Gene regulation

  • Article
    | Open Access

    CTCF is as an architectural protein involved in 3D genome folding; however its contribution to animal development has not been well characterized. Here the authors show that CTCF is not only pivotal for 3D chromatin structure and enhancer-promoter interactions in zebrafish, but it is also essential for controlling the expression of thousands of genes during development.

    • Martin Franke
    • , Elisa De la Calle-Mustienes
    •  & José L. Gómez-Skarmeta
  • Article
    | Open Access

    Many genetic loci have been linked to obesity, but knowledge of their functional mechanisms is limited. Here, the authors perform reporter assays and temporal functional genomics data generation to characterize obesity genetic loci and find that loci often harbor multiple functional variants.

    • Amelia C. Joslin
    • , Débora R. Sobreira
    •  & Marcelo A. Nóbrega
  • Article
    | Open Access

    The global pattern of the mammalian methylome is formed by changes in methylation and demethylation. Here the authors describe a metric methylation concurrence that measures the ratio of unmethylated CpGs inside the partially methylated reads and show that methylation concurrence is associated with epigenetically regulated tumour suppressor genes.

    • Jiejun Shi
    • , Jianfeng Xu
    •  & Wei Li
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Genetic mechanisms underlying fetal hemoglobin (HbF) regulation and switching are not fully understood. Here, the authors develop a single-cell genome editing functional assay to model how effects of mutation-harbouring functional elements contribute to HbF expression.

    • Yong Shen
    • , Jeffrey M. Verboon
    •  & Vijay G. Sankaran
  • Article
    | Open Access

    Local gene co-expression is found throughout the genome, but systematic analysis of these co-expressed genes is needed. Here, the authors identify local co-expressed genes in 49 tissues and characterize the genetic variants which may affect their expression and contribute to disease.

    • Diogo M. Ribeiro
    • , Simone Rubinacci
    •  & Olivier Delaneau
  • Article
    | Open Access

    Globin loci harbor genes that are expressed embryonically and silenced postnatally. Here the authors show that zeta-globin silencing depends upon selective hypoacetylation of its TAD subdomain, which blocks its interaction with the alpha-globin super-enhancer, and zeta-globin can be reactivated by acetylation.

    • Andrew J. King
    • , Duantida Songdej
    •  & Christian Babbs
  • Article
    | Open Access

    Poised enhancers (PEs) in embryonic stem cells have accessible chromatin, are bound by repressive Polycomb Group proteins, and interact with their targets prior to activation. However, whether this is recapitulated in vivo is unknown. Here the authors show PEs display these features in mouse embryos, are prevalent across vertebrates, and are required for developmental gene expression.

    • Giuliano Crispatzu
    • , Rizwan Rehimi
    •  & Alvaro Rada-Iglesias
  • Article
    | Open Access

    Single-cell RNA-seq reveals the cellular heterogeneity in development and disease. Here the authors present a single-nucleus RNA-seq2 that allows deep characterization of nuclei isolated from frozen archived tissues, apply it for transcriptional profiling of individual hepatocytes, and determine a functional crosstalk between liver zonation and ploidy.

    • M. L. Richter
    • , I. K. Deligiannis
    •  & C. P. Martinez-Jimenez
  • Article
    | Open Access

    Stable epigenetic changes are relatively rare. Here the authors report that mating induces stable silencing of a single-copy transgene in C. elegans. Components of small RNA silencing are required for this stable silencing.

    • Sindhuja Devanapally
    • , Pravrutha Raman
    •  & Antony M. Jose
  • Article
    | Open Access

    P53 is a well-known tumour suppressor, however its role in intestinal type 2 immunity is currently unclear. Here authors report that during parasitic infections, p53 triggers tuft cell Ca2+ influx and IL-25 release, and shows a regulatory role for p53 in intestinal type 2 immunity via transcriptional regulation of the Lrmp gene.

