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| Open AccessTFvelo: gene regulation inspired RNA velocity estimation
Most RNA velocity models extract dynamics from the phase delay between unspliced and spliced mRNA for each gene. Here, authors propose TFvelo, broadening RNA velocity beyond splicing information to include gene regulation. TFvelo accurately models genes dynamics and infers cell pseudo-time from RNA abundance data.
- Jiachen Li
- , Xiaoyong Pan
- & Hong-Bin Shen
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Article
| Open AccessPredicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing
A profibrotic, proinflammatory kidney cell population has been identified as a driver of chronic kidney disease. Here, authors generate a human kidney single cell multiomic dataset and apply a regularised regression approach to identify transcription factors underpinning this cell population.
- Nicolas Ledru
- , Parker C. Wilson
- & Benjamin D. Humphreys
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Article
| Open AccessHaplotype-aware modeling of cis-regulatory effects highlights the gaps remaining in eQTL data
Genetic variants that influence gene expression play a major role in human phenotypic variability and disease susceptibility. Here, the authors introduce a computational method to estimate the regulatory effect size in genes with multiple conditionally independent regulatory variants.
- Nava Ehsan
- , Bence M. Kotis
- & Pejman Mohammadi
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| Open AccessMarsGT: Multi-omics analysis for rare population inference using single-cell graph transformer
Identifying rare cell populations is key to understanding cancer progression and response to therapy. Here, authors introduce MarsGT, an end-to-end deep learning model for rare cell population identification from scMulti-omics data.
- Xiaoying Wang
- , Maoteng Duan
- & Qin Ma
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Article
| Open AccessGenome-resolved metatranscriptomics reveals conserved root colonization determinants in a synthetic microbiota
The identification of processes activated by specific microbes during microbiota colonization of plant roots is hampered by technical issues in metatranscriptomics. Here, Vannier et al. colonized germ-free plants with a defined root microbiota comprising over 100 microbial isolates, and addressed those issues in various ways to identify strain-specific processes as well as common gene sets activated by microbes during root colonization.
- Nathan Vannier
- , Fantin Mesny
- & Stéphane Hacquard
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| Open AccessTranscriptional responses of cancer cells to heat shock-inducing stimuli involve amplification of robust HSF1 binding
The authors compare the heat shock response between different cell lines and stimuli and reveal the genome-wide binding of its master transcription factor HSF1 as a platform for context-specific transcription activation.
- Sayantani Ghosh Dastidar
- , Bony De Kumar
- & Sergei Nechaev
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Article
| Open AccessCamoTSS: analysis of alternative transcription start sites for cellular phenotypes and regulatory patterns from 5' scRNA-seq data
Five-prime single-cell RNA-seq, especially the read 1, has precise capture of transcription start sites (TSS), but such information is often overlooked. Here, authors present a computational method suite, CamoTSS, to precisely identify TSS and quantify its expression, enabling effective detection of alternative TSS usage in different biological processes.
- Ruiyan Hou
- , Chung-Chau Hon
- & Yuanhua Huang
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Article
| Open AccessRewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication
The integration of transcriptomics and epigenomics data helps to better understand the regulatory and topological changes in glioblastoma subtypes. Here, the authors map the promoter-enhancer interactome and regulatory landscape and show changes in promoter-enhancer interactions, chromatin accessibility, and redistribution of histone marks across four glioblastoma subtypes.
- Chaitali Chakraborty
- , Itzel Nissen
- & Silvia Remeseiro
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Article
| Open AccessBile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides
Wang et al. clarify the regional heterogeneity of intestinal AMPs and identify that chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs.
- Yue Wang
- , Yanbo Yu
- & Yanqing Li
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Article
| Open AccessIntegrative analysis of transcriptome dynamics during human craniofacial development identifies candidate disease genes
Craniofacial disorders are among the most common congenital defects. Here, the authors examined the genetic causes of non-syndromic craniofacial disorders during human development through analysis of gene expression and epigenomics.
