bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2022‒09‒25
24 papers selected by
Connor Rogerson
University of Cambridge
  1. Intrinsic bias estimation for improved analysis of bulk and single-cell chromatin accessibility profiles using SELMA.
  2. Integrative analysis reveals histone demethylase LSD1 promotes RNA polymerase II pausing.
  3. Genome-wide fetalization of enhancer architecture in heart disease.
  4. EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma.
  5. CTCF acetylation at lysine 20 is required for the early cardiac mesoderm differentiation of embryonic stem cells.
  6. OCT4 interprets and enhances nucleosome flexibility.
  7. Dominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm.
  8. Deciphering multi-way interactions in the human genome.
  9. The transcriptional coactivator Eya1 exerts transcriptional repressive activity by interacting with REST corepressors and REST-binding sequences to maintain nephron progenitor identity.
  10. DNA methylation underpins the epigenomic landscape regulating genome transcription in Arabidopsis.
  11. HTCA: a database with an in-depth characterization of the single-cell human transcriptome.
  12. Single-cell sequencing reveals activation of core transcription factors in PRC2-deficient malignant peripheral nerve sheath tumor.
  13. Greenscreen: A simple method to remove artifactual signals and enrich for true peaks in genomic datasets including ChIP-seq data.
  14. Chromatin transitions triggered by LH density as epigenetic regulators of the genome.
  15. The oncogenic transcription factor FOXQ1 is a differential regulator of Wnt target genes.
  16. TFLink: an integrated gateway to access transcription factor-target gene interactions for multiple species.
  17. Confined migration induces heterochromatin formation and alters chromatin accessibility.
  18. c-MAF coordinates enterocyte zonation and nutrient uptake transcriptional programs.
  19. msPIPE: a pipeline for the analysis and visualization of whole-genome bisulfite sequencing data.
  20. The evolutionary dynamics of extrachromosomal DNA in human cancers.
  21. Asymmetric chromatin retention and nuclear envelopes separate chromosomes in fused cells in vivo.
  22. ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer.
  23. CTCF DNA-binding domain undergoes dynamic and selective protein-protein interactions.
  24. Single-cell transcriptomics identifies conserved regulators of neuroglandular lineages.
  1. Nat Commun. 2022 Sep 21. 13(1): 5533
    Intrinsic bias estimation for improved analysis of bulk and single-cell chromatin accessibility profiles using SELMA.
    Shengen Shawn Hu, Lin Liu, Qi Li, Wenjing Ma, Michael J Guertin, Clifford A Meyer, Ke Deng, Tingting Zhang, Chongzhi Zang.
      Genome-wide profiling of chromatin accessibility by DNase-seq or ATAC-seq has been widely used to identify regulatory DNA elements and transcription factor binding sites. However, enzymatic DNA cleavage exhibits intrinsic sequence biases that confound chromatin accessibility profiling data analysis. Existing computational tools are limited in their ability to account for such intrinsic biases and not designed for analyzing single-cell data. Here, we present Simplex Encoded Linear Model for Accessible Chromatin (SELMA), a computational method for systematic estimation of intrinsic cleavage biases from genomic chromatin accessibility profiling data. We demonstrate that SELMA yields accurate and robust bias estimation from both bulk and single-cell DNase-seq and ATAC-seq data. SELMA can utilize internal mitochondrial DNA data to improve bias estimation. We show that transcription factor binding inference from DNase footprints can be improved by incorporating estimated biases using SELMA. Furthermore, we show strong effects of intrinsic biases in single-cell ATAC-seq data, and develop the first single-cell ATAC-seq intrinsic bias correction model to improve cell clustering. SELMA can enhance the performance of existing bioinformatics tools and improve the analysis of both bulk and single-cell chromatin accessibility sequencing data.
    DOI:  https://doi.org/10.1038/s41467-022-33194-z
  2. iScience. 2022 Oct 21. 25(10): 105049
    Integrative analysis reveals histone demethylase LSD1 promotes RNA polymerase II pausing.
