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Bioinformatics approaches to analyzing CRISPR screen data:from dropout screens to single-cell CRISPR screens

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Quantitative Biology 2022年第4期10卷 307-320页

作者： Yueshan Zhao Min Zhang Da Yang Center for Pharmacogenetics Department of Pharmaceutical SciencesUniversity of PittsburghPittsburgh PA 15261USA UPMC Hillman cancer Institute University of PittsburghPittsburghPA 15261USA Department of Computational and Systems Biology University of PittsburghPittsburghPA 15261USA

Background:Pooled CRISPR screen is a promising tool in drug targets or essential genes identification with the utilization of three different systems including CRISPR knockout(CRISPRko),CRISPR interference(CRISPRi)and CRISPR activation(CRISPRa).Aside from continuous improvements in technology,more and more bioinformatics methods have been developed to analyze the data obtained by CRISPR screens which facilitate better understanding of physiological ***:Here,we provide an overview on the application of CRISPR screens and bioinformatics approaches to analyzing different types of CRISPR screen *** also discuss mechanisms and underlying challenges for the analysis of dropout screens,sorting-based screens and single-cell ***:Different analysis approaches should be chosen based on the design of *** review will help community to better design novel algorithms and provide suggestions for wet-lab researchers to choose from different analysis methods.

关键词： CRISPR/Cas9 dropout screen sorting-based screen single-cell CRISPR screen drug-gene interaction

Combating CHK1 resistance in triple negative breast cancer:EGFR inhibition as potential combinational therapy

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cancer Drug Resistance 2022年第1期5卷 229-232页

作者： Casey D.Stefanski Jenifer R.Prosperi Department of Biological Sciences University of Notre DameNotre DameIN 46617USA Department of Biochemistry and Molecular Biology Indiana University School of Medicine-South BendSouth BendIN 46617USA

Triple negative breast cancer(TNBC)is marked by a lack of expression of the Estrogen Receptor,Progesterone Receptor,and human epidermal growth factor receptor ***,targeted therapies are being investigated based on the expression profiles of *** to the potential for acquired and intrinsic resistance,there is a need for combination therapy to overcome *** the article by Lee et al.,the authors identify that,while prexasertib(a CHK1 inhibitor)lacks efficacy alone,combination with an EGFR inhibitor provides synergistic anti-tumor *** in targeted therapy for TNBC will benefit the clinical landscape for this disease,with this study initiating a new avenue of investigation.

关键词： CHK1 TNBC EGFR chemoresistance

Transcriptional repression by androgen receptor: roles in castration-resistant prostate cancer

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Asian Journal of Andrology 2019年第3期21卷 215-223页

作者： Galina Gritsina Wei-Qiang Gao Jindan Yu Division of Hematology/Oncology Department of Medicine Northwestern University Feinberg School of Medicine Chicago IL 60611 USA Med-X research Institute and School of Biomedical Engineering Shanghai Jiao Tong University Shanghai 200030 China Department of Biochemistry and Molecular Genetics Northwestern University Feinberg School of Medicine Chicago IL 60611 USA Robert H. Lurie Comprehensive cancer Center Northwestern University Chicago IL 60611 USA

Androgen receptor (AR), a hormonal transcription factor, plays important roles during prostate cancer progression and is a key target for therapeutic interventions. While androgen-deprivation therapies are initially successful in regressing prostate tumors, the disease ultimately comes back as castration-resistant prostate cancer (CRPC) or at the late stage as neuroendocrine prostate cancer (NEPC). CRPC remains largely dependent on hyperactive AR signaling in the milieu of low androgen, while NEPC is negative of AR expression but positive of many AR-repressed genes. Recent technological advances in genome-wide analysis of transcription factor binding sites have revealed an unprecedented set of AR target genes. In addition to its well-known function in activating gene expression, AR is increasingly known to also act as a transcriptional repressor. Here, we review the molecular mechanisms by which AR represses gene expression. We also summarize AR-repressed genes that are aberrantly upregulated in CRPC and NEPC and represent promising targets for therapeutic intervention.

