New insights on human essential genes based on integrated analysis and the construction of the HEGIAP web-based platform

Abstract Essential genes are those whose loss of function compromises organism viability or results in profound loss of fitness. Recent gene-editing technologies have provided new opportunities to characterize essential genes. Here, we present an integrated analysis that comprehensively and systematically elucidates the genetic and regulatory characteristics of human essential genes. First, we found that essential genes act as ‘hubs’ in protein–protein interaction networks, chromatin structure and epigenetic modification. Second, essential genes represent conserved biological processes across species, although gene essentiality changes differently among species. Third, essential genes are important for cell development due to their discriminate transcription activity in embryo development and oncogenesis. In addition, we developed an interactive web server, the Human Essential Genes Interactive Analysis Platform (http://sysomics.com/HEGIAP/), which integrates abundant analytical tools to enable global, multidimensional interpretation of gene essentiality. Our study provides new insights that improve the understanding of human essential genes.

[1]  Jing-Dong J Han,et al.  Evolution of Alu elements toward enhancers. , 2014, Cell reports.

[2]  Donavan T. Cheng,et al.  Mutational Landscape of Metastatic Cancer Revealed from Prospective Clinical Sequencing of 10,000 Patients , 2017, Nature Medicine.

[3]  Ronald W. Davis,et al.  Functional profiling of the Saccharomyces cerevisiae genome , 2002, Nature.

[4]  Antti Häkkinen,et al.  Effects of gene length on the dynamics of gene expression , 2012, Comput. Biol. Chem..

[5]  P. Cook,et al.  Transcription factories: genome organization and gene regulation. , 2013, Chemical reviews.

[6]  David Tamborero,et al.  OncodriveROLE classifies cancer driver genes in loss of function and activating mode of action , 2014, Bioinform..

[7]  Jing Liang,et al.  Chromatin architecture reorganization during stem cell differentiation , 2015, Nature.

[8]  Alexander F Schier,et al.  The Maternal-Zygotic Transition: Death and Birth of RNAs , 2007, Science.

[9]  Steve D. M. Brown,et al.  High-throughput discovery of novel developmental phenotypes , 2017 .

[10]  G. Superti-Furga,et al.  Gene essentiality and synthetic lethality in haploid human cells , 2015, Science.

[11]  Jianzhi Zhang,et al.  Null mutations in human and mouse orthologs frequently result in different phenotypes , 2008, Proceedings of the National Academy of Sciences.

[12]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[13]  W. Sung,et al.  Chromatin connectivity maps reveal dynamic promoter–enhancer long-range associations , 2013, Nature.

[14]  Jeffry D. Sander,et al.  CRISPR-Cas systems for editing, regulating and targeting genomes , 2014, Nature Biotechnology.

[15]  Marco Foiani,et al.  Maintaining genome stability at the replication fork , 2010, Nature Reviews Molecular Cell Biology.

[16]  Eric S. Lander,et al.  Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras , 2017, Cell.

[17]  T. Mikkelsen,et al.  The NIH Roadmap Epigenomics Mapping Consortium , 2010, Nature Biotechnology.

[18]  Giovanni Scardoni,et al.  Analyzing biological network parameters with CentiScaPe , 2009, Bioinform..

[19]  Eugene V Koonin,et al.  The universal distribution of evolutionary rates of genes and distinct characteristics of eukaryotic genes of different apparent ages , 2009, Proceedings of the National Academy of Sciences.

[20]  Devin K. Schweppe,et al.  Architecture of the human interactome defines protein communities and disease networks , 2017, Nature.

[21]  Piero Fariselli,et al.  eSLDB: eukaryotic subcellular localization database , 2006, Nucleic Acids Res..

[22]  Wei Wu,et al.  NONCODE 2016: an informative and valuable data source of long non-coding RNAs , 2015, Nucleic Acids Res..

[23]  P. Laird.  Principles and challenges of genome-wide DNA methylation analysis , 2010, Nature Reviews Genetics.

[24]  A. Tanay,et al.  Single cell Hi-C reveals cell-to-cell variability in chromosome structure , 2013, Nature.

[25]  Rick Stevens,et al.  Essential genes on metabolic maps. , 2006, Current opinion in biotechnology.