    Hani Jieun Kim, Pishun Li, Taiyun Kim, Andrew J Oldfield, Xiaofeng Zheng, Pengyi Yang.
      Lysine-specific demethylase 1 (LSD1) is well-known for its role in decommissioning enhancers during mouse embryonic stem cell (ESC) differentiation. Its role in gene promoters remains poorly understood despite its widespread presence at these sites. Here, we report that LSD1 promotes RNA polymerase II (RNAPII) pausing, a rate-limiting step in transcription regulation, in ESCs. We found the knockdown of LSD1 preferentially affects genes with higher RNAPII pausing. Next, we demonstrate that the co-localization sites of LSD1 and MYC, a factor known to regulate pause-release, are enriched for other RNAPII pausing factors. We show that LSD1 and MYC directly interact and MYC recruitment to genes co-regulated with LSD1 is dependent on LSD1 but not vice versa. The co-regulated gene set is significantly enriched for housekeeping processes and depleted of transcription factors compared to those bound by LSD1 alone. Collectively, our integrative analysis reveals a pleiotropic role of LSD1 in promoting RNAPII pausing.
    Keywords:  Molecular biology; molecular mechanism of gene regulation; omics
    DOI:  https://doi.org/10.1016/j.isci.2022.105049
  3. Cell Rep. 2022 Sep 20. pii: S2211-1247(22)01237-2. [Epub ahead of print]40(12): 111400
    Genome-wide fetalization of enhancer architecture in heart disease.
    Cailyn H Spurrell, Iros Barozzi, Michael Kosicki, Brandon J Mannion, Matthew J Blow, Yoko Fukuda-Yuzawa, Neil Slaven, Sarah Y Afzal, Jennifer A Akiyama, Veena Afzal, Stella Tran, Ingrid Plajzer-Frick, Catherine S Novak, Momoe Kato, Elizabeth A Lee, Tyler H Garvin, Quan T Pham, Anne N Kronshage, Steven Lisgo, James Bristow, Thomas P Cappola, Michael P Morley, Kenneth B Margulies, Len A Pennacchio, Diane E Dickel, Axel Visel.
      Heart disease is associated with re-expression of key transcription factors normally active only during prenatal development of the heart. However, the impact of this reactivation on the regulatory landscape in heart disease is unclear. Here, we use RNA-seq and ChIP-seq targeting a histone modification associated with active transcriptional enhancers to generate genome-wide enhancer maps from left ventricle tissue from up to 26 healthy controls, 18 individuals with idiopathic dilated cardiomyopathy (DCM), and five fetal hearts. Healthy individuals have a highly reproducible epigenomic landscape, consisting of more than 33,000 predicted heart enhancers. In contrast, we observe reproducible disease-associated changes in activity at 6,850 predicted heart enhancers. Combined analysis of adult and fetal samples reveals that the heart disease epigenome and transcriptome both acquire fetal-like characteristics, with 3,400 individual enhancers sharing fetal regulatory properties. We also provide a comprehensive data resource (http://heart.lbl.gov) for the mechanistic exploration of DCM etiology.
    Keywords:  CP: Molecular biology; RNA-seq; enhancers; fetalization; genomics; hIP-seq; heart disease; regulatory elements; transgenic assay
    DOI:  https://doi.org/10.1016/j.celrep.2022.111400
  4. Nucleic Acids Res. 2022 Sep 23. 50(17): 9814-9837
    EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma.
    Iftekhar A Showpnil, Julia Selich-Anderson, Cenny Taslim, Megann A Boone, Jesse C Crow, Emily R Theisen, Stephen L Lessnick.