- Tara N. Yankee
- , Sungryong Oh
- & Justin Cotney
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Article
| Open AccessModelling genetic stability in engineered cell populations
Predicting the evolution of engineered cell populations is an increasingly popular topic in biotechnology. Here the authors build a model that explores evolution in engineered cell populations which can generate hypotheses that could lead to important insights into strategies for assessing and mitigating the effects of evolution.
- Duncan Ingram
- & Guy-Bart Stan
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Article
| Open AccessInference of cell type-specific gene regulatory networks on cell lineages from single cell omic datasets
Cell type-specific gene expression patterns are outputs of transcriptional gene regulatory networks (GRNs) that connect transcription factors and signaling proteins to target genes. Here, the authors present single-cell Multi-Task Network Inference (scMTNI), a multi-task learning framework to infer cell type-specific GRN dynamics from scRNA-seq and scATAC-seq datasets collected for diverse cell fate specification trajectories.
- Shilu Zhang
- , Saptarshi Pyne
- & Sushmita Roy
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Article
| Open AccessWound infiltrating adipocytes are not myofibroblasts
Adipocyte plasticity during injury repair is debated. Here, the authors find that injury causes temporary adipocyte migration, but without lineage conversion to myofibroblasts. Distinct migration patterns, transcriptomics and ECM depositions indicate that adipocytes, unlike fibroblasts, do not contribute to fibrotic scars.
- Shruthi Kalgudde Gopal
- , Ruoxuan Dai
- & Yuval Rinkevich
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Article
| Open AccessSingle-cell RNA-seq uncovers dynamic processes orchestrated by RNA-binding protein DDX43 in chromatin remodeling during spermiogenesis
Germ cells undergo dramatic chromatin and transcriptomic changes during spermatogenesis, though how this is controlled is not well established. Here they show that RNA-binding protein DDX43 directs the spermatid differentiation trajectory and regulates chromatin remodeling in spermiogenesis, which is partially mediated by its target gene Elfn2.
- Huanhuan Tan
- , Weixu Wang
- & Ke Zheng
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Article
| Open AccessTranscription factor binding site orientation and order are major drivers of gene regulatory activity
Gene regulatory grammar remains difficult to decipher, hindering our ability to link genotype to phenotype. Here they use massively parallel reporter assays to test over 200,000 synthetic sequences, finding that transcription factor binding site order and orientation have a major effect on gene regulatory activity.
- Ilias Georgakopoulos-Soares
- , Chengyu Deng
- & Nadav Ahituv
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| Open AccessSingle-cell biological network inference using a heterogeneous graph transformer
Single-cell multi-omics and deep learning could lead to the inference of biological networks across specific cell types. Here, the authors develop DeepMAPS, a deep learning, graph-based approach for cell-type specific network inference from single-cell multi-omics data that is tested on healthy and tumour tissue datasets.
- Anjun Ma
- , Xiaoying Wang
- & Qin Ma
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Article
| Open AccessEpigenetic and transcriptional regulations prime cell fate before division during human pluripotent stem cell differentiation
Many stem cells exhibit cell division coupled to differentiation, though the changes occurring between consecutive cell divisions have been difficult to study. Here they use synchronized hPSC culture to show that production of transcription factors and epigenetic changes are linked with cell division timing.
- Pedro Madrigal
- , Siwei Deng
- & Siim Pauklin
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Article
| Open AccessComparative analysis of genome-scale, base-resolution DNA methylation profiles across 580 animal species
DNA methylation is involved in regulatory processes throughout the animal kingdom. Here, the authors map DNA methylation in 535 vertebrates and 45 invertebrates, establishing a reference dataset for cross-species analysis and exploring epigenetic variation across vertebrate evolution.
- Johanna Klughammer
- , Daria Romanovskaia
- & Christoph Bock
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Article
| Open AccessSpatial transcriptomics landscape of lesions from non-communicable inflammatory skin diseases
Inflammatory skin diseases involve various different immune cells in a localised area. Here the authors use spatial transcriptomics to show that disease relevant cytokine transcripts are sparsely expressed in lesional skin, yet are associated with local amplification cascades that promote skin inflammation.