    • Chun-Yuan Chang
    • , Jianming Wang
    •  & Wenwei Hu
  • Article
    | Open Access

    Bacterial stress responses are potential targets for new antimicrobials. Here, Avican et al. present global transcriptomes for 32 bacterial pathogens grown under 11 stress conditions, and identify common and unique regulatory responses, as well as processes participating in different stress responses.

    • Kemal Avican
    • , Jehad Aldahdooh
    •  & Maria Fällman
  • Article
    | Open Access

    Cornelia de Lange syndrome is a developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The authors, here, by analysing previously identified mutations in BRD4 associated with the disease, reveal that a BRD4 mutation affects DNA damage signalling, and perturbs regulation of DNA repair in mutant cells.

    • Gabrielle Olley
    • , Madapura M. Pradeepa
    •  & Charlene Boumendil
  • Article
    | Open Access

    Brush border gene regulation in various different tissues is incompletely understood. Here, the authors show HNF4 regulates the brush border gene program in multiple organs, such as intestine, kidney and yolk sac, and also intestinal chromatin looping in these tissues between promoters and enhancers.

    • Lei Chen
    • , Shirley Luo
    •  & Michael P. Verzi
  • Article
    | Open Access

    Single-nucleotide variants in enhancers or promoters may affect gene transcription by altering transcription factor binding sites. Here the authors present a meta-analysis empowered by a new statistical method covering thousands of ChIP-Seq experiments resulting in the identification of more than 500 thousand allele-specific binding (ASB) events in the human genome.

    • Sergey Abramov
    • , Alexandr Boytsov
    •  & Ivan V. Kulakovskiy
  • Article
    | Open Access

    Splicing-disrupting mutations are linked to diseases. By employing a machine learning approach, the authors show that certain exons, termed hotspot exons, are enriched for splicing-disruption variants and susceptible to splicing perturbations.

    • David T. Glidden
    • , Jeramiah L. Buerer
    •  & William G. Fairbrother
  • Article
    | Open Access

    Selection on alleles contributing to human evolution is not well understood. Here, the authors investigate positive selection on skin barrier adaptation, identifying a selective sweep on involucrin alleles associated with migration out of Africa, and confirming enhancer regulatory effects with functional assays.

    • Mary Elizabeth Mathyer
    • , Erin A. Brettmann
    •  & Cristina de Guzman Strong
  • Article
    | Open Access

    How transcription factors regulate cell fates in native tissues is unclear. Here, the authors report that differential chromatin binding of NKX2-1 determines opposing alveolar cell fates in the murine lung, showing loss of YAP/TAZ directs NKX2-1 to alternative binding sites leading to cell fate conversion.

    • Danielle R. Little
    • , Anne M. Lynch
    •  & Jichao Chen
  • Article
    | Open Access

    Lineage-restricted transcription factor PAX8 is oncogenic in ovarian cancer cells. Here the authors show that PAX8 interacts and recruits a splice variant of the MECOM locus PRDM3 to control the gene expression module involved in adhesion and extracellular matrix, and consequently promotes ovarian tumorigenesis.

    • Melusine Bleu
    • , Fanny Mermet-Meillon
    •  & Giorgio Giacomo Galli
  • Article
    | Open Access

    PU.1 is a master regulator of myeloid development but its role in disease-relevant neutrophils is not well known. Here, the authors look at primary neutrophils from a human population and find that genetic variants affecting binding of PU.1 are associated with cell count and disease susceptibility.

    • Stephen Watt
    • , Louella Vasquez
    •  & Nicole Soranzo
  • Article
    | Open Access

    The role of transcriptional enhancers and 3D chromatin organisation in coordinating the transition from naive to primed pluripotency remains poorly understood. Here the authors generate a high-resolution atlas of gene regulatory interactions, chromatin profiles and transcription factor occupancy in naive and primed human pluripotent stem cells to provide insights into these developmental processes.