关键词： androgen receptor CRPC EZH2 histone modifications NEPC targeted therapy transcriptional repressor

PDGFRαreporter activity identifies periosteal progenitor cells critical for bone formation and fracture repair

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Bone research 2022年第1期10卷 122-136页

作者： Jiajia Xu Yiyun Wang Zhu Li Ye Tian Zhao Li Amy Lu Ching-Yun Hsu Stefano Negri Cammy Tang Robert J.Tower Carol Morris Aaron W.James Departments of Pathology Johns Hopkins UniversityBaltimoreMD 21205USA Departments of Orthopedics Johns Hopkins UniversityBaltimoreMD 21205USA Department of Oral and Maxillofacial Surgery School of StomatologyChina Medical UniversityShenyangLiaoningPR China

The outer coverings of the skeleton,which is also known as the periosteum,are arranged in concentric layers and act as a reservoir for tissue-specific bone *** cellular heterogeneity within this tissue depot is being increasingly ***,inducible PDGFRαreporter animals were found to mark a population of cells within the periosteum that act as a stem cell reservoir for periosteal appositional bone formation and fracture *** these processes,PDGFRαreporter^(+)progenitors give rise to Nestin+periosteal cells before becoming osteoblasts and *** diphtheria toxin-mediated ablation of PDGFRαreporter^(+)cells led to deficits in cortical bone formation during homeostasis and a diminutive hard callus during fracture *** ossicle transplantation,both mouse PDGFRαreporter^(+)periosteal cells and human Pdgfrα+periosteal progenitors expand,ossify,and recruit marrow to a greater extent than their counterpart periosteal cells,whereas PDGFRαreporter^(−)periosteal cells exhibit a predisposition to chondrogenesis in *** RNA sequencing identified enrichment of the secreted factors Fermt3 and Ptpn6 within PDGFRαreporter^(+)periosteal cells,which partly underlie the osteoblastogenic features of this cell population.

关键词： progenitor fracture reservoir

Von Hippel-Lindau tumor suppressor pathways&corresponding therapeutics in kidney cancer

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Journal of Genetics and Genomics 2021年第7期48卷 552-559页

作者： Maxwell Shulman Rachel Shi Qing Zhang Department of Pathology University of Texas Southwestern Medical CenterDallasTXUSA

The identification and application of the Von Hippel-Lindau(VHL)gene is a seminal breakthrough in kidney cancer *** and its protein p VHL are the root cause of most kidney cancers,and the cascading pathway below them is crucial for understanding hypoxia,in addition to the aforementioned tumorigenesis routes and *** reviewed the history and functions of VHL/pVHL and Hypoxia-inducible factor(HIF),their well-known activities under low-oxygen environments as an E3 ubiquitin ligase and as a transcription factor,respectively,as well as their non-canonical functions revealed ***,we discussed how their dysregulation promotes tumorigenesis:beginning with chromosome 3 p-arm(3p)loss/epigenetic methylation,followed by two-allele knockout,before the loss of complimentary tumor suppressor genes leads cells down predictable oncological *** different pathways can ultimately determine the grade,outcome,and severity of the deadliest genitourinary *** finished by investigating current and proposed schemes to therapeutically treat clear cell renal cell carcinoma(cc RCC)by manipulating the hypoxic pathway utilizing Vascular Endothelial Growth Factor(VEGF)inhibitors,mammalian target of rapamycin complex 1(mTORC1)inhibitors,small molecule HIF inhibitors,immune checkpoint blockade therapy,and synthetic lethality.

关键词： VHL HIF ccRCC Kidney cancer Hypoxia

Blood pressure-related white matter microstructural disintegrity and associated cognitive function impairment in asymptomatic adults

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Stroke & Vascular Neurology 2023年第5期8卷 358-367页

作者： Julián N Acosta Stefan P Haider Cyprien Rivier Audrey C Leasure Kevin N Sheth Guido J Falcone Seyedmehdi Payabvash Department of Neurology Yale School of MedicineNew HavenConnecticutUSA Department of Radiology and Biomedical Imaging Yale School of MedicineNew HavenConnecticutUSA Department of Otorhinolaryngology Ludwig Maximilians University MunichMunchenGermany

Background and objectives We aimed to investigate the white matter(WM)microstructural/cytostructural disintegrity patterns related to higher systolic blood pressure(SBP),and whether they mediate SBP effects on cognitive performance in middle-aged *** Using the UK Biobank study of community-dwelling volunteers aged 40-69 years,we included participants without a history of stroke,dementia,demyelinating disease or traumatic brain *** investigated the association of SBP with MRI diffusion metrics:fractional anisotropy(FA),mean diffusivity(MD),intracellular volume fraction(a measure of neurite density),isotropic(free)water volume fraction(ISOVF)and orientation dispersion across WM ***,we determined whether WM diffusion metrics mediated the effects of SBP on cognitive *** We analysed 31363 participants-mean age of 63.8 years(SD:7.7),and 16523(53%)*** SBP was associated with lower FA and neurite density,but higher MD and *** different WM tracts,diffusion metrics of the internal capsule anterior limb,external capsule,superior and posterior corona radiata were most affected by higher *** seven cognitive metrics,SBP levels were only associated with‘fluid intelligence’(adjusted p<0.001).In mediation analysis,the averaged FA of external capsule,internal capsule anterior limb and superior cerebellar peduncle mediated 13%,9%and 13%of SBP effects on fluid intelligence,while the averaged MD of external capsule,internal capsule anterior and posterior limbs,and superior corona radiata mediated 5%,7%,7%and 6%of SBP effects on fluid intelligence,*** Among asymptomatic adults,higher SBP is associated with pervasive WM microstructure disintegrity,partially due to reduced neuronal count,which appears to mediate SBP adverse effects on fluid *** metrics of select WM tracts,which are most reflective of SBP-related parenchymal damage and cognitive impairment,may serve as imaging biomarkers to