      Ewing sarcoma is a prototypical fusion transcription factor-associated pediatric cancer that expresses EWS/FLI or a highly related FET/ETS chimera. EWS/FLI dysregulates transcription to induce and maintain sarcomagenesis, but the mechanisms utilized are not fully understood. We therefore sought to define the global effects of EWS/FLI on chromatin conformation and transcription in Ewing sarcoma cells using a well-validated 'knock-down/rescue' model of EWS/FLI function in combination with next generation sequencing assays to evaluate how the chromatin landscape changes with loss, and recovery, of EWS/FLI expression. We found that EWS/FLI (and EWS/ERG) genomic localization is largely conserved across multiple patient-derived Ewing sarcoma cell lines. This EWS/FLI binding signature is associated with establishment of topologically-associated domain (TAD) boundaries, compartment activation, enhancer-promoter looping that involve both intra- and inter-TAD interactions, and gene activation. In addition, EWS/FLI co-localizes with the loop-extrusion factor cohesin to promote chromatin loops and TAD boundaries. Importantly, local chromatin features provide the basis for transcriptional heterogeneity in regulation of direct EWS/FLI target genes across different Ewing sarcoma cell lines. These data demonstrate a key role of EWS/FLI in mediating genome-wide changes in chromatin configuration and support the notion that fusion transcription factors serve as master regulators of three-dimensional reprogramming of chromatin.
    DOI:  https://doi.org/10.1093/nar/gkac747
  5. Cell Regen. 2022 Sep 19. 11(1): 34
    CTCF acetylation at lysine 20 is required for the early cardiac mesoderm differentiation of embryonic stem cells.
    Shixin Gong, Gongcheng Hu, Rong Guo, Jie Zhang, Yiqi Yang, Binrui Ji, Gang Li, Hongjie Yao.
      The CCCTC-binding factor (CTCF) protein and its modified forms regulate gene expression and genome organization. However, information on CTCF acetylation and its biological function is still lacking. Here, we show that CTCF can be acetylated at lysine 20 (CTCF-K20) by CREB-binding protein (CBP) and deacetylated by histone deacetylase 6 (HDAC6). CTCF-K20 is required for the CTCF interaction with CBP. A CTCF point mutation at lysine 20 had no effect on self-renewal but blocked the mesoderm differentiation of mouse embryonic stem cells (mESCs). The CTCF-K20 mutation reduced CTCF binding to the promoters and enhancers of genes associated with early cardiac mesoderm differentiation, resulting in diminished chromatin accessibility and decreased enhancer-promoter interactions, impairing gene expression. In summary, this study reveals the important roles of CTCF-K20 in regulating CTCF genomic functions and mESC differentiation into mesoderm.
    Keywords:  CBP; CTCF; CTCF acetylation; Early cardiac mesoderm differentiation; HDAC6
    DOI:  https://doi.org/10.1186/s13619-022-00131-w
  6. Nucleic Acids Res. 2022 Sep 22. pii: gkac755. [Epub ahead of print]
    OCT4 interprets and enhances nucleosome flexibility.
    Caitlin M MacCarthy, Jan Huertas, Claudia Ortmeier, Hermann Vom Bruch, Daisylyn Senna Tan, Deike Reinke, Astrid Sander, Tim Bergbrede, Ralf Jauch, Hans R Schöler, Vlad Cojocaru.
      Pioneer transcription factors are proteins that induce cellular identity transitions by binding to inaccessible regions of DNA in nuclear chromatin. They contribute to chromatin opening and recruit other factors to regulatory DNA elements. The structural features and dynamics modulating their interaction with nucleosomes are still unresolved. From a combination of experiments and molecular simulations, we reveal here how the pioneer factor and master regulator of pluripotency, Oct4, interprets and enhances nucleosome structural flexibility. The magnitude of Oct4's impact on nucleosome dynamics depends on the binding site position and the mobility of the unstructured tails of nucleosomal histone proteins. Oct4 uses both its DNA binding domains to propagate and stabilize open nucleosome conformations, one for specific sequence recognition and the other for nonspecific interactions with nearby regions of DNA. Our findings provide a structural basis for the versatility of transcription factors in engaging with nucleosomes and have implications for understanding how pioneer factors induce chromatin dynamics.
