstrate the value of SpliceAI to inform curation of rare variants previously classified as benign/likely benign (B/LB) under current guidelines.

METHODS: Exome sequencing data from 576 pediatric cancer patients enrolled in the Texas KidsCanSeq study were filtered for intronic or synonymous variants absent from population databases, predicted to alter splicing via SpliceAI (>0.20), and scored >10 by combined annotation-dependent depletion. Rare synonymous or intronic B/LB variants in 61 genes submitted to ClinVar were …

Bi-Allelic Variants In Cep295 Cause Seckel-Like Syndrome Presenting With Primary Microcephaly, Developmental Delay, Intellectual Disability, Short Stature, Craniofacial And Digital Abnormalities, Niu Li, Yufei Xu, Hongzhu Chen, Jingqi Lin, Lama Alabdi, Mir Reza Bekheirnia, Guoqiang Li, Yoel Gofin, Nasim Bekheirnia, Eissa Faqeih, Lina Chen, Guoying Chang, Jie Tang, Ruen Yao, Tingting Yu, Xiumin Wang, Wei Fu, Qihua Fu, Yiping Shen, Fowzan S Alkuraya, Keren Machol, Jian Wang

Faculty, Staff and Students Publications

BACKGROUND: Pathogenic variants in the centrosome protein (CEP) family have been implicated in primary microcephaly, Seckel syndrome, and classical ciliopathies. However, most CEP genes remain unlinked to specific Mendelian genetic diseases in humans. We sought to explore the roles of CEP295 in human pathology.

METHODS: Whole-exome sequencing was performed to screen for pathogenic variants in patients with severe microcephaly. Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying pathomechanisms, including centriole/centrosome development, cell cycle and proliferation changes, and ciliogenesis. Complementary experiments using CEP295 mRNA were performed to determine the pathogenicity of the identified missense variant. …

Triobp Modulates Β-Catenin Signaling By Regulation Of Mir-29b In Idiopathic Pulmonary Fibrosis, Lan Wang, Wenyu Zhao, Cong Xia, Shuaichen Ma, Zhongzheng Li, Ningdan Wang, Linke Ding, Yaxuan Wang, Lianhui Cheng, Huibing Liu, Juntang Yang, Yajun Li, Ivan Rosas, Guoying Yu

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited …

Abnormal Patterns Of Sleep And Waking Behaviors Are Accompanied By Neocortical Oscillation Disturbances In An Ank3 Mouse Model Of Epilepsy-Bipolar Disorder Comorbidity, Juan E Villacres, Nicholas Riveira, Sohmee Kim, Laura L Colgin, Jeffrey L Noebels, Angel Y Lopez

Faculty, Staff and Students Publications

ANK3 is a leading bipolar disorder (BD) candidate gene in humans and provides a unique opportunity for studying epilepsy-BD comorbidity. Previous studies showed that deletion of Ank3-1b, a BD-associated variant of Ank3 in mice leads to increased firing threshold and diminished action potential dynamic range of parvalbumin (PV) interneurons and absence epilepsy, thus providing a biological mechanism linking epilepsy and BD. To explore the behavioral overlap of these disorders, we characterized behavioral patterns of Ank3-1b KO mice during overnight home-cage activity and examined network activity during these behaviors using paired video and EEG recordings. Since PV interneurons contribute to the …

Extended-Synaptotagmin-1 And -2 Control T Cell Signaling And Function, Nathalia Benavides, Claudio G. Giraudo

Department of Microbiology and Immunology Faculty Papers

Upon T-cell activation, the levels of the secondary messenger diacylglycerol (DAG) at the plasma membrane need to be controlled to ensure appropriate T-cell receptor signaling and T-cell functions. Extended-Synaptotagmins (E-Syts) are a family of inter-organelle lipid transport proteins that bridge the endoplasmic reticulum and the plasma membrane. In this study, we identify a novel regulatory mechanism of DAG-mediated signaling for T-cell effector functions based on E-Syt proteins. We demonstrate that E-Syts downmodulate T-cell receptor signaling, T-cell-mediated cytotoxicity, degranulation, and cytokine production by reducing plasma membrane levels of DAG. Mechanistically, E-Syt2 predominantly modulates DAG levels at the plasma membrane in resting-state …