- A. Schäbitz
- , C. Hillig
- & S. Eyerich
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| Open AccessBroad misappropriation of developmental splicing profile by cancer in multiple organs
The molecular mechanisms underlying the overlap between oncogenic and embryonic development remain to be explored. Here, the authors use temporal transcriptomic data during development in multiple human organs and suggest the involvement of alternative splicing events, splicing factors, and transcription factors.
- Arashdeep Singh
- , Arati Rajeevan
- & Sridhar Hannenhalli
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Article
| Open AccessAn alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons
Krach et al. dissect the molecular mechanism of the alternative splicing modulator Branaplam in Huntington’s disease. They show that the drug lowers mutant HTT protein levels and ameliorates alternative splicing pathology in an iPSC disease model.
- Florian Krach
- , Judith Stemick
- & Juergen Winkler
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Article
| Open AccessSystems-biology analysis of rheumatoid arthritis fibroblast-like synoviocytes implicates cell line-specific transcription factor function
Fibroblast-like synoviocytes (FLS) are used as a model of rheumatoid arthritis synoviocytes, although cell lines derived from individual patients can have heterogeneous biology. Here the authors use a Taiji computational approach to analyze gene expression, chromatin accessibility and functional differences between individual patient-derived RA FLS lines.
- Richard I. Ainsworth
- , Deepa Hammaker
- & Wei Wang
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Article
| Open AccessHOXA9 has the hallmarks of a biological switch with implications in blood cancers
HOXA9 plays an important role in acute myeloid leukaemia (AML), but its relevance for other blood malignancies is unclear. Here, the authors show that HOXA9 has a binary switch function that can clinically stratify AML patients, and model how the interactions with JAK2, TET2 and NOTCH impact myeloproliferative neoplasms.
- Laure Talarmain
- , Matthew A. Clarke
- & Benjamin A. Hall
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Article
| Open AccessDiverse cell-specific patterns of alternative polyadenylation in Drosophila
Single cell data provides cellular resolution on gene expression, but is rarely mined for isoforms. Analysis of 3' isoforms across ~250 Drosophila cell types reveals the cellular bases for numerous tissue-specific 3' programs, identifies new 3' programs, and nominates candidate trans-acting factors
- Seungjae Lee
- , Yen-Chung Chen
- & Eric C. Lai
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Article
| Open AccessMultimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression
Diabetic kidney disease leads to changes in glucose metabolism and inflammation. Here the authors use multimodal single cell sequencing to show that this disease leads to reduced accessibility of glucocorticoid receptor binding sites in the proximal tubule and increased gluconeogenesis.
- Parker C. Wilson
- , Yoshiharu Muto
- & Benjamin D. Humphreys
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Article
| Open AccessTemporally restricted activation of IFNβ signaling underlies response to immune checkpoint therapy in mice
Immune checkpoint blockade (ICB) is partially successful as a cancer therapy. Here using mouse models, the authors transcriptionally monitor responding and non-responding tumours showing that responding tumours were associated with transient IFN-β signalling which could promote the anti-tumour response.
- Rachael M. Zemek
- , Wee Loong Chin
- & W. Joost Lesterhuis
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Article
| Open AccessTranscriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration
Age-related macular degeneration (AMD) is a leading cause of vision loss, and there is no approved treatment for AMD with geographic atrophy. Here, the authors used transcriptomic and proteomic analyses of patient induced pluripotent stem cell-derived retinal pigment epithelium to better understand disease mechanisms.
- Anne Senabouth
- , Maciej Daniszewski
- & Alice Pébay
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Article
| Open AccessAggregative trans-eQTL analysis detects trait-specific target gene sets in whole blood
Large-scale genetic association studies have identified many trait-associated variants that influence gene expression. Here, the authors present ARCHIE, a tool for identifying sets of genes whose regulation may be related to specific complex traits.
- Diptavo Dutta
- , Yuan He
- & Nilanjan Chatterjee
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| Open AccessA multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer
Super-enhancers and their associated transcription factor networks have been shown to influence ovarian cancer biology. Here, based on an integrated set of genomic and epigenomic datasets, the authors identify clinically relevant super-enhancers amplified in ovarian cancer patients and functionally validate their activity.