    DOI:  https://doi.org/10.1093/nar/gkac755
  7. Nat Commun. 2022 Sep 19. 13(1): 5447
    Dominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm.
    Zeyang Wang, Rui Fan, Angela Russo, Filippo M Cernilogar, Alexander Nuber, Silvia Schirge, Irina Shcherbakova, Iva Dzhilyanova, Enes Ugur, Tobias Anton, Lisa Richter, Heinrich Leonhardt, Heiko Lickert, Gunnar Schotta.
      Silencing of endogenous retroviruses (ERVs) is largely mediated by repressive chromatin modifications H3K9me3 and DNA methylation. On ERVs, these modifications are mainly deposited by the histone methyltransferase Setdb1 and by the maintenance DNA methyltransferase Dnmt1. Knock-out of either Setdb1 or Dnmt1 leads to ERV de-repression in various cell types. However, it is currently not known if H3K9me3 and DNA methylation depend on each other for ERV silencing. Here we show that conditional knock-out of Setdb1 in mouse embryonic endoderm results in ERV de-repression in visceral endoderm (VE) descendants and does not occur in definitive endoderm (DE). Deletion of Setdb1 in VE progenitors results in loss of H3K9me3 and reduced DNA methylation of Intracisternal A-particle (IAP) elements, consistent with up-regulation of this ERV family. In DE, loss of Setdb1 does not affect H3K9me3 nor DNA methylation, suggesting Setdb1-independent pathways for maintaining these modifications. Importantly, Dnmt1 knock-out results in IAP de-repression in both visceral and definitive endoderm cells, while H3K9me3 is unaltered. Thus, our data suggest a dominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm cells. Our findings suggest that Setdb1-meditated H3K9me3 is not sufficient for IAP silencing, but rather critical for maintaining high DNA methylation.
    DOI:  https://doi.org/10.1038/s41467-022-32978-7
  8. Nat Commun. 2022 Sep 20. 13(1): 5498
    Deciphering multi-way interactions in the human genome.
    Gabrielle A Dotson, Can Chen, Stephen Lindsly, Anthony Cicalo, Sam Dilworth, Charles Ryan, Sivakumar Jeyarajan, Walter Meixner, Cooper Stansbury, Joshua Pickard, Nicholas Beckloff, Amit Surana, Max Wicha, Lindsey A Muir, Indika Rajapakse.
      Chromatin architecture, a key regulator of gene expression, can be inferred using chromatin contact data from chromosome conformation capture, or Hi-C. However, classical Hi-C does not preserve multi-way contacts. Here we use long sequencing reads to map genome-wide multi-way contacts and investigate higher order chromatin organization in the human genome. We use hypergraph theory for data representation and analysis, and quantify higher order structures in neonatal fibroblasts, biopsied adult fibroblasts, and B lymphocytes. By integrating multi-way contacts with chromatin accessibility, gene expression, and transcription factor binding, we introduce a data-driven method to identify cell type-specific transcription clusters. We provide transcription factor-mediated functional building blocks for cell identity that serve as a global signature for cell types.
    DOI:  https://doi.org/10.1038/s41467-022-32980-z
  9. Nucleic Acids Res. 2022 Sep 21. pii: gkac760. [Epub ahead of print]
    The transcriptional coactivator Eya1 exerts transcriptional repressive activity by interacting with REST corepressors and REST-binding sequences to maintain nephron progenitor identity.
    Jun Li, Chunming Cheng, Jinshu Xu, Ting Zhang, Bengu Tokat, Georgia Dolios, Aarthi Ramakrishnan, Li Shen, Rong Wang, Pin-Xian Xu.