Life, The Genome And Everything, Susan M Rosenberg

Faculty, Staff and Students Publications

In this issue of the Journal of Bacteriology, N. J. Bonde, E. A. Wood, K. S. Myers, M. Place, J. L. Keck, and M. M. Cox (J Bacteriol 205:e00184-23, 2023, https://doi.org/10.1128/jb.00184-23) used an unbiased transposon-sequencing (Tn-seq) screen to identify proteins required for life when cells lose the RecG branched-DNA helicase (synthetic lethality). The proteins’ identities indicate pathways that prevent endogenous DNA damage, pathways that prevent its homology-directed repair (HDR) “strand-exchange” intermediates between sister chromosomes, and pathways that resolve those intermediates. All avoid intermediate pile-up, which blocks chromosome segregation, causing “death-by-recombination.” DNA damage is managed to regulate crucial but …

Allelic Strengths Of Encephalopathy-Associated Uba5 Variants Correlate Between In Vivo And In Vitro Assays, Xueyang Pan, Albert N Alvarez, Mengqi Ma, Shenzhao Lu, Michael W Crawford, Lauren C Briere, Oguz Kanca, Shinya Yamamoto, David A Sweetser, Jenny L Wilson, Ruth J Napier, Jonathan N Pruneda, Hugo J Bellen

Faculty, Staff and Students Publications

Protein UFMylation downstream of the E1 enzyme UBA5 plays essential roles in development and endoplasmic reticulum stress. Variants in the UBA5 gene are associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder characterized by early-onset encephalopathy, movement abnormalities, global developmental delay, intellectual disability, and seizures. DEE44 is caused by at least 12 different missense variants described as loss of function (LoF), but the relationships between genotypes and molecular or clinical phenotypes remain to be established. We developed a humanized UBA5 fly model and biochemical activity assays in order to describe in vivo and in vitro genotype–phenotype relationships …

Nicotinic Acetylcholine Receptor Signaling Maintains Epithelial Barrier Integrity, Nadja S Katheder, Kristen C Browder, Diana Chang, Ann De Maziere, Pekka Kujala, Suzanne Van Dijk, Judith Klumperman, Tzu-Chiao Lu, Hongjie Li, Zijuan Lai, Dewakar Sangaraju, Heinrich Jasper

Faculty, Staff and Students Publications

Disruption of epithelial barriers is a common disease manifestation in chronic degenerative diseases of the airways, lung, and intestine. Extensive human genetic studies have identified risk loci in such diseases, including in chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. The genes associated with these loci have not fully been determined, and functional characterization of such genes requires extensive studies in model organisms. Here, we report the results of a screen in

Whole Genome Analysis Of Snv And Indel Polymorphism In Common Marmosets (Callithrix Jacchus), R Alan Harris, Muthuswamy Raveendran, Wes Warren, Hillier W Ladeana, Chad Tomlinson, Tina Graves-Lindsay, Richard E Green, Jenna K Schmidt, Julia C Colwell, Allison T Makulec, Shelley A Cole, Ian H Cheeseman, Corinna N Ross, Saverio Capuano, Evan E Eichler, Jon E Levine, Jeffrey Rogers

Faculty, Staff and Students Publications

The common marmoset (Callithrix jacchus) is one of the most widely used nonhuman primate models of human disease. Owing to limitations in sequencing technology, early genome assemblies of this species using short-read sequencing suffered from gaps. In addition, the genetic diversity of the species has not yet been adequately explored. Using long-read genome sequencing and expert annotation, we generated a high-quality genome resource creating a 2.898 Gb marmoset genome in which most of the euchromatin portion is assembled contiguously (contig N50 = 25.23 Mbp, scaffold N50 = 98.2 Mbp). We then performed whole genome sequencing on 84 marmosets …

The Application Of Simultaneous Mainstem Bronchus Dilation With Pulmonary Artery Stenting In The Context Of Hypoplastic Left Heart Syndrome, Sylwia Hasterok, Thomas G Scott, Devin G Roller, Adam Spencer, Arun B Dutta, Kizhakke M Sathyan, Daniel E Frigo, Michael J Guertin, Daniel Gioeli