- Michael R. Kelly
- , Kamila Wisniewska
- & Hector L. Franco
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Article
| Open AccessSingle-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration
After acute injury, kidneys either successfully repair/regenerate or become fibrotic. Here the authors use scRNA-seq to study adaptive/maladaptive kidney regeneration and identify proinflammatory/fibrotic proximal tubule cells with pharmacologically targetable pyroptosis/ferroptosis signatures.
- Michael S. Balzer
- , Tomohito Doke
- & Katalin Susztak
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Article
| Open AccessA hexa-species transcriptome atlas of mammalian embryogenesis delineates metabolic regulation across three different implantation modes
Mammalian embryogenesis relies on glycolysis and oxidative phosphorylation, but understanding of the dynamics of metabolic regulation in the postimplantation embryo in vivo remains elusive. Here the authors compile single-cell embryo profiling data in six mammalian species and reveal a conserved metabolic programme despite different implantation modes.
- Anna Malkowska
- , Christopher Penfold
- & Thorsten E. Boroviak
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Article
| Open AccessNuclear oligo hashing improves differential analysis of single-cell RNA-seq
Using spike-in controls with current single cell RNA-seq platforms remains a challenge. Here, the authors use a mixture of short, unmodified DNA oligos as a normalization standard for sci-RNAseq to improve the detection of global transcriptome changes.
- Hyeon-Jin Kim
- , Greg Booth
- & Cole Trapnell
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Article
| Open AccessMYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets
The role of MYC in transcriptional reprogramming in prostate cancer remains poorly characterized. Here, MYC overexpression antagonizes the canonical AR transcriptional program leading to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.
- Xintao Qiu
- , Nadia Boufaied
- & David P. Labbé
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Article
| Open AccessA hierarchy of biomolecular proportional-integral-derivative feedback controllers for robust perfect adaptation and dynamic performance
The design of feedback biomolecular controllers is essential to synthetically regulate biological processes in a robust and timely fashion. Here the authors introduce a wide array of biomolecular Proportional-Integral-Derivative (PID) controllers that are capable of enhancing stability and dynamic performance, and also reducing stochastic noise.
- Maurice Filo
- , Sant Kumar
- & Mustafa Khammash
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Article
| Open AccessA single-cell analysis of breast cancer cell lines to study tumour heterogeneity and drug response
The impact of tumour heterogeneity on drug response in breast cancer is not fully understood. Here, the authors characterise cell lines from all main breast cancer subtypes using single-cell RNA-seq and train a deconvolution algorithm to predict drug responses in heterogeneous tumour cell populations.
- G. Gambardella
- , G. Viscido
- & D. di Bernardo
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Article
| Open AccessPluripotency factors determine gene expression repertoire at zygotic genome activation
Zygotic genome activation in zebrafish relies on pluripotency transcription factors Pou5f3 and Sox19b. Here the authors investigate how these factors interact in vivo by analyzing the changes in chromatin state and time-resolved transcription in Pou5f3 and Sox19b single and double mutant embryos.
- Meijiang Gao
- , Marina Veil
- & Daria Onichtchouk
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Article
| Open AccessMapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities
The molecular landscape of breast cancer brain metastases (BCBM) is still understudied, especially for different breast cancer subtypes. Here, the authors characterise subtype-specific BCBMs using genomics and transcriptomics and identify homologous recombination deficiency as a key therapeutic vulnerability.
- Nicola Cosgrove
- , Damir Varešlija
- & Leonie S. Young
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Article
| Open AccessTissue-specific multi-omics analysis of atrial fibrillation
Numerous disease-associated variants have been described in GWAS for atrial fibrillation. Here the authors integrate omics data to investigate the consequences of genetic variants for transcript and protein levels in the atrium of the human heart. With this multi-omics approach, authors reveal the regulatory network underlying atrial fibrillation and provide a resource for cardiac gene prioritization.
- Ines Assum
- , Julia Krause
- & Matthias Heinig
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Article
| Open AccessLifelong single-cell profiling of cranial neural crest diversification in zebrafish
Cranial neural crest generates a wide diversity of cell types. Here the authors perform single-cell profiling of neural crest to identify key enhancers and transcription factors for cell fate competency, thus revealing progressive acquisition of fate potential.
