Featured
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| Open AccessEngineering inducible biomolecular assemblies for genome imaging and manipulation in living cells
Imaging non-repetitive loci in living cells remains challenging. Here, the authors engineered an inducible system whereby biomolecular assemblies can be guided to specific genomic loci by a nuclease-defective Cas9, allowing the simultaneous imaging and manipulation of the loci.
- Qin Peng
- , Ziliang Huang
- & Yingxiao Wang
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Article
| Open AccessLoss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation in mice
SUMOylation is a mechanism of posttranslational modification involved in eukaryotic cell homeostasis. Here the authors report that mice unable to control SUMOylation in the adrenal cortex develop a selective defect in glucocorticoid production due to disrupted differentiation of cells involved in steroid hormone synthesis.
- Damien Dufour
- , Typhanie Dumontet
- & Antoine Martinez
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| Open AccessLimited conservation in cross-species comparison of GLK transcription factor binding suggested wide-spread cistrome divergence
Unlike microbes and mammals, cistrome dynamics in plants remains unclear. Here, using GOLDEN2-LIKE (GLK) transcription factor as an example, the authors find that most GLK binding sites are species-specific and the binding divergence is caused by cis-variations through inter-species transformation experiment.
- Xiaoyu Tu
- , Sibo Ren
- & Silin Zhong
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Article
| Open AccessMolecular basis for DNA recognition by the maternal pioneer transcription factor FoxH1
FoxH1 is an essential maternal pioneer factor during embryonic development. Here, the authors present several FoxH1—DNA structures that reveal the molecular basis for FoxH1 binding specificity and pioneer factor activity.
- Radoslaw Pluta
- , Eric Aragón
- & Maria J. Macias
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Article
| Open AccessA non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes
Germline variants may pre-dispose patients to an increased risk of developing anthracycline-induced cardiotoxicity. This report provides insights into the mechanism by which a common genetic variant, rs28714259, may confer an increased risk of cardiac damage.
- Xi Wu
- , Fei Shen
- & Bryan Paul Schneider
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Article
| Open AccessLearning the histone codes with large genomic windows and three-dimensional chromatin interactions using transformer
Existing deep learning-based approaches for the prediction of gene expression by histone modifications (HMs) can only focus on narrow and linear genomic regions around promoters. Here, the authors address these problems by developing a transformer-based deep learning architecture named Chromoformer.
- Dohoon Lee
- , Jeewon Yang
- & Sun Kim
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| Open AccessIntegration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes
Here the authors characterize structural variations (SVs) in a cohort of individuals with complex genomic rearrangements, identifying breakpoints by employing short- and long-read genome sequencing and investigate their impact on gene expression and the three-dimensional chromatin architecture. They find breakpoints are enriched in inactive regions and can result in chromatin domain fusions.
- Robert Schöpflin
- , Uirá Souto Melo
- & Stefan Mundlos
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Article
| Open AccessArctic introgression and chromatin regulation facilitated rapid Qinghai-Tibet Plateau colonization by an avian predator
The Qinghai-Tibet Plateau is as cold as the Arctic, but presents unique hypoxia and high ultraviolet conditions. Here the authors find that gene flow from Arctic gyrfalcons aids plateau saker falcons’ cold adaptation, and independent non-coding genomic changes underlie hypoxic and ultraviolet responses.
- Li Hu
- , Juan Long
- & Xiangjiang Zhan
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Article
| Open AccessRetinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer
Here the authors identify retinoblastoma (RB) protein as an intrinsic inhibitor of BRD4 and demonstrate that loss of RB induces BRD4 cistrome changes in the genome and enrichment of GPCR-cAMP signaling pathway, conferring resistance to small molecule BET inhibitor.
- Donglin Ding
- , Rongbin Zheng
- & Haojie Huang
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Article
| Open AccessEpigenetic control of chromosome-associated lncRNA genes essential for replication and stability
Heskett et al. describe several members of a class of long non-coding RNAs, known as ASARs, which show distinct epigenetic regulation between subclonal lineages and are essential for normal DNA replication timing and stability of human autosomes.