[26]  Peter H. L. Krijger,et al.  Regulation of disease-associated gene expression in the 3D genome , 2016, Nature Reviews Molecular Cell Biology.

[27]  Bradley E. Bernstein,et al.  Genome-wide Chromatin State Transitions Associated with Developmental and Environmental Cues , 2013, Cell.

[28]  Yan Lin,et al.  DEG 10, an update of the database of essential genes that includes both protein-coding genes and noncoding genomic elements , 2013, Nucleic Acids Res..

[29]  B. Garvik,et al.  Principles for the Buffering of Genetic Variation , 2001, Science.

[30]  David Haussler,et al.  Integration of the cytogenetic map with the draft human genome sequence. , 2003, Human molecular genetics.

[31]  E V Koonin,et al.  How many genes can make a cell: the minimal-gene-set concept. , 2000, Annual review of genomics and human genetics.

[32]  David Z. Chen,et al.  Architecture of the human regulatory network derived from ENCODE data , 2012, Nature.

[33]  Michael Q. Zhang,et al.  Epigenomic Analysis of Multilineage Differentiation of Human Embryonic Stem Cells , 2013, Cell.

[34]  Eugene V. Koonin,et al.  Comparative genomics, minimal gene-sets and the last universal common ancestor , 2003, Nature Reviews Microbiology.

[35]  Eric S. Lander,et al.  Genomic Maps and Comparative Analysis of Histone Modifications in Human and Mouse , 2005, Cell.

[36]  J. Mattick.  The Genetic Signatures of Noncoding RNAs , 2009, PLoS genetics.

[37]  J. Häsler,et al.  Alu elements as regulators of gene expression , 2006, Nucleic acids research.

[38]  Zhang Zhang,et al.  Old genes experience stronger translational selection than young genes. , 2016, Gene.

[39]  A. Tanay,et al.  Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome , 2012, Cell.

[40]  Amandeep Kaur,et al.  Essential gene identification and drug target prioritization in Leishmania species. , 2014, Molecular bioSystems.

[41]  Gary D. Bader,et al.  An automated method for finding molecular complexes in large protein interaction networks , 2003, BMC Bioinformatics.

[42]  Craig M. Crews,et al.  Induced protein degradation: an emerging drug discovery paradigm , 2016, Nature Reviews Drug Discovery.

[43]  Norman Pavelka,et al.  Emerging and evolving concepts in gene essentiality , 2017, Nature Reviews Genetics.

[44]  David S. Wishart,et al.  DrugBank 4.0: shedding new light on drug metabolism , 2013, Nucleic Acids Res..

[45]  Terry Roemer,et al.  Essential Gene Identification and Drug Target Prioritization in Aspergillus fumigatus , 2007, PLoS pathogens.

[46]  C. A. Hutchinson,et al.  Genome transplantation in bacteria: changing one species to another. , 2007, Nature Reviews Microbiology.

[47]  C. Cañestro,et al.  Evolution by gene loss , 2016, Nature Reviews Genetics.

[48]  J. Shapiro,et al.  Why repetitive DNA is essential to genome function , 2005, Biological reviews of the Cambridge Philosophical Society.

[49]  B. Tabak,et al.  Higher-Order Inter-chromosomal Hubs Shape 3D Genome Organization in the Nucleus , 2018, Cell.

[50]  Benjamin J. Raphael,et al.  Mutational landscape and significance across 12 major cancer types , 2013, Nature.

[51]  D. Zilberman,et al.  Genome-Wide Evolutionary Analysis of Eukaryotic DNA Methylation , 2010, Science.

[52]  David L. Adelson,et al.  Evolutionary conservation and functional roles of ncRNA , 2012, Front. Gene..

[53]  Michael Y. Galperin,et al.  Searching for drug targets in microbial genomes. , 1999, Current opinion in biotechnology.

[54]  Samantha A. Morris,et al.  Making a firm decision: multifaceted regulation of cell fate in the early mouse embryo , 2009, Nature Reviews Genetics.

[55]  Christian von Mering,et al.  Cell-wide analysis of protein thermal unfolding reveals determinants of thermostability , 2017, Science.