Faculty, Staff and Student Publications

The clinical success of combined androgen deprivation therapy (ADT) and radiotherapy (RT) in prostate cancer created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at a steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes …

Clinical Exome Sequencing Efficacy And Phenotypic Expansions Involving Anomalous Pulmonary Venous Return, Emily A Huth, Xiaonan Zhao, Nichole Owen, Pamela N Luna, Ida Vogel, Inger L H Dorf, Shelagh Joss, Jill Clayton-Smith, Michael J Parker, Jacoba J Louw, Marc Gewillig, Jeroen Breckpot, Alison Kraus, Erina Sasaki, Usha Kini, Trent Burgess, Tiong Y Tan, Ruth Armstrong, Katherine Neas, Giovanni B Ferrero, Alfredo Brusco, Wihelmina S Kerstjens-Frederikse, Julia Rankin, Lindsey R Helvaty, Benjamin J Landis, Gabrielle C Geddes, Kim L Mcbride, Stephanie M Ware, Chad A Shaw, Seema R Lalani, Jill A Rosenfeld, Daryl A Scott

Faculty, Staff and Students Publications

Anomalous pulmonary venous return (APVR) frequently occurs with other congenital heart defects (CHDs) or extra-cardiac anomalies. While some genetic causes have been identified, the optimal approach to genetic testing in individuals with APVR remains uncertain, and the etiology of most cases of APVR is unclear. Here, we analyzed molecular data from 49 individuals to determine the diagnostic yield of clinical exome sequencing (ES) for non-isolated APVR. A definitive or probable diagnosis was made for 8 of those individuals yielding a diagnostic efficacy rate of 16.3%. We then analyzed molecular data from 62 individuals with APVR accrued from three databases to …

Biallelic Med27 Variants Lead To Variable Ponto-Cerebello-Lental Degeneration With Movement Disorders, Reza Maroofian, Rauan Kaiyrzhanov, Elisa Cali, Mina Zamani, Maha S Zaki, Matteo Ferla, Domenico Tortora, Saeid Sadeghian, Saadia Maryam Saadi, Uzma Abdullah, Ehsan Ghayoor Karimiani, Stephanie Efthymiou, Gözde Yeşil, Shahryar Alavi, Aisha M Al Shamsi, Homa Tajsharghi, Mohamed S Abdel-Hamid, Nebal Waill Saadi, Fuad Al Mutairi, Lama Alabdi, Christian Beetz, Zafar Ali, Mehran Beiraghi Toosi, Sabine Rudnik-Schöneborn, Meisam Babaei, Pirjo Isohanni, Jameel Muhammad, Sheraz Khan, Maha Al Shalan, Scott E Hickey, Daphna Marom, Emil Elhanan, Manju A Kurian, Dana Marafi, Alihossein Saberi, Mohammad Hamid, Robert Spaull, Linyan Meng, Seema Lalani, Shazia Maqbool, Fatima Rahman, Jürgen Seeger, Timothy Blake Palculict, Tracy Lau, David Murphy, Niccolo Emanuele Mencacci, Katharina Steindl, Anais Begemann, Anita Rauch, Sinan Akbas, Ayça Dilruba Aslanger, Vincenzo Salpietro, Hammad Yousaf, Shay Ben-Shachar, Katarina Ejeskär, Aida I Al Aqeel, Frances A High, Amy E Armstrong-Javors, Seyed Mohammadsaleh Zahraei, Tahereh Seifi, Jawaher Zeighami, Gholamreza Shariati, Alireza Sedaghat, Samaneh Noroozi Asl, Mohmmad Shahrooei, Giovanni Zifarelli, Lydie Burglen, Claudia Ravelli, Johannes Zschocke, Ulrich A Schatz, Maryam Ghavideldarestani, Walaa A Kamel, Hilde Van Esch, Annette Hackenberg, Jenny C Taylor, Lihadh Al-Gazali, Peter Bauer, Joseph J Gleeson, Fowzan Sami Alkuraya, James R Lupski, Hamid Galehdari, Reza Azizimalamiri, Wendy K Chung, Shahid Mahmood Baig, Henry Houlden, Mariasavina Severino

