Browsing by Author "Chen, Steven X."

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    Asian American Experience in the Largest Allopathic Medical School
    (2023-04-28) Chen, Steven X.; Wang, Manda Y.; Padgett, Craig M.; Kochhar, Komal; Ko, Paul
    Asians generally comprise around 20% of medical professionals but make up about 7% of the United States population. They are considered an overrepresented minority within the field of medicine. We studied the Pan- Asian diaspora at the only allopathic medical school in Indiana by identifying relationships and trends of medical students. The percentage of the Asian population in the state of Indiana is approximately 2.7%. The Indiana University School of Medicine possesses two unique qualities that make it stand out among its counterparts and suitable for a study regarding representation across Indiana and comparable midwestern schools: 1) It has nine statewide campuses covering the entire state, and 2) it is largest medical school in the nation. In this cross-sectional study, we obtained matriculation and graduation data from classes entering IUSM between 2013-2022. Data were de-identified per protocols within IUSM’s Business Intelligence office. IRB review not required due to a determination of not human research. The racial category of Asian was determined by self- identification on one or more application and/or onboarding forms. It includes, but is not limited to, Chinese, Filipino, Indian, Korea, Indian, Japanese, Vietnamese. The category may also include those who identify as two or more races. Excluded are American Indian, Alaska Native, Native Hawaiian, Pacific Islander. Asian representation at IUSM were comparable to the overall representation of Asians in medicine. While regional variation differed among each of the nine statewide campuses, the population of Asian students were overrepresented compared to their respective campus’s county population. There was also no significant difference between Asians and non-Asians matching outside of Indiana for residency nor was there any selection for a specific specialty (e.g. primary care, surgery). Our work stands to highlight the importance of quantifying the Asian experience and to benefit future work in diversity, equity, and inclusion. The Asian experience is unique when considering the group’s underrepresentation in society but overrepresentation in the medical field. Given the “model minority” myth surrounding Asians at large, more data and studies are needed to examine and understand the experience of medical students as they interface with the hidden curriculum and patient care.
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    Bioinformatics detection of modulators controlling splicing factor‐dependent intron retention in the human brain
    (Wiley, 2022) Chen, Steven X.; Simpson, Ed; Reiter, Jill L.; Liu, Yunlong; Medical and Molecular Genetics, School of Medicine
    Alternative RNA splicing is an important means of genetic control and transcriptome diversity. However, when alternative splicing events are studied independently, coordinated splicing modulated by common factors is often not recognized. As a result, the molecular mechanisms of how splicing regulators promote or repress splice site recognition in a context‐dependent manner are not well understood. The functional coupling between multiple gene regulatory layers suggests that splicing is modulated by additional genetic or epigenetic components. Here, we developed a bioinformatics approach to identify causal modulators of splicing activity based on the variation of gene expression in large RNA sequencing datasets. We applied this approach in a neurological context with hundreds of dorsolateral prefrontal cortex samples. Our model is strengthened with the incorporation of genetic variants to impute gene expression in a Mendelian randomization‐based approach. We identified novel modulators of the splicing factor SRSF1, including UIMC1 and the long noncoding RNA CBR3‐AS1, that function over dozens of SRSF1 intron retention splicing targets. This strategy can be widely used to identify modulators of RNA‐binding proteins involved in tissue‐specific alternative splicing.
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    Endothelial disruptive proinflammatory effects of nicotine and e-cigarette vapor exposures
    (American Physiological Society, 2015-07-15) Schweitzer, Kelly S.; Chen, Steven X.; Law, Sarah; Van Demark, Mary; Poirier, Christophe; Justice, Matthew J.; Hubbard, Walter C.; Kim, Elena S.; Lai, Xianyin; Wang, Mu; Kranz, William D.; Carroll, Clinton J.; Ray, Bruce D.; Bittman, Robert; Goodpaster, John V.; Petrache, Irina; Department of Biochemistry & Molecular Biology, IU School of Medicine
    The increased use of inhaled nicotine via e-cigarettes has unknown risks to lung health. Having previously shown that cigarette smoke (CS) extract disrupts the lung microvasculature barrier function by endothelial cell activation and cytoskeletal rearrangement, we investigated the contribution of nicotine in CS or e-cigarettes (e-Cig) to lung endothelial injury. Primary lung microvascular endothelial cells were exposed to nicotine, e-Cig solution, or condensed e-Cig vapor (1-20 mM nicotine) or to nicotine-free CS extract or e-Cig solutions. Compared with nicotine-containing extract, nicotine free-CS extract (10-20%) caused significantly less endothelial permeability as measured with electric cell-substrate impedance sensing. Nicotine exposures triggered dose-dependent loss of endothelial barrier in cultured cell monolayers and rapidly increased lung inflammation and oxidative stress in mice. The endothelial barrier disruptive effects were associated with increased intracellular ceramides, p38 MAPK activation, and myosin light chain (MLC) phosphorylation, and was critically mediated by Rho-activated kinase via inhibition of MLC-phosphatase unit MYPT1. Although nicotine at sufficient concentrations to cause endothelial barrier loss did not trigger cell necrosis, it markedly inhibited cell proliferation. Augmentation of sphingosine-1-phosphate (S1P) signaling via S1P1 improved both endothelial cell proliferation and barrier function during nicotine exposures. Nicotine-independent effects of e-Cig solutions were noted, which may be attributable to acrolein, detected along with propylene glycol, glycerol, and nicotine by NMR, mass spectrometry, and gas chromatography, in both e-Cig solutions and vapor. These results suggest that soluble components of e-Cig, including nicotine, cause dose-dependent loss of lung endothelial barrier function, which is associated with oxidative stress and brisk inflammation.