- Michael B. Heskett
- , Athanasios E. Vouzas
- & Mathew J. Thayer
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Article
| Open AccessThe hypoxia response pathway promotes PEP carboxykinase and gluconeogenesis in C. elegans
The hypoxia response pathway can counter pathological damage caused by low oxygen availability. Here the authors employ a multiomics approach to show how the pathway reprograms metabolism towards gluconeogenesis to combat oxidative stress.
- Mehul Vora
- , Stephanie M. Pyonteck
- & Christopher Rongo
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Article
| Open AccessMaintenance of neurotransmitter identity by Hox proteins through a homeostatic mechanism
To remain functional throughout life, neuronal cells must maintain the ability to synthesize and release specific neurotransmitters. Here, the authors show that this ability critically depends on the activity of Hox proteins.
- Weidong Feng
- , Honorine Destain
- & Paschalis Kratsios
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Article
| Open AccessA single transcription factor facilitates an insect host combating Bacillus thuringiensis infection while maintaining fitness
Plutella xylostella endures Bt toxins with no performance costs. This study reveals how, depending on the presence of the toxin, this insect modifies MAPK phosphorylation to modulate the transcription factor FTZ-F1 binding, to up- or down- regulate Bt receptors or non-receptor (resistant) paralogs.
- Zhaojiang Guo
- , Le Guo
- & Youjun Zhang
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| Open AccessAllele-specific differential regulation of monoallelically expressed autosomal genes in the cardiac lineage
The authors use allele-specific single cell transcriptomic analysis to elucidate the establishment of monoallelic gene expression in the cardiac lineage. The findings emphasize the importance of allele-specific insight into gene regulation in development, homeostasis and disease.
- Gayan I. Balasooriya
- & David L. Spector
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Article
| Open AccessVariation in the fruit development gene POINTED TIP regulates protuberance of tomato fruit tip
While auxin has been implicated in the development of tomato fruit with pointed tips, the mechanism are largely unknown. Here, the authors report variation of a C2H2-type zinc finger transcription factor affects transcription of FUL2, which consequently regulates auxin transport and distribution to determine tomato fruit shape.
- Jianwen Song
- , Lele Shang
- & Junhong Zhang
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Article
| Open AccessHigh-resolution genome topology of human retina uncovers super enhancer-promoter interactions at tissue-specific and multifactorial disease loci
The genome-wide high-resolution chromatin contact of the human retina identifies genetic control of cell-type specific gene expression pattern, missing heritability in retinopathies, and candidate genes/variants for diseases including AMD and glaucoma.
- Claire Marchal
- , Nivedita Singh
- & Anand Swaroop
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Article
| Open AccessDecoding the spatial chromatin organization and dynamic epigenetic landscapes of macrophage cells during differentiation and immune activation
Here the authors delineate the dynamic changes in 3D genome and epigenome of differentiating macrophages and during infection with Mycobacterium tuberculosis. They reveal a role for NF-κB upon infection and identify SNPs in disease-susceptible loci, including rs1873613 that is located in the anchor of a dynamic chromatin loop.
- Da Lin
- , Weize Xu
- & Gang Cao
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Article
| Open AccessMulti-context genetic modeling of transcriptional regulation resolves novel disease loci
Transcriptome-wide association studies (TWAS) often ignore the specificity and sharing of effects across contexts (e.g., tissues). Here, the authors describe a method to split genetic effects into context-shared and context-specific terms. They apply their method to tissue and single-cell RNA-seq and show improved power in TWAS.
- Mike Thompson
- , Mary Grace Gordon
- & Noah Zaitlen
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Article
| Open AccessA stem cell roadmap of ribosome heterogeneity reveals a function for RPL10A in mesoderm production
How ribosomes differ in composition and function to regulate gene expression is poorly understood. Here, the authors show that ribosome composition changes during stem cell differentiation and identify a ribosomal protein that regulates production of the mesoderm lineage.
