Regulatory elements can be essential for maintaining broad chromatin organization and cell viability

Increasing evidence shows that promoters and enhancers could be related to 3D chromatin structure, thus affecting cellular functions. Except for functioning through the canonical chromatin loops formed by promoters and enhancers, their roles in maintaining broad chromatin organization have not been well studied. Here, we focused on the active promoters/enhancers (referred to as hotspots) predicted to form many 3D contacts with other active promoters/enhancers, and identified dozens of loci critical for cell survival. While the essentiality of hotspots is not resulted from their association with essential genes, deletion of an essential hotspot could lead to change of broad chromatin organization and expressions of distal genes. We demonstrated that multiple affected genes that are individually non-essential could have synergistic effects to cause cell death.

[1]  Bo Ding,et al.  Noncoding loci without epigenomic signals can be essential for maintaining global chromatin organization and cell viability , 2021, Science advances.

[2]  William Stafford Noble,et al.  HiCRep.py: fast comparison of Hi-C contact matrices in Python , 2020, bioRxiv.

[3]  Rushad Pavri,et al.  Spt5-mediated enhancer transcription directly couples enhancer activation with physical promoter interaction , 2020, Nature Genetics.

[4]  Michael P Snyder,et al.  Mitigation of off-target toxicity in CRISPR-Cas9 screens for essential non-coding elements , 2019, Nature Communications.

[5]  Steven L Salzberg,et al.  Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype , 2019, Nature Biotechnology.

[6]  Stefan Schoenfelder,et al.  Long-range enhancer–promoter contacts in gene expression control , 2019, Nature Reviews Genetics.

[7]  Michael Wainberg,et al.  Identification and mitigation of pervasive off-target activity in CRISPR-Cas9 screens for essential non-coding elements , 2019, bioRxiv.

[8]  Ying Liu,et al.  Genome-wide screening for functional long noncoding RNAs in human cells by Cas9 targeting of splice sites , 2018, Nature Biotechnology.

[9]  E. Furlong,et al.  Developmental enhancers and chromosome topology , 2018, Science.

[10]  Max W. Chang,et al.  Transcription Elongation Can Affect Genome 3D Structure , 2018, Cell.

[11]  Mikhail G. Dozmorov,et al.  HiCcompare: an R-package for joint normalization and comparison of HI-C datasets , 2018, BMC Bioinformatics.

[12]  Fidel Ramírez,et al.  Galaxy HiCExplorer: a web server for reproducible Hi-C data analysis, quality control and visualization , 2018, Nucleic Acids Res..

[13]  J. Lis,et al.  Enhancer transcription: what, where, when, and why? , 2018, Genes & development.

[14]  William Stafford Noble,et al.  HiCRep: assessing the reproducibility of Hi-C data using a stratum-adjusted correlation coefficient , 2017, bioRxiv.

[15]  Gaelen T. Hess,et al.  Genome-scale measurement of off-target activity using Cas9 toxicity in high-throughput screens , 2017, Nature Communications.

[16]  Jonathan M. Cairns,et al.  Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation. , 2017, Molecular cell.

[17]  Kin Chung Lam,et al.  High-resolution TADs reveal DNA sequences underlying genome organization in flies , 2017, Nature Communications.

[18]  R. Young,et al.  A Phase Separation Model for Transcriptional Control , 2017, Cell.

[19]  Yuri Pritykin,et al.  GuideScan software for improved single and paired CRISPR guide RNA design , 2017, Nature Biotechnology.

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

[21]  Andrew J. Hill,et al.  Single-cell mRNA quantification and differential analysis with Census , 2017, Nature Methods.

[22]  Minoru Kanehisa,et al.  KEGG: new perspectives on genomes, pathways, diseases and drugs , 2016, Nucleic Acids Res..

[23]  R. Tjian,et al.  CTCF and cohesin regulate chromatin loop stability with distinct dynamics , 2016, bioRxiv.

[24]  Zhongzheng Cao,et al.  Genome-scale deletion screening of human long non-coding RNAs using a paired-guide RNA CRISPR–Cas9 library , 2016, Nature Biotechnology.

[25]  J. Wysocka,et al.  Ever-Changing Landscapes: Transcriptional Enhancers in Development and Evolution , 2016, Cell.

[26]  Max A. Horlbeck,et al.  Compact and highly active next-generation libraries for CRISPR-mediated gene repression and activation , 2016, eLife.

[27]  Jeffrey T Leek,et al.  Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown , 2016, Nature Protocols.