      Eya1 is critical for establishing and maintaining nephron progenitor cells (NPCs). It belongs to a family of proteins called phosphatase-transcriptional activators but without intrinsic DNA-binding activity. However, the spectrum of the Eya1-centered networks is underexplored. Here, we combined transcriptomic, genomic and proteomic approaches to characterize gene regulation by Eya1 in the NPCs. We identified Eya1 target genes, associated cis-regulatory elements and partner proteins. Eya1 preferentially occupies promoter sequences and interacts with general transcription factors (TFs), RNA polymerases, different types of TFs, chromatin-remodeling factors with ATPase or helicase activity, and DNA replication/repair proteins. Intriguingly, we identified REST-binding motifs in 76% of Eya1-occupied sites without H3K27ac-deposition, which were present in many Eya1 target genes upregulated in Eya1-deficient NPCs. Eya1 copurified REST-interacting chromatin-remodeling factors, histone deacetylase/lysine demethylase, and corepressors. Coimmunoprecipitation validated physical interaction between Eya1 and Rest/Hdac1/Cdyl/Hltf in the kidneys. Collectively, our results suggest that through interactions with chromatin-remodeling factors and specialized DNA-binding proteins, Eya1 may modify chromatin structure to facilitate the assembly of regulatory complexes that regulate transcription positively or negatively. These findings provide a mechanistic basis for how Eya1 exerts its activity by forming unique multiprotein complexes in various biological processes to maintain the cellular state of NPCs.
    DOI:  https://doi.org/10.1093/nar/gkac760
  10. Genome Biol. 2022 Sep 20. 23(1): 197
    DNA methylation underpins the epigenomic landscape regulating genome transcription in Arabidopsis.
    Lun Zhao, Qiangwei Zhou, Li He, Li Deng, Rosa Lozano-Duran, Guoliang Li, Jian-Kang Zhu.
      BACKGROUND: It is challenging to determine the effect of DNA methylation on the epigenetic landscape and the function in higher organisms due to the lack of DNA methylation-free mutants.RESULTS: Here, the analysis of a recently generated Arabidopsis mutant completely devoid of DNA methylation reveals that DNA methylation underpins the genome-wide landscape of histone modifications. Complete loss of DNA methylation causes an upheaval of the histone modification landscape, including complete loss of H3K9me2 and widespread redistribution of active and H3K27me3 histone marks, mostly owing to the role of DNA methylation in initiating H3K9me2 deposition and excluding active marks and repressive mark H3K27me3; CG and non-CG methylation can act independently at some genomic regions while they act cooperatively at many other regions. The transcriptional reprogramming upon loss of all DNA methylation correlates with the extensive redistribution or switches of the examined histone modifications. Histone modifications retained or gained in the DNA methylation-free mutant serve as DNA methylation-independent transcriptional regulatory signals: active marks promote genome transcription, whereas the repressive mark H3K27me3 compensates for the lack of DNA hypermethylation/H3K9me2 at multiple transposon families.
    CONCLUSIONS: Our results show that an intact DNA methylome constitutes the scaffolding of the epigenomic landscape in Arabidopsis and is critical for controlled genome transcription and ultimately for proper growth and development.
    Keywords:  Chromatin state; DNA methylation-free plant; Histone modification
    DOI:  https://doi.org/10.1186/s13059-022-02768-x
  11. Nucleic Acids Res. 2022 Sep 21. pii: gkac791. [Epub ahead of print]
    HTCA: a database with an in-depth characterization of the single-cell human transcriptome.
    Lu Pan, Shaobo Shan, Roman Tremmel, Weiyuan Li, Zehuan Liao, Hangyu Shi, Qishuang Chen, Xiaolu Zhang, Xuexin Li.