- Naomi R. Genuth
- , Zhen Shi
- & Maria Barna
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Article
| Open AccessSystematic analysis of low-affinity transcription factor binding site clusters in vitro and in vivo establishes their functional relevance
Here the authors quantitatively characterize binding to transcription factor (TF) binding site clusters in vitro, followed by characterizing clusters in synthetic and native gene regulatory systems in yeast. They show low-affinity clusters achieve high TF occupancies in vitro and gene activation in vivo, suggesting occupancy rather than individual TF dwell times drive transcriptional activation.
- Amir Shahein
- , Maria López-Malo
- & Sebastian J. Maerkl
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Article
| Open AccessRegulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1
LSD1 inhibition blocks the neuroendocrine phenotype of some small cell lung cancers (SCLCs). Here, a genome-wide CRISPR/Cas9 LSD1 inhibitor resistance screen identifies the mRNA-binding protein ZFP36L1 as a gene repressed by LSD1 that when restored inhibits SCLC neuroendocrine differentiation.
- Hsiao-Yun Chen
- , Yavuz T. Durmaz
- & Matthew G. Oser
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Article
| Open AccessSplicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci
Splicing QTL (sQTL), genetic variants regulating alternative splicing, can be biologically important, but complex to detect and interpret. Here, the authors identify sQTL by focusing on protein coding sequences, as an alternative to junction-based approaches.
- Kensuke Yamaguchi
- , Kazuyoshi Ishigaki
- & Yuta Kochi
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Article
| Open AccessKLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress
Here the authors studied pulmonary arterial endothelial cells (PAEC) under laminar shear stress and show that this physiologic condition markedly changes chromatin accessibility at regulatory regions, when compared to cells grown in a static state. They find that KLF4 organizes chromatin by interacting with the SWI/SNF nucleosome remodeling complex to regulate vasculo-protective gene expression.
- Jan-Renier Moonen
- , James Chappell
- & Marlene Rabinovitch
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Article
| Open AccessFerritin-mediated iron detoxification promotes hypothermia survival in Caenorhabditis elegans and murine neurons
Strategies to improve cold resistance are of potential biomedical interest. Here the authors demonstrate that ferritin-mediated detoxification of iron, preventing the generation of reactive oxygen species, promotes cold survival in both Caenorhabditis elegans and cultured mammalian neurons.
- Tina Pekec
- , Jarosław Lewandowski
- & Rafal Ciosk
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Article
| Open AccessPKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression
ADPKD, a common aetiology of kidney failure, is caused by heterozygous PKD1 or PKD2 mutations. Here the authors show that preventing 3′-UTR cis-inhibition of mRNAs produced by the non-inactivated PKD1/2 alleles ameliorates preclinical ADPKD.
- Ronak Lakhia
- , Harini Ramalingam
- & Vishal Patel
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Article
| Open AccessTRIM28-dependent SUMOylation protects the adult ovary from activation of the testicular pathway
Gonadal fate in mammals is determined during embryogenesis and is actively maintained in adulthood. This study shows that E3-SUMO ligase activity of TRIM28 is required for ovarian identity maintenance and testicular-specific gene repression in mouse adult ovary; in its absence, ovarian granulosa cells transdifferentiate to Sertoli cells.
- Moïra Rossitto
- , Stephanie Déjardin
- & Francis Poulat
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Article
| Open AccessBalanced gene dosage control rather than parental origin underpins genomic imprinting
Here the authors investigate whether for imprinted genes the parent-of-origin of the expressed allele or rather appropriate gene dosage is more important for normal development. Using the differentially methylated region of Dlk1-Dio3 gene involved in imprinting, they show that correct parent-of-origin imprinting pattern is secondary to balanced gene dosage.
- Ariella Weinberg-Shukron
- , Raz Ben-Yair
- & Yonatan Stelzer
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Article
| Open AccessCDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors
Epidermal progenitors are poised for differentiation, which allows for continual balance of self-renewal and differentiation. Here they show that the Super Elongation Complex regulates this process through direct regulation of a set of rapid response genes that involves a CDK9 activity switch.