[28]  Joshua M. Korn,et al.  CRISPR Screens Provide a Comprehensive Assessment of Cancer Vulnerabilities but Generate False-Positive Hits for Highly Amplified Genomic Regions. , 2016, Cancer discovery.

[29]  T. Golub,et al.  Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting. , 2016, Cancer discovery.

[30]  R. Tjian,et al.  A dynamic mode of mitotic bookmarking by transcription factors , 2016, bioRxiv.

[31]  Jure Leskovec,et al.  Higher-order organization of complex networks , 2016, Science.

[32]  Neva C. Durand,et al.  Juicer Provides a One-Click System for Analyzing Loop-Resolution Hi-C Experiments. , 2016, Cell systems.

[33]  J. Leskovec,et al.  SNAP: A General-Purpose Network Analysis and Graph-Mining Library , 2016, ACM Trans. Intell. Syst. Technol..

[34]  Wei Wang,et al.  Constructing 3D interaction maps from 1D epigenomes , 2016, Nature Communications.

[35]  L. Chin,et al.  HiCPlotter integrates genomic data with interaction matrices , 2015, Genome Biology.

[36]  Eric S. Lander,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2015, Cell.

[37]  Marc Timme,et al.  Collective Relaxation Dynamics of Small-World Networks , 2015, Physical review. E, Statistical, nonlinear, and soft matter physics.

[38]  Evan Z. Macosko,et al.  Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets , 2015, Cell.

[39]  A. Pombo,et al.  Three-dimensional genome architecture: players and mechanisms , 2015, Nature Reviews Molecular Cell Biology.

[40]  Steven L Salzberg,et al.  HISAT: a fast spliced aligner with low memory requirements , 2015, Nature Methods.

[41]  S. Salzberg,et al.  StringTie enables improved reconstruction of a transcriptome from RNA-seq reads , 2015, Nature Biotechnology.

[42]  Jong-il Kim,et al.  Digenome-seq: genome-wide profiling of CRISPR-Cas9 off-target effects in human cells , 2015, Nature Methods.

[43]  Michael Q. Zhang,et al.  Integrative analysis of 111 reference human epigenomes , 2015, Nature.

[44]  Wesley R. Legant,et al.  3D imaging of Sox2 enhancer clusters in embryonic stem cells , 2014, eLife.

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

[46]  H. Bussemaker,et al.  In search of the determinants of enhancer-promoter interaction specificity. , 2014, Trends in cell biology.

[47]  Kun Zhang,et al.  Whole-genome sequencing analysis reveals high specificity of CRISPR/Cas9 and TALEN-based genome editing in human iPSCs. , 2014, Cell stem cell.

[48]  A. Dean,et al.  Enhancer function: mechanistic and genome-wide insights come together. , 2014, Molecular cell.

[49]  Wolfgang Huber,et al.  Enhancer loops appear stable during development and are associated with paused polymerase , 2014, Nature.

[50]  Cole Trapnell,et al.  The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells , 2014, Nature Biotechnology.

[51]  T. Meehan,et al.  An atlas of active enhancers across human cell types and tissues , 2014, Nature.

[52]  W. Bickmore,et al.  Flashing a Light on the Spatial Organization of Transcription , 2013, Science.

[53]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[54]  J. Dekker,et al.  The long-range interaction landscape of gene promoters , 2012, Nature.

[55]  Lee E. Edsall,et al.  A map of the cis-regulatory sequences in the mouse genome , 2012, Nature.

[56]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[57]  P. Gregory,et al.  Controlling Long-Range Genomic Interactions at a Native Locus by Targeted Tethering of a Looping Factor , 2012, Cell.

[58]  K. Zhao,et al.  Characterization of genome-wide enhancer-promoter interactions reveals co-expression of interacting genes and modes of higher order chromatin organization , 2012, Cell Research.

[59]  Timothy J. Durham,et al.  "Systematic" , 1966, Comput. J..

[60]  Reuven Cohen,et al.  Complex Networks: Structure, Robustness and Function , 2010 .

[61]  M. Newman,et al.  Finding community structure in very large networks. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[62]  D. Dorsett,et al.  Chip, a widely expressed chromosomal protein required for segmentation and activity of a remote wing margin enhancer in Drosophila. , 1997, Genes & development.

[63]  D. Tuan,et al.  Transcription of the HS2 enhancer toward a cis-linked gene is independent of the orientation, position, and distance of the enhancer relative to the gene , 1997, Molecular and cellular biology.

[64]  R. W. Morris,et al.  The Wilcoxon rank sum test , 1976 .

[65]  W. W. Ball,et al.  Mathematical Recreations and Essays , 1905, Nature.