关键词： capsule Blood impairment

Hepatic transcriptome profiling reveals early signatures associated with disease transition from non-alcoholic steatosis to steatohepatitis

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Liver research 2022年第4期6卷 238-250页

作者： Nancy Magee Forkan Ahamed Natalie Eppler Elizabeth Jones Priyanka Ghosh Lily He Yuxia Zhang Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKSUSA Liver Center University of KansasKansas CityKSUSA

Background and aim:Non-alcoholic fatty liver disease(NAFLD)is becoming a leading cause of chronic liver disease *** molecular events that influence disease progression from non-alcoholic fatty liver(NAFL)to aggressive non-alcoholic steatohepatitis(NASH)remain incompletely understood,leading to lack of mechanism-based targeted treatment options for *** study aims to identify early signatures associated with disease progression from NAFL to NASH in mice and *** and methods:Male C57BL/6J mice were fed a high-fat,-cholesterol,and-fructose(HFCF)diet for up to 9 *** extent of steatosis,inflammation,and fibrosis was evaluated in liver *** RNA sequencing(RNA-seq)was conducted to determine liver transcriptomic ***:After being fed the HFCF diet,mice sequentially developed steatosis,early steatohepatitis,steatohepatitis with fibrosis,and eventually spontaneous liver *** RNA-seq revealed that the key signatures during steatosis progression to early steatohepatitis were pathways related to extracel-lular matrix organization and immune responses such as T cell migration,arginine biosynthesis,C-type lectin receptor signaling,and cytokine-cytokine receptor *** regulated by transcription factors forkhead box M1(FOXM1)and negative elongation factor complex member E(NELFE)were significantly altered during disease *** phenomenon was also observed in patients with NASH.

关键词： Liver Transcriptome Steatosis Inflammation Fibrosis Non-alcoholic steatohepatitis(NASH)

Chromatin and epigenetic regulation of the telomerase reverse transcriptase gene

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Protein & Cell 2010年第1期1卷 22-32页

作者： Jiyue Zhu Yuanjun Zhao Shuwen Wang Department of Cellular and Molecular Physiology Pennsylvania State University College of MedicineHersheyPA 17033USA

Telomerase expression and telomere maintenance are critical for long-term cell proliferation and survival,and they play important roles in development,aging,and *** evidence has indicated that regulation of the rate-limiting subunit of human telomerase reverse transcriptase gene(hTERT)is a complex process in normal cells and many cancer *** addition to a number of transcriptional activators and repressors,the chromatin environment and epigenetic status of the endogenous hTERT locus are also pivotal for its regulation in normal human somatic cells and in tumorigenesis.

关键词： telomerase transcriptional regulation chromatin epigenetic regulation cancer

MicroRNAs mediate therapeutic and preventive effects of natural agents in breast cancer

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Chinese Journal of Natural Medicines 2016年第12期14卷 881-887页

作者： LIANG Zhipin XI Yaguang Department of Genetics and Stanley S.Scott cancer Center Louisiana State University Health Sciences Center

MicroRNAs(miRNAs) are a set of non-coding small RNA molecules that play a critical role in regulation of protein coding genes in cells. Mi RNAs have been extensively studied as novel biomarkers, therapeutic targets, and new drugs in various human diseases. Breast cancer is a one of the leading tumor types significantly affecting women health worldwide. Over the past decade, a number of natural agents, such as paclitaxel and curcumin, have been applied for treatment and prevention of breast cancer due to their relatively low toxicity. However, the mechanisms of action have not been completely understood. Investigation on mi RNAs is able to potentially provide a novel insight into better understanding the anticancer activities of these natural products. Given that a single miRNA can target multiple genes, theoretically, those genes involved in a certain phenotype can be clustered with one or a few miRNAs. Therefore, pleiotropic activities of natural agents should be interpreted by interactions between selected miRNAs and their targets. In this review, we summarize the latest publications related to the alterations of mi RNAs by two natural agents(paclitaxel and curcumin) that are currently used in intervention of breast cancer, and conclude that the mechanism involving the regulation of miRNA expression is one of the keys to understand pleiotropic activities of natural agents.

关键词： MicroRNA Natural agents Breast cancer cancer prevention Therapeutics