- Sarah M. Lloyd
- , Daniel B. Leon
- & Xiaomin Bao
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Article
| Open AccessTranscription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration in mice
Here the authors couple an integrative genomic analysis with substantial in vitro and in vivo experimental validation, identifying REST as a novel suppressor of a pro-regenerative gene program and CNS axon regeneration in mice.
- Yuyan Cheng
- , Yuqin Yin
- & Daniel H. Geschwind
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Article
| Open AccessPostmitotic differentiation of human monocytes requires cohesin-structured chromatin
How chromatin structure and gene accessibility changes during monocyte differentiation is not clearly defined. Here the authors characterize the chromatin changes during macrophage or dendritic cell maturation from monocytes and the dependence of this upon cohesin and CTCF.
- Julia Minderjahn
- , Alexander Fischer
- & Michael Rehli
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Article
| 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 AccessNatural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity
Natural Killer cells are key mediators of anti-tumour immunosurveillance and anti-viral immunity. Here, the authors map regulatory genetic variation in primary Natural Killer cells, providing new insights into their role in human health and disease.
- James J. Gilchrist
- , Seiko Makino
- & Benjamin P. Fairfax
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Article
| Open AccessSenescent cells limit p53 activity via multiple mechanisms to remain viable
To develop therapeutics that selectively eliminate pathological senescent cells it is important to understand their survival mechanisms. Here, the authors show that senescent cells manage to survive by keeping p53 activity in check through multiple mechanisms, including inhibitory mechanisms that involve p53 binding to ribonucleases.
- Ines Sturmlechner
- , Chance C. Sine
- & Jan M. van Deursen
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Article
| Open AccessRNase III-CLASH of multi-drug resistant Staphylococcus aureus reveals a regulatory mRNA 3′UTR required for intermediate vancomycin resistance
Regulatory small RNA (sRNA) interact with mRNAs to regulate their stability, transcription, and translation via diverse mechanisms. Here, Mediati et al. apply RNase III-CLASH to multidrug-resistant Staphylococcus aureus to characterise the network of RNA–RNA interactions associated with RNase III and identify a regulatory mRNA 3′UTR, named vigR-3′UTR, involved in the regulation of genes relevant for vancomycin sensitivity.
- Daniel G. Mediati
- , Julia L. Wong
- & Jai J. Tree
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Article
| Open AccessRIViT-seq enables systematic identification of regulons of transcriptional machineries
Here the authors present their method ‘regulon identification by in vitro transcription-sequencing’ (RIViT-seq), which enables systematic identification of target genes of transcription factors of interest. They applied RIViT-seq to 13 sigma factors from Streptomyces coelicolor A3(2) and successfully identified target genes of 11 of these, expanding the regulatory characterisation in this organism.
- Hiroshi Otani
- & Nigel J. Mouncey
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Article
| Open AccessThe impact of species-wide gene expression variation on Caenorhabditis elegans complex traits
Gene expression links genomic variation to organismal trait differences. Here, the authors identify regulatory loci underlying gene expression variation in C. elegans and demonstrate how this variation could impact other complex traits.
- Gaotian Zhang
- , Nicole M. Roberto
- & Erik C. Andersen
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Article
| Open AccessIntegrating 3D genomic and epigenomic data to enhance target gene discovery and drug repurposing in transcriptome-wide association studies
Transcriptome-wide association studies can be used to test the effects of predicted gene expression in a cohort of individuals based on genetic data. Here, the authors developed a transcriptome-wide association method that integrates 3D genomic and epigenomic data with expression quantitative trait loci to improve gene expression predictions.
- Chachrit Khunsriraksakul
- , Daniel McGuire
- & Dajiang J. Liu
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Article
| Open AccessDietary restriction and the transcription factor clock delay eye aging to extend lifespan in Drosophila Melanogaster
Circadian dysfunction is a potential driver of eye aging. Here the authors report that in conjunction with the core molecular clock transcription factor Clock, dietary restriction promotes rhythmic homeostatic mechanisms within photoreceptors to delay visual senescence and extend lifespan in Drosophila Melanogaster.