Faculty, Staff and Students Publications

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± …

Complex Evolutionary History With Extensive Ancestral Gene Flow In An African Primate Radiation, Axel Jensen, Frances Swift, Dorien De Vries, Robin M D Beck, Lukas F K Kuderna, Sascha Knauf, Idrissa S Chuma, Julius D Keyyu, Andrew C Kitchener, Kyle Farh, Jeffrey Rogers, Tomas Marques-Bonet, Kate M Detwiler, Christian Roos, Katerina Guschanski

Faculty, Staff and Students Publications

Understanding the drivers of speciation is fundamental in evolutionary biology, and recent studies highlight hybridization as an important evolutionary force. Using whole-genome sequencing data from 22 species of guenons (tribe Cercopithecini), one of the world's largest primate radiations, we show that rampant gene flow characterizes their evolutionary history and identify ancient hybridization across deeply divergent lineages that differ in ecology, morphology, and karyotypes. Some hybridization events resulted in mitochondrial introgression between distant lineages, likely facilitated by cointrogression of coadapted nuclear variants. Although the genomic landscapes of introgression were largely lineage specific, we found that genes with immune functions were overrepresented …

Gene Transcription Regulation By Er At The Single Cell And Allele Level, Fabio Stossi, Alejandra Rivera Tostado, Hannah L Johnson, Ragini M Mistry, Maureen G Mancini, Michael A Mancini

Faculty, Staff and Students Publications

In this short review we discuss the current view of how the estrogen receptor (ER), a pivotal member of the nuclear receptor superfamily of transcription factors, regulates gene transcription at the single cell and allele level, focusing on in vitro cell line models. We discuss central topics and new trends in molecular biology including phenotypic heterogeneity, single cell sequencing, nuclear phase separated condensates, single cell imaging, and image analysis methods, with particular focus on the methodologies and results that have been reported in the last few years using microscopy-based techniques. These observations augment the results from biochemical assays that lead …

The Brd4-Nut Fusion Alone Drives Malignant Transformation Of Nut Carcinoma, R Taylor Durall, Julianna Huang, Luke Wojenski, Yeying Huang, Prafulla C Gokhale, Brittaney A Leeper, Joshua O Nash, Pedro L Ballester, Scott Davidson, Adam Shlien, Emmanuel Sotirakis, Fabien Bertaux, Vincent Dubus, Jia Luo, Catherine J Wu, Derin B Keskin, Kyle P Eagen, Geoffrey I Shapiro, Christopher A French

Faculty, Staff and Students Publications

NUT carcinoma (NC) is an aggressive squamous carcinoma defined by the BRD4-NUT fusion oncoprotein. Routinely effective systemic treatments are unavailable for most NC patients. The lack of an adequate animal model precludes identifying and leveraging cell-extrinsic factors therapeutically in NC. Here, we created a genetically engineered mouse model (GEMM) of NC that forms a Brd4::NUTM1 fusion gene upon tamoxifen induction of Sox2-driven Cre. The model displayed complete disease penetrance, with tumors arising from the squamous epithelium weeks after induction and all mice succumbing to the disease shortly thereafter. Closely resembling human NC (hNC), GEMM tumors (mNC) were poorly differentiated squamous …

Birth Defects In Offspring Of Adolescent And Young Adults With A History Of Cancer: A Population-Based Study Of 27,000 Women, Caitlin C Murphy, Andrea C Betts, Sandi L Pruitt, Barbara A Cohn, L Aubree Shay, Marlyn A Allicock, Jennifer S Wang, Philip J Lupo

Faculty, Staff and Students Publications

BACKGROUND: We examined birth defects in offspring of adolescent and young adult (AYA) women with a history of cancer (age 15-39 years at diagnosis).

