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1.
Nat Commun ; 11(1): 5093, 2020 10 09.
Article in English | MEDLINE | ID: mdl-33037226

ABSTRACT

The mechanisms behind the ability of Plasmodium falciparum to evade host immune system are poorly understood and are a major roadblock in achieving malaria elimination. Here, we use integrative genomic profiling and a longitudinal pediatric cohort in Burkina Faso to demonstrate the role of post-transcriptional regulation in host immune response in malaria. We report a strong signature of miRNA expression differentiation associated with P. falciparum infection (127 out of 320 miRNAs, B-H FDR 5%) and parasitemia (72 miRNAs, B-H FDR 5%). Integrative miRNA-mRNA analysis implicates several infection-responsive miRNAs (e.g., miR-16-5p, miR-15a-5p and miR-181c-5p) promoting lymphocyte cell death. miRNA cis-eQTL analysis using whole-genome sequencing data identified 1,376 genetic variants associated with the expression of 34 miRNAs (B-H FDR 5%). We report a protective effect of rs114136945 minor allele on parasitemia mediated through miR-598-3p expression. These results highlight the impact of post-transcriptional regulation, immune cell death processes and host genetic regulatory control in malaria.


Subject(s)
Immune Evasion/genetics , Malaria, Falciparum/genetics , Malaria, Falciparum/immunology , MicroRNAs/genetics , Plasmodium falciparum/pathogenicity , Burkina Faso , Child , Child, Preschool , Gene Expression Regulation , Genome, Human , Humans , Longitudinal Studies , Parasitemia/genetics , Parasitemia/immunology , Plasmodium falciparum/immunology , Polymorphism, Single Nucleotide , Proto-Oncogene Proteins c-bcl-2/genetics , RNA, Messenger/genetics , Whole Genome Sequencing
2.
BMC Bioinformatics ; 21(1): 267, 2020 Jun 29.
Article in English | MEDLINE | ID: mdl-32600310

ABSTRACT

BACKGROUND: As high-throughput sequencing applications continue to evolve, the rapid growth in quantity and variety of sequence-based data calls for the development of new software libraries and tools for data analysis and visualization. Often, effective use of these tools requires computational skills beyond those of many researchers. To ease this computational barrier, we have created a dynamic web-based platform, NASQAR (Nucleic Acid SeQuence Analysis Resource). RESULTS: NASQAR offers a collection of custom and publicly available open-source web applications that make extensive use of a variety of R packages to provide interactive data analysis and visualization. The platform is publicly accessible at http://nasqar.abudhabi.nyu.edu/ . Open-source code is on GitHub at https://github.com/nasqar/NASQAR , and the system is also available as a Docker image at https://hub.docker.com/r/aymanm/nasqarall . NASQAR is a collaboration between the core bioinformatics teams of the NYU Abu Dhabi and NYU New York Centers for Genomics and Systems Biology. CONCLUSIONS: NASQAR empowers non-programming experts with a versatile and intuitive toolbox to easily and efficiently explore, analyze, and visualize their Transcriptomics data interactively. Popular tools for a variety of applications are currently available, including Transcriptome Data Preprocessing, RNA-seq Analysis (including Single-cell RNA-seq), Metagenomics, and Gene Enrichment.


Subject(s)
High-Throughput Nucleotide Sequencing/methods , Software , Gene Expression Profiling , Genomics , Internet , Metagenomics , RNA-Seq , User-Computer Interface
3.
FASEB J ; 32(3): 1296-1314, 2018 03.
Article in English | MEDLINE | ID: mdl-29101221

ABSTRACT

During differentiation and development, cell fate and identity are established by waves of genetic reprogramming. Although the mechanisms are largely unknown, during these events, dynamic chromatin reorganization is likely to ensure that multiple genes involved in the same cellular functions are coregulated, depending on the nuclear environment. In this study, using high-content screening of embryonic fibroblasts from a ß-actin knockout (KO) mouse, we found major chromatin rearrangements and changes in histone modifications, such as methylated histone (H)3-lysine-(K)9. Genome-wide H3K9 trimethylation-(Me)3 landscape changes correlate with gene up- and down-regulation in ß-actin KO cells. Mechanistically, we found loss of chromatin association by the Brahma-related gene ( Brg)/Brahma-associated factor (BAF) chromatin remodeling complex subunit Brg1 in the absence of ß-actin. This actin-dependent chromatin reorganization was concomitant with the up-regulation of sets of genes involved in angiogenesis, cytoskeletal organization, and myofibroblast features in ß-actin KO cells. Some of these genes and phenotypes were gained in a ß-actin dose-dependent manner. Moreover, reintroducing a nuclear localization signal-containing ß-actin in the knockout cells affected nuclear features and gene expression. Our results suggest that, by affecting the genome-wide organization of heterochromatin through the chromatin-binding activity of the BAF complex, ß-actin plays an essential role in the determination of gene expression programs and cellular identity.-Xie, X., Almuzzaini, B., Drou, N., Kremb, S., Yousif, A., Östlund Farrants, A.-K., Gunsalus, K., Percipalle, P. ß-Actin-dependent global chromatin organization and gene expression programs control cellular identity.


Subject(s)
Actins/physiology , Cellular Reprogramming/genetics , Chromatin Assembly and Disassembly/genetics , Embryo, Mammalian/metabolism , Fibroblasts/metabolism , Gene Expression Regulation, Developmental , Animals , Cell Differentiation , Embryo, Mammalian/cytology , Fibroblasts/cytology , Gene Expression Profiling , Gene Regulatory Networks , High-Throughput Nucleotide Sequencing , Mice , Mice, Knockout
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