- Brian A. Hodge
- , Geoffrey T. Meyerhof
- & Pankaj Kapahi
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Article
| Open AccessDifferential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction
Alternative promoters differ in their expression patterns, whose mechanisms are not well understood. Here the authors show that alternative promoters of a Drosophila embryonic gene hunchback are regulated by different action modes of two enhancers.
- Jingyao Wang
- , Shihe Zhang
- & Heng Xu
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Article
| Open AccessActivation of Xist by an evolutionarily conserved function of KDM5C demethylase
Here the authors show eutherian mammals co-opted the histone demethylase KDM5C during sex-chromosome evolution to induce X-chromosome inactivation by upregulating Xist expression selectively in females.
- Milan Kumar Samanta
- , Srimonta Gayen
- & Sundeep Kalantry
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Article
| Open AccessPreventing erosion of X-chromosome inactivation in human embryonic stem cells
Cloutier et al. discover that human embryonic stem cells (hESCs) cultured with media containing inhibitors of GSK3 proteins undergo erosion of X-chromosome inactivation, which equalizes X-linked gene expression between females and males. The findings inform the faithful culture of hESCs.
- Marissa Cloutier
- , Surinder Kumar
- & Sundeep Kalantry
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Article
| Open AccessContext-specific effects of sequence elements on subcellular localization of linear and circular RNAs
Ron and Ulitsky found using massively parallel assays that the effects of short RNA sequences on the subcellular localization of their host RNAs are strongly dependent on the host RNA form, linear or circular, and spliced or unspliced.
- Maya Ron
- & Igor Ulitsky
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Article
| Open AccessPlacental multi-omics integration identifies candidate functional genes for birthweight
The placenta plays key roles in fetal development and subsequent health. Here, the authors integrate placental methylation and transcriptome data with genetic loci associated with birthweight to identify functional genes underpinning fetal growth regulation.
- Fasil Tekola-Ayele
- , Xuehuo Zeng
- & Ronald Wapner
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Article
| Open AccessA leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation
Non-coding variants can regulate transcription factor binding and gene expression at variable chromatin modules. Here, the authors show that a germline variant induces transcription factor nucleation through chromatin compaction leading to AXIN2 up-regulation and is associated to better prognosis in chronic lymphocytic leukaemia.
- Gerard Llimos
- , Vincent Gardeux
- & Bart Deplancke
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Article
| Open AccessAnalysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF
Chromosome conformation capture (3 C) techniques have captured largescale 3D genome architecture. Here the authors present their “Tiled-MCC” approach for generation of 3 C data across megabase-scale loci at very high (up to 20 bp) resolution, which allowed them to observe nano-scale chromatin structures and investigate how these structures depend on cohesin and CTCF.
- Abrar Aljahani
- , Peng Hua
- & A. Marieke Oudelaar
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Article
| Open AccessMultilayered regulations of alternative splicing, NMD, and protein stability control temporal induction and tissue-specific expression of TRIM46 during axon formation
The genetic control underlying axon formation in neurons is unknown. Here, the authors report that neural-specific induction of TRIM46, one of the earliest axonal markers, is regulated by alternative splicing, NMD, and protein stability controls.
- John K. Vuong
- , Volkan Ergin
- & Sika Zheng
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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 AccessMultidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers
Alterations in cis-regulatory elements (CREs) can contribute to pancreatic diseases. Here the authors combine chromatin profiling and interaction points with in vivo reporter assays in zebrafish to uncover functionally equivalent human CREs, helping to predict disease-relevant enhancers.
- Renata Bordeira-Carriço
- , Joana Teixeira
- & José Bessa
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Article
| Open AccessLupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery
The functional effects of genetic loci associated with autoimmune disease are not well understood. By dissecting an autoimmune disease genetic locus, the authors define an immune cell-type-specific enhancer and the molecular mechanisms underlying the dysregulation of IRF8 expression by lupus risk variants.
- Tian Zhou
- , Xinyi Zhu
- & Nan Shen