METHODS: We identified AYA women diagnosed with cancer between January 1, 1999, and December 31, 2015 using population-based data from the Texas Cancer Registry; data were linked with live birth and fetal death certificates through December 31, 2016 to identify singleton births to AYA women after diagnosis. Birth defects in offspring through age 12 months were ascertained from the Texas Birth Defects Registry. We estimated risk of birth defects in offspring of AYA women and women …

Clinical, Genetic And Structural Delineation Of Rpl13-Related Spondyloepimetaphyseal Dysplasia Suggest Extra-Ribosomal Functions Of El13, Prince Jacob, Hillevi Lindelöf, Cecilie F Rustad, Vernon Reid Sutton, Shahida Moosa, Prajna Udupa, Anna Hammarsjö, Gandham Srilakshmi Bhavani, Dominyka Batkovskyte, Kristian Tveten, Ashwin Dalal, Eva Horemuzova, Ann Nordgren, Emma Tham, Hitesh Shah, Else Merckoll, Laura Orellana, Gen Nishimura, Katta M Girisha, Giedre Grigelioniene

Faculty, Staff and Students Publications

Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2-64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, …

Clinical, Genetic And Structural Delineation Of Rpl13-Related Spondyloepimetaphyseal Dysplasia Suggest Extra-Ribosomal Functions Of El1, Prince Jacob, Hillevi Lindelöf, Cecilie F Rustad, Vernon Reid Sutton, Shahida Moosa, Prajna Udupa, Anna Hammarsjö, Gandham Srilakshmi Bhavani, Dominyka Batkovskyte, Kristian Tveten, Ashwin Dalal, Eva Horemuzova, Ann Nordgren, Emma Tham, Hitesh Shah, Else Merckoll, Laura Orellana, Gen Nishimura, Katta M Girisha, Giedre Grigelioniene

Faculty, Staff and Students Publications

Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2-64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, …

The Role Of Noncoding Rnas In Pancreatic Birth Defects, Ziyue Zoey Yang, Ronald J Parchem

Faculty, Staff and Students Publications

Congenital defects in the pancreas can cause severe health issues such as pancreatic cancer and diabetes which require lifelong treatment. Regenerating healthy pancreatic cells to replace malfunctioning cells has been considered a promising cure for pancreatic diseases including birth defects. However, such therapies are currently unavailable in the clinic. The developmental gene regulatory network underlying pancreatic development must be reactivated for in vivo regeneration and recapitulated in vitro for cell replacement therapy. Thus, understanding the mechanisms driving pancreatic development will pave the way for regenerative therapies. Pancreatic progenitor cells are the precursors of all pancreatic cells which use epigenetic changes …

Nad+ Rescues Aging-Induced Blood-Brain Barrier Damage Via The Cx43-Parp1 Axis, Rui Zhan, Xia Meng, Dongping Tian, Jie Xu, Hongtu Cui, Jialei Yang, Yangkai Xu, Mingming Shi, Jing Xue, Weiwei Yu, Gaofei Hu, Ke Li, Xiaoxiao Ge, Qi Zhang, Mingming Zhao, Jianyong Du, Xin Guo, Wenli Xu, Yang Gao, Changyu Yao, Fan Chen, Yue Chen, Wenxin Shan, Yujie Zhu, Liang Ji, Bing Pan, Yan Yu, Wenguang Li, Xuyang Zhao, Qihua He, Xiaohui Liu, Yue Huang, Shengyou Liao, Bin Zhou, Dehua Chui, Y Eugene Chen, Zheng Sun, Erdan Dong, Yongjun Wang, Lemin Zheng

Faculty, Staff and Students Publications

Blood-brain barrier (BBB) function deteriorates during aging, contributing to cognitive impairment and neurodegeneration. It is unclear what drives BBB leakage in aging and how it can be prevented. Using single-nucleus transcriptomics, we identified decreased connexin 43 (CX43) expression in cadherin-5

Associations Between Birth Defects With Neural Crest Cell Origins And Pediatric Embryonal Tumors, Eugene C Wong, Philip J Lupo, Tania A Desrosiers, Hazel B Nichols, Susan M Smith, Charles Poole, Mark Canfield, Charles Shumate, Tiffany M Chambers, Jeremy M Schraw, Wendy N Nembhard, Mahsa M Yazdy, Eirini Nestoridi, Amanda E Janitz, Andrew F Olshan

Faculty, Staff and Students Publications

BACKGROUND: There are few assessments evaluating associations between birth defects with neural crest cell developmental origins (BDNCOs) and embryonal tumors, which are characterized by undifferentiated cells having a molecular profile similar to neural crest cells. The effect of BDNCOs on embryonal tumors was estimated to explore potential shared etiologic pathways and genetic origins.