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    Highly robust model of transcription regulator activity predicts breast cancer overall survival
    (BMC, 2020) Dong, Chuanpeng; Liu, Jiannan; Chen, Steven X.; Dong, Tianhan; Jiang, Guanglong; Wang, Yue; Wu, Huanmei; Reiter, Jill L.; Liu, Yunlong; Medical and Molecular Genetics, School of Medicine
    Background: While several multigene signatures are available for predicting breast cancer prognosis, particularly in early stage disease, effective molecular indicators are needed, especially for triple-negative carcinomas, to improve treatments and predict diagnostic outcomes. The objective of this study was to identify transcriptional regulatory networks to better understand mechanisms giving rise to breast cancer development and to incorporate this information into a model for predicting clinical outcomes. Methods: Gene expression profiles from 1097 breast cancer patients were retrieved from The Cancer Genome Atlas (TCGA). Breast cancer-specific transcription regulatory information was identified by considering the binding site information from ENCODE and the top co-expressed targets in TCGA using a nonlinear approach. We then used this information to predict breast cancer patient survival outcome. Result: We built a multiple regulator-based prediction model for breast cancer. This model was validated in more than 5000 breast cancer patients from the Gene Expression Omnibus (GEO) databases. We demonstrated our regulator model was significantly associated with clinical stage and that cell cycle and DNA replication related pathways were significantly enriched in high regulator risk patients. Conclusion: Our findings demonstrate that transcriptional regulator activities can predict patient survival. This finding provides additional biological insights into the mechanisms of breast cancer progression.
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    Integration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes
    (Springer Nature, 2021-03-12) Novikova, Gloriia; Kapoor, Manav; TCW, Julia; Abud, Edsel M.; Efthymiou, Anastasia G.; Chen, Steven X.; Cheng, Haoxiang; Fullard, John F.; Bendl, Jaroslav; Liu, Yiyuan; Roussos, Panos; Björkegren, Johan LM; Liu, Yunlong; Poon, Wayne W.; Hao, Ke; Marcora, Edoardo; Goate, Alison M.; Medical and Molecular Genetics, School of Medicine
    Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.
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    Modulator-Dependent RBPs Changes Alternative Splicing Outcomes in Kidney Cancer
    (Frontiers Media, 2020) Wang, Yang; Chen, Steven X.; Rao, Xi; Liu, Yunlong; Medical and Molecular Genetics, School of Medicine
    Alternative splicing alterations can contribute to human disease. The ability of an RNA-binding protein to regulate alternative splicing outcomes can be modulated by a variety of genetic and epigenetic mechanisms. In this study, we use a computational framework to investigate the roles of certain genes, termed modulators, on changing RBPs’ effect on splicing regulation. A total of 1,040,254 modulator-mediated RBP-splicing interactions were identified, including 137 RBPs, 4,309 splicing events and 2,905 modulator candidates from TCGA-KIRC RNA sequencing data. Modulators function categories were defined according to the correlation changes between RBPs expression and their targets splicing outcomes. QKI, as one of the RBPs influencing the most splicing events, attracted our attention in this study: 2,014 changing triplets were identified, including 1,101 modulators and 187 splicing events. Pathway enrichment analysis showed that QKI splicing targets were enriched in tight junction pathway, endocytosis and MAPK signaling pathways, all of which are highly associated with cancer development and progression. This is the first instance of a comprehensive study on how alternative splicing outcomes changes are associated with different expression level of certain proteins, even though they were regulated by the same RBP. Our work may provide a novel view on understanding alternative splicing mechanisms in kidney cancer.
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    RNA alternative splicing impacts the risk for alcohol use disorder
    (Springer Nature, 2023) Li, Rudong; Reiter, Jill L.; Chen, Andy B.; Chen, Steven X.; Foroud, Tatiana; Edenberg, Howard J.; Lai, Dongbing; Liu, Yunlong; Medical and Molecular Genetics, School of Medicine
    Alcohol use disorder (AUD) is a complex genetic disorder characterized by problems arising from excessive alcohol consumption. Identifying functional genetic variations that contribute to risk for AUD is a major goal. Alternative splicing of RNA mediates the flow of genetic information from DNA to gene expression and expands proteome diversity. We asked whether alternative splicing could be a risk factor for AUD. Herein, we used a Mendelian randomization (MR)-based approach to identify skipped exons (the predominant splicing event in brain) that contribute to AUD risk. Genotypes and RNA-seq data from the CommonMind Consortium were used as the training dataset to develop predictive models linking individual genotypes to exon skipping in the prefrontal cortex. We applied these models to data from the Collaborative Studies on Genetics of Alcoholism to examine the association between the imputed cis-regulated splicing outcome and the AUD-related traits. We identified 27 exon skipping events that were predicted to affect AUD risk; six of these were replicated in the Australian Twin-family Study of Alcohol Use Disorder. Their host genes are DRC1, ELOVL7, LINC00665, NSUN4, SRRM2 and TBC1D5. The genes downstream of these splicing events are enriched in neuroimmune pathways. The MR-inferred impacts of the ELOVL7 skipped exon on AUD risk was further supported in four additional large-scale genome-wide association studies. Additionally, this exon contributed to changes of gray matter volumes in multiple brain regions, including the visual cortex known to be involved in AUD. In conclusion, this study provides strong evidence that RNA alternative splicing impacts the susceptibility to AUD and adds new information on AUD-relevant genes and pathways. Our framework is also applicable to other types of splicing events and to other complex genetic disorders.