    • Peter Chovanec
    • , Amanda J. Collier
    •  & Peter J. Rugg-Gunn
  • Article
    | Open Access

    In Pseudomonas aeruginosa, the protein AlpA activates the expression of the alp locus in response to DNA damage, leading to lysis in a subset of cells and enhancing virulence of other, surviving cells. Here, the authors show that AlpA acts as an antiterminator rather than a transcriptional activator.

    • Jennifer M. Peña
    • , Samantha M. Prezioso
    •  & Simon L. Dove
  • Article
    | Open Access

    The SWI/SNF complex BAF and the histone H3K4 methyltransferase MLL4 (KMT2D) play critical roles in enhancer activation, however the interplay between them has remained unclear. Here the authors show that BAF and MLL4 are interdependent in promoting enhancer activation by lineage-determining transcription factors during adipogenesis.

    • Young-Kwon Park
    • , Ji-Eun Lee
    •  & Kai Ge
  • Article
    | Open Access

    Thousands of genetic variants have been associated with lupus, but causal variants and mechanisms are unknown. Here, the authors combine a massively parallel reporter assay with genome-wide ChIP experiments to identify risk variants with allelic enhancer activity mediated through transcription factor binding.

    • Xiaoming Lu
    • , Xiaoting Chen
    •  & Leah C. Kottyan
  • Article
    | Open Access

    While recent studies suggest that transcriptional activators form condensates at active loci, less is known about the distribution of repressor proteins. Here, the authors develop an expression assay in living Ciona embryos and visualize puncta of Hes repressors, with the Groucho/TLE corepressor, observing that the Hes.a/Gro puncta have the properties of viscous liquid droplets that undergo limited fusion events due to association with DNA.

    • Nicholas Treen
    • , Shunsuke F. Shimobayashi
    •  & Michael Levine
  • Article
    | Open Access

    The significance of translated upstream open reading frames is not well known. Here, the authors investigate genetic variants in these regions, finding that they are under high evolutionary constraint and may contribute to disease.

    • David S. M. Lee
    • , Joseph Park
    •  & Yoseph Barash
  • Article
    | Open Access

    The NCI-60 cancer cell line panel covers multiple cancer types but has not been extensively investigated at the epigenetic level. Here, the authors present H3K4me3, H3K27ac, H3K9me3, and H4K20me3 ChIP-Seq analysis of the cell lines, and describe features of chromatin states and integrative analyses of expression, epigenetic and genetic mutation data.

    • Lijin K. Gopi
    •  & Benjamin L. Kidder
  • Article
    | Open Access

    Piwi deficiency results in sterility and is associated with transposon expression and genomic instability. Here the authors show that sterility of C. elegans Piwi prg-1 mutant is not associated with transposon-induced DNA damage but is associated with and is phenocopied by dysfunction of germ granules.

    • Maya Spichal
    • , Bree Heestand
    •  & Shawn Ahmed
  • Article
    | Open Access

    Interaction between transcription factors and chromatin is fundamental for genome organization and regulation. Here, the authors use information theory to measure signatures of organized chromatin resulting from transcription factor-chromatin interactions, termed chromatin information enrichment, and find that variations in the information encoded in chromatin architecture reflects functional biological variation.

    • Ricardo D’Oliveira Albanus
    • , Yasuhiro Kyono
    •  & Stephen C. J. Parker
  • Article
    | Open Access

    Understanding the molecular effects of disease variants in relevant tissues is essential to understanding and treating disease. Here, the authors discover expression and protein quantitative trait loci in cartilage and synovium from 115 osteoarthritis patients to pinpoint genes of action and potential drug treatments.

    • Julia Steinberg
    • , Lorraine Southam
    •  & Eleftheria Zeggini
  • Article
    | Open Access

    Upstream open reading frames (uORFs) have widespread regulatory functions in eukaryotes, their genomic distribution and evolution is understudied. Here, the authors characterise ~17 million putative uORFs across 478 eukaryotic species, showing how evolution has shaped uORF contents and distribution.