METHODS: With the use of a multistate, registry-linkage cohort study, BDNCO-embryonal tumor associations were evaluated by generating hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox regression models. BDNCOs consisted of ear, face, and neck defects, Hirschsprung disease, and a selection of congenital heart defects. Embryonal …

Counts, Incidence Rates, And Trends Of Pediatric Cancer In The United States, 2003–2019, David A Siegel, Jessica B King, Philip J Lupo, Eric B Durbin, Eric Tai, Kathi Mills, Elizabeth Van Dyne, Natasha Buchanan Lunsford, S Jane Henley, Reda J Wilson

Faculty, Staff and Students Publications

BACKGROUND: Cancer is a leading cause of death by disease among children and adolescents in the United States. This study updates cancer incidence rates and trends using the most recent and comprehensive US cancer registry data available.

METHODS: We used data from US Cancer Statistics to evaluate counts, age-adjusted incidence rates, and trends among children and adolescents younger than 20 years of age diagnosed with malignant tumors between 2003 and 2019. We calculated the average annual percent change (APC) and APC using joinpoint regression. Rates and trends were stratified by demographic and geographic characteristics and by cancer type.

RESULTS: With …

A Single Cell Genomics Atlas Of The Drosophila Larval Eye Reveals Distinct Photoreceptor Developmental Timelines, Komal Kumar Bollepogu Raja, Kelvin Yeung, Yoon-Kyung Shim, Yumei Li, Rui Chen, Graeme Mardon

Faculty, Staff and Students Publications

The Drosophila eye is a powerful model system to study the dynamics of cell differentiation, cell state transitions, cell maturation, and pattern formation. However, a high-resolution single cell genomics resource that accurately profiles all major cell types of the larval eye disc and their spatiotemporal relationships is lacking. Here, we report transcriptomic and chromatin accessibility data for all known cell types in the developing eye. Photoreceptors appear as strands of cells that represent their dynamic developmental timelines. As photoreceptor subtypes mature, they appear to assume a common transcriptomic profile that is dominated by genes involved in axon function. We identify …

Mechanistic Toxicology In Light Of Genetic Compensation, Mary Jane Elizalde, Daniel A Gorelick

Faculty, Staff and Students Publications

Mechanistic toxicology seeks to identify the molecular and cellular mechanisms by which toxicants exert their deleterious effects. One powerful approach is to generate mutations in genes that respond to a particular toxicant, and then test how such mutations change the effects of the toxicant. CRISPR is a rapid and versatile approach to generate mutations in cultured cells and in animal models. Many studies use CRISPR to generate short insertions or deletions in a target gene and then assume that the resulting mutation, such as a premature termination codon, causes a loss of functional protein. However, recent studies demonstrate that this …

Molecular Mechanisms Of Twist1-Regulated Transcription In Emt And Cancer Metastasis, Xiaobin Yu, Tao He, Zhangwei Tong, Lan Liao, Shixia Huang, Walid D Fakhouri, Dean P Edwards, Jianming Xu

Faculty, Staff and Students Publications

TWIST1 induces epithelial-to-mesenchymal transition (EMT) to drive cancer metastasis. It is yet unclear what determines TWIST1 functions to activate or repress transcription. We found that the TWIST1 N-terminus antagonizes TWIST1-regulated gene expression, cancer growth and metastasis. TWIST1 interacts with both the NuRD complex and the NuA4/TIP60 complex (TIP60-Com) via its N-terminus. Non-acetylated TWIST1-K73/76 selectively interacts with and recruits NuRD to repress epithelial target gene transcription. Diacetylated TWIST1-acK73/76 binds BRD8, a component of TIP60-Com that also binds histone H4-acK5/8, to recruit TIP60-Com to activate mesenchymal target genes and MYC. Knockdown of BRD8 abolishes TWIST1 and TIP60-Com interaction and TIP60-Com recruitment to …