- Peter Fabian
- , Kuo-Chang Tseng
- & J. Gage Crump
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Article
| Open AccessMachine learning of genomic features in organotropic metastases stratifies progression risk of primary tumors
The location and timing of metastasis are still fundamentally unpredictable. Here the authors present the Metastatic Network model, a machine learning framework that integrates clinical data and DNA alterations to predict the risk of metastasis to specific organs as well as clinical outcomes
- Biaobin Jiang
- , Quanhua Mu
- & Jiguang Wang
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Article
| Open AccessLocal DNA shape is a general principle of transcription factor binding specificity in Arabidopsis thaliana
Methods to predict transcription factor binding sites typically focus on sequence motifs without considering DNA shape. Here the authors use a random forest machine learning approach that incorporates DNA shape and improves binding site prediction for Arabidopsis thaliana transcription factors.
- Janik Sielemann
- , Donat Wulf
- & Andrea Bräutigam
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Article
| Open AccessSingle-cell normalization and association testing unifying CRISPR screen and gene co-expression analyses with Normalisr
Normalisr removes technical bias in single-cell RNA-seq and detects gene differential and coexpression accurately and efficiently. It also infers gene regulatory and co-expression networks from conventional and CRISPR screen single-cell RNA-seq datasets.
- Lingfei Wang
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Article
| Open AccessChromatin-accessibility estimation from single-cell ATAC-seq data with scOpen
scATAC-Seq yields data that is extremely sparse. Here, the authors present a computationally efficient imputation method called scOpen that improves the downstream analyses of scATAC-Seq data and use it to identify transcriptional regulators of kidney fibrosis.
- Zhijian Li
- , Christoph Kuppe
- & Ivan G. Costa
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Article
| Open AccessGain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within processing bodies
Mutations in the splicing factor RBM20 cause aggressive Dilated Cardiomyopathy. Here the authors generated RBM20 R636S mutants and knockout in human iPSC-derived cardiomyocytes. Mutant RBM20 showed different target RNA binding, altered splicing and localization to cytoplasmic processing bodies.
- Aidan M. Fenix
- , Yuichiro Miyaoka
- & Nathan Salomonis
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Article
| Open AccessA frequency-amplitude coordinator and its optimal energy consumption for biological oscillators
Calibrating both anomalous frequency and amplitude of biorhythm prevents physiological dysfunctions or diseases. Here, the authors propose a universal approach to design a frequency-amplitude coordinator rigorously via dynamical systems tools.
- Bo-Wei Qin
- , Lei Zhao
- & Wei Lin
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Article
| Open AccessChromatin accessibility associates with protein-RNA correlation in human cancer
Studies show the cancer transcriptome correlates poorly with the cancer proteome, questioning the role of chromatin regulation. Here the authors demonstrate proximal-gene-body chromatin elements and transcription predict abundances of differentially expressed proteins in thyroid and breast cancers.
- Akshay Sanghi
- , Joshua J. Gruber
- & Michael P. Snyder
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Article
| Open AccessChromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma
Despite extensive genetic heterogeneity, nearly half of all multiple myeloma (MM) cases are driven by cyclin D2 (CCND2) over-expression. Here the authors dissect the chromatin landscape of MM to provide insights into the transcriptional regulatory landscape driving MM and divergent transcriptomes corresponding to different MM genetic subtypes.
- Jaime Alvarez-Benayas
- , Nikolaos Trasanidis
- & Anastasios Karadimitris
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Article
| Open AccessThe basis of easy controllability in Boolean networks
Boolean networks allow a simplified representation of interactions. Here, the authors systematically analyze regulation in dozens of biological Boolean networks, finding mathematical regularities that suggest biological systems could be controlled through a relatively small number of components.
- Enrico Borriello
- & Bryan C. Daniels
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Article
| Open AccessThe regulatory impact of RNA-binding proteins on microRNA targeting
miRNAs are loaded into Argonaute protein and repress complementary mRNA targets. Here the authors show the unappreciated role of RNA binding proteins for efficient miRNA targeting and expand the current understanding of miRNA targeting.
- Sukjun Kim
- , Soyoung Kim
- & Daehyun Baek