    • Hong Zhang
    • , Yirong Wang
    •  & Jian Lu
  • Article
    | Open Access

    Although the Drosophila genome has widespread contact domains and CTCF, it remains unclear whether CTCF-dependent domains exist in flies. Here, the authors ablate CTCF in Drosophila and find that CTCF is required to form a small fraction of all domain boundaries, suggesting differences in the role of CTCF for genome folding in flies and vertebrates.

    • Anjali Kaushal
    • , Giriram Mohana
    •  & Maria Cristina Gambetta
  • Article
    | Open Access

    Nematode P granules are cytoplasmic RNA–protein biomolecule condensates central to germ cell development. Here the authors show that dimerization of the PGL-1 scaffolding protein is crucial to granule formation and mRNA repression, and that the WAGO-1 Argonaute protein is a cofactor in repressing PGL-1 bound mRNAs.

    • Scott Takeo Aoki
    • , Tina R. Lynch
    •  & Judith Kimble
  • Article
    | Open Access

    Germ-free mosquitoes generated with current methods exhibit developmental deficits. Here, the authors use genetically modified bacteria to allow complete decolonisation at any developmental stage of Aedes aegypti mosquitoes and show that bacteria support larval development by contributing to folate biosynthesis and enhancing energy storage.

    • Ottavia Romoli
    • , Johan Claes Schönbeck
    •  & Mathilde Gendrin
  • Article
    | Open Access

    How PRC1 recognises and interacts with its target genes remains poorly understood. Here, the authors use genome engineering and single particle tracking to dissect how PRC1 binds to chromatin in live mouse embryonic stem cells, revealing that this repressor is highly dynamic, with only a small fraction stably interacting with chromatin.

    • Miles K. Huseyin
    •  & Robert J. Klose
  • Article
    | Open Access

    Enzalutamide, an approved drug for prostate cancer, acts on TMPRSS2 expression, a key mediator for SARS-CoV-2 infection. Here, the authors characterize the anti-SARS-CoV-2 effects of Enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and in hACE2-transduced Tmprss2 knockout mice and show lack antiviral action in human lung cells and human lung organoids, likely due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells.

    • Fei Li
    • , Ming Han
    •  & Dong Gao
  • Article
    | Open Access

    The dynamics of genome architecture during human cell differentiation and upon neoplastic transformation remain poorly characterized. Here, the authors integrate in situ Hi-C and nine additional omic layers to characterize the dynamic changes in 3D genome architecture during normal B cell differentiation and in neoplastic cells from chronic lymphocytic leukemia and mantle cell lymphoma patients.

    • Roser Vilarrasa-Blasi
    • , Paula Soler-Vila
    •  & José Ignacio Martin-Subero
  • Article
    | Open Access

    Pioneer transcription factors access their DNA binding motifs in closed chromatin and often act in cell fate reprogramming. Here, Jin et al. present biochemical evidence for a pioneer factor in plants and show that LFY promotes floral cell fate and locally unlocks chromatin by displacing histone H1 and recruiting SWI/SNF chromatin remodelers.

    • Run Jin
    • , Samantha Klasfeld
    •  & Doris Wagner
  • Article
    | Open Access

    Genetic elements that control inflammatory gene expression are not fully elucidated. Here the authors conduct a multi-species analysis of chromatin landscape and NF-κB binding in response to the proinflammatory cytokine TNFα, finding that conserved NF-κB bound regions are linked to enhancer activity and disease.

    • Azad Alizada
    • , Nadiya Khyzha
    •  & Michael D. Wilson
  • Article
    | Open Access

    Targeting chromatin regulators to a gene is emerging as powerful tool to control transcription. Here the authors demonstrate the use of nanobodies against chromatin regulators to control gene expression and epigenetic memory.

    • Mike V. Van
    • , Taihei Fujimori
    •  & Lacramioara Bintu