Machine Learning Methods For Endocrine Disrupting Potential Identification Based On Single-Cell Data, Zahir Aghayev, Adam T Szafran, Anh Tran, Hari S Ganesh, Fabio Stossi, Lan Zhou, Michael A Mancini, Efstratios N Pistikopoulos, Burcu Beykal

Faculty, Staff and Students Publications

Humans are continuously exposed to a variety of toxicants and chemicals which is exacerbated during and after environmental catastrophes such as floods, earthquakes, and hurricanes. The hazardous chemical mixtures generated during these events threaten the health and safety of humans and other living organisms. This necessitates the development of rapid decision-making tools to facilitate mitigating the adverse effects of exposure on the key modulators of the endocrine system, such as the estrogen receptor alpha (ERα), for example. The mechanistic stages of the estrogenic transcriptional activity can be measured with high content/high throughput microscopy-based biosensor assays at the single-cell level, which …

Srcap Mutations Drive Clonal Hematopoiesis Through Epigenetic And Dna Repair Dysregulation, Chun-Wei Chen, Linda Zhang, Ravi Dutta, Abhishek Niroula, Peter G Miller, Christopher J Gibson, Alexander G Bick, Jaime M Reyes, Yi-Tang Lee, Ayala Tovy, Tianpeng Gu, Sarah Waldvogel, Yi-Hung Chen, Bryan J Venters, Pierre-Olivier Estève, Sriharsa Pradhan, Michael-Christopher Keogh, Pradeep Natarajan, Koichi Takahashi, Adam S Sperling, Margaret A Goodell

Faculty, Staff and Students Publications

Somatic mutations accumulate in all cells with age and can confer a selective advantage, leading to clonal expansion over time. In hematopoietic cells, mutations in a subset of genes regulating DNA repair or epigenetics frequently lead to clonal hematopoiesis (CH). Here, we describe the context and mechanisms that lead to enrichment of hematopoietic stem cells (HSCs) with mutations in SRCAP, which encodes a chromatin remodeler that also influences DNA repair. We show that SRCAP mutations confer a selective advantage in human cells and in mice upon treatment with the anthracycline-class chemotherapeutic doxorubicin and bone marrow transplantation. Furthermore, Srcap mutations lead …

Rare De Novo Gain-Of-Function Missense Variants In Dot1l Are Associated With Developmental Delay And Congenital Anomalies, Zelha Nil, Ashish R Deshwar, Yan Huang, Scott Barish, Xi Zhang, Sanaa Choufani, Polona Le Quesne Stabej, Ian Hayes, Patrick Yap, Chad Haldeman-Englert, Carolyn Wilson, Trine Prescott, Kristian Tveten, Arve Vøllo, Devon Haynes, Patricia G Wheeler, Jessica Zon, Cheryl Cytrynbaum, Rebekah Jobling, Moira Blyth, Siddharth Banka, Alexandra Afenjar, Cyril Mignot, Florence Robin-Renaldo, Boris Keren, Oguz Kanca, Xiao Mao, Daniel J Wegner, Kathleen Sisco, Marwan Shinawi, Undiagnosed Disease Network, Michael F Wangler, Rosanna Weksberg, Shinya Yamamoto, Gregory Costain, Hugo J Bellen

Faculty, Staff and Students Publications

Misregulation of histone lysine methylation is associated with several human cancers and with human developmental disorders. DOT1L is an evolutionarily conserved gene encoding a lysine methyltransferase (KMT) that methylates histone 3 lysine-79 (H3K79) and was not previously associated with a Mendelian disease in OMIM. We have identified nine unrelated individuals with seven different de novo heterozygous missense variants in DOT1L through the Undiagnosed Disease Network (UDN), the SickKids Complex Care genomics project, and GeneMatcher. All probands had some degree of global developmental delay/intellectual disability, and most had one or more major congenital anomalies. To assess the pathogenicity of the DOT1L …