[56]  Judith A. Blake,et al.  Mouse Genome Database (MGD)-2017: community knowledge resource for the laboratory mouse , 2016, Nucleic Acids Res..

[57]  Raymond K. Auerbach,et al.  Extensive Promoter-Centered Chromatin Interactions Provide a Topological Basis for Transcription Regulation , 2012, Cell.

[58]  J. Sedat,et al.  Spatial partitioning of the regulatory landscape of the X-inactivation centre , 2012, Nature.

[59]  K. Kinzler,et al.  Cancer Genome Landscapes , 2013, Science.

[60]  Howard Y. Chang,et al.  NONCODING RNA: CRISPRi‐based genome‐scale identification of functional long noncoding RNA loci in human cells , 2017 .

[61]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[62]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[63]  M. Albà,et al.  Inverse relationship between evolutionary rate and age of mammalian genes. , 2005, Molecular biology and evolution.

[64]  Zhaolei Zhang,et al.  Enrichment analysis of Alu elements with different spatial chromatin proximity in the human genome , 2016, Protein & Cell.

[65]  Chee Seng Chan,et al.  CTCF-Mediated Functional Chromatin Interactome in Pluripotent Cells , 2011, Nature Genetics.

[66]  Hendrik G. Stunnenberg,et al.  The interplay of epigenetic marks during stem cell differentiation and development , 2017, Nature Reviews Genetics.

[67]  Wei Xie,et al.  The landscape of accessible chromatin in mammalian preimplantation embryos , 2016, Nature.

[68]  Davide Heller,et al.  STRING v10: protein–protein interaction networks, integrated over the tree of life , 2014, Nucleic Acids Res..

[69]  E. Lander,et al.  Identification and characterization of essential genes in the human genome , 2015, Science.

[70]  S. Gabriel,et al.  Discovery and saturation analysis of cancer genes across 21 tumor types , 2014, Nature.

[71]  Anthony D. Schmitt,et al.  A Compendium of Chromatin Contact Maps Reveals Spatially Active Regions in the Human Genome. , 2016, Cell reports.

[72]  H. Bussey,et al.  Large‐scale essential gene identification in Candida albicans and applications to antifungal drug discovery , 2003, Molecular microbiology.

[73]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing , 2002, Science.

[74]  Peer Bork,et al.  Younger Genes Are Less Likely to Be Essential than Older Genes, and Duplicates Are Less Likely to Be Essential than Singletons of the Same Age , 2012, Molecular biology and evolution.

[75]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[76]  Yan Li,et al.  A high-resolution map of three-dimensional chromatin interactome in human cells , 2013, Nature.

[77]  Qikai Xu,et al.  Global Protein Stability Profiling in Mammalian Cells , 2008, Science.

[78]  Yao Lu,et al.  Predicting essential genes for identifying potential drug targets in Aspergillus fumigatus , 2014, Comput. Biol. Chem..

[79]  Peer Bork,et al.  OGEE: an online gene essentiality database , 2011, Nucleic Acids Res..

[80]  Feng Gao,et al.  Protein Localization Analysis of Essential Genes in Prokaryotes , 2014, Scientific Reports.

[81]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[82]  R. Schultz,et al.  The molecular foundations of the maternal to zygotic transition in the preimplantation embryo. , 2002, Human reproduction update.

[83]  Y. Zhang,et al.  Allelic reprogramming of the histone modification H3K4me3 in early mammalian development , 2016, Nature.

[84]  E. Lander,et al.  Development and Applications of CRISPR-Cas9 for Genome Engineering , 2014, Cell.

[85]  Feng Zhang,et al.  Identification of essential genes for cancer immunotherapy , 2017, Nature.

[86]  M. Johnston,et al.  The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methylation. , 2003, Molecular cell.

[87]  D. Durocher,et al.  High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities , 2015, Cell.

[88]  Apiwat Mutirangura,et al.  Alu siRNA to increase Alu element methylation and prevent DNA damage. , 2018, Epigenomics.

[89]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[90]  Adam P. Rosebrock,et al.  A global genetic interaction network maps a wiring diagram of cellular function , 2016, Science.