      Single-cell RNA-sequencing (scRNA-seq) is one of the most used single-cell omics in recent decades. The exponential growth of single-cell data has immense potential for large-scale integration and in-depth explorations that are more representative of the study population. Efforts have been made to consolidate published data, yet extensive characterization is still lacking. Many focused on raw-data database constructions while others concentrate mainly on gene expression queries. Hereby, we present HTCA (www.htcatlas.org), an interactive database constructed based on ∼2.3 million high-quality cells from ∼3000 scRNA-seq samples and comprised in-depth phenotype profiles of 19 healthy adult and matching fetal tissues. HTCA provides a one-stop interactive query to gene signatures, transcription factor (TF) activities, TF motifs, receptor-ligand interactions, enriched gene ontology (GO) terms, etc. across cell types in adult and fetal tissues. At the same time, HTCA encompasses single-cell splicing variant profiles of 16 adult and fetal tissues, spatial transcriptomics profiles of 11 adult and fetal tissues, and single-cell ATAC-sequencing (scATAC-seq) profiles of 27 adult and fetal tissues. Besides, HTCA provides online analysis tools to perform major steps in a typical scRNA-seq analysis. Altogether, HTCA allows real-time explorations of multi-omics adult and fetal phenotypic profiles and provides tools for a flexible scRNA-seq analysis.
    DOI:  https://doi.org/10.1093/nar/gkac791
  12. Cell Rep. 2022 Sep 20. pii: S2211-1247(22)01195-0. [Epub ahead of print]40(12): 111363
    Single-cell sequencing reveals activation of core transcription factors in PRC2-deficient malignant peripheral nerve sheath tumor.
    Xiyuan Zhang, Hannah E Lou, Vishaka Gopalan, Zhihui Liu, Hilda M Jafarah, Haiyan Lei, Paige Jones, Carly M Sayers, Marielle E Yohe, Prashant Chittiboina, Brigitte C Widemann, Carol J Thiele, Michael C Kelly, Sridhar Hannenhalli, Jack F Shern.
      Loss-of-function mutations in the polycomb repressive complex 2 (PRC2) occur frequently in malignant peripheral nerve sheath tumor, an aggressive sarcoma that arises from NF1-deficient Schwann cells. To define the oncogenic mechanisms underlying PRC2 loss, we use engineered cells that dynamically reassemble a competent PRC2 coupled with single-cell sequencing from clinical samples. We discover a two-pronged oncogenic process: first, PRC2 loss leads to remodeling of the bivalent chromatin and enhancer landscape, causing the upregulation of developmentally regulated transcription factors that enforce a transcriptional circuit serving as the cell's core vulnerability. Second, PRC2 loss reduces type I interferon signaling and antigen presentation as downstream consequences of hyperactivated Ras and its cross talk with STAT/IRF transcription factors. Mapping of the transcriptional program of these PRC2-deficient tumor cells onto a constructed developmental trajectory of normal Schwann cells reveals that changes induced by PRC2 loss enforce a cellular profile characteristic of a primitive mesenchymal neural crest stem cell.
    Keywords:  CP: Cancer; FOXC1; HOXB8; NF1; PRC2; bivalent gene; neural crest stem cell; neurofibromatosis type 1; polycomb repressive complex 2; single-cell sequencing; transcription factor
    DOI:  https://doi.org/10.1016/j.celrep.2022.111363
  13. Plant Cell. 2022 Sep 19. pii: koac282. [Epub ahead of print]
    Greenscreen: A simple method to remove artifactual signals and enrich for true peaks in genomic datasets including ChIP-seq data.
    Samantha Klasfeld, Thomas Roulé, Doris Wagner.
      Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is widely used to identify factor binding to genomic DNA and chromatin modifications. ChIP-seq data analysis is affected by genomic regions that generate ultra-high artifactual signals. To remove these signals from ChIP-seq data, the ENCODE project developed comprehensive sets of regions defined by low mappability and ultra-high signals called blacklists for human, mouse (Mus musculus), nematode (Caenorhabditis elegans), and fruit fly (Drosophila melanogaster). However, blacklists are not currently available for many model and non-model species. Here we describe an alternative approach for removing false-positive peaks called greenscreen. Greenscreen is easy to implement, requires few input samples, and uses analysis tools frequently employed for ChIP-seq. Greenscreen removes artifactual signals as effectively as blacklists in Arabidopsis thaliana and human ChIP-seq dataset while covering less of the genome and dramatically improves ChIP-seq peak calling and downstream analyses. Greenscreen filtering reveals true factor binding overlap and occupancy changes in different genetic backgrounds or tissues. Because it is effective with as few as two inputs, greenscreen is readily adaptable for use in any species or genome build. Although developed for ChIP-seq, greenscreen also identifies artifactual signals from other genomic datasets including CUT&RUN. We present an improved ChIP-seq pipeline incorporating greenscreen that detects more true peaks than other methods.
    DOI:  https://doi.org/10.1093/plcell/koac282
  14. Nucleic Acids Res. 2022 Sep 21. pii: gkac757. [Epub ahead of print]
    Chromatin transitions triggered by LH density as epigenetic regulators of the genome.
    Stephanie Portillo-Ledesma, Meghna Wagley, Tamar Schlick.
      Motivated by experiments connecting linker histone (LH) deficiency to lymphoma progression and retinal disorders, we study by mesoscale chromatin modeling how LH density (ρ) induces gradual, as well sudden, changes in chromatin architecture and how the process depends on DNA linker length, LH binding dynamics and binding mode, salt concentration, tail modifications, and combinations of ρ and linker DNA length. We show that ρ tightly regulates the overall shape and compaction of the fiber, triggering a transition from an irregular disordered state to a compact and ordered structure. Such a structural transition, resembling B to A compartment transition connected with lymphoma of B cells, appears to occur around ρ = 0.5. The associated mechanism is DNA stem formation by LH binding, which is optimal when the lengths of the DNA linker and LH C-terminal domain are similar. Chromatin internal and external parameters are key regulators, promoting or impeding the transition. The LH density thus emerges as a critical tunable variable in controlling cellular functions through structural transitions of the genome.
    DOI:  https://doi.org/10.1093/nar/gkac757
  15. J Cell Sci. 2022 Sep 20. pii: jcs.260082. [Epub ahead of print]
    The oncogenic transcription factor FOXQ1 is a differential regulator of Wnt target genes.
    Giulia Pizzolato, Lavanya Moparthi, Simon Söderholm, Claudio Cantù, Stefan Koch.
      The forkhead box transcription factor FOXQ1 contributes to the pathogenesis of carcinomas. In colorectal cancers, FOXQ1 promotes tumour metastasis by inducing epithelial-to-mesenchymal transition (EMT) of cancer cells. FOXQ1 may exacerbate cancer by activating the oncogenic Wnt/-catenin signalling pathway. However, the role of FOXQ1 in the Wnt pathway remains to be resolved. Here, we report that FOXQ1 is an activator of Wnt-induced transcription and regulator of b-catenin target gene expression. Upon Wnt pathway activation, FOXQ1 synergises with the b-catenin nuclear complex to boost the expression of major Wnt targets. In parallel, we find that FOXQ1 controls the differential expression of various Wnt target genes in a b-catenin-independent manner. Using RNA sequencing of colorectal cancer cell lines, we show that Wnt signalling and FOXQ1 converge on a transcriptional program linked to EMT and cell migration. Additionally, we demonstrate that FOXQ1 occupies Wnt-responsive elements in b-catenin target gene promoters and recruits a similar set of co-factors as the b-catenin-associated transcription factor Tcf7l1. Taken together, our results indicate a multifaceted role of FOXQ1 in Wnt/b-catenin signalling, which may drive the metastasis of colorectal cancers.
    Keywords:  Colorectal cancer; Forkhead box; Gene expression; Proteomics; Wnt signalling
    DOI:  https://doi.org/10.1242/jcs.260082
  16. Database (Oxford). 2022 Sep 16. pii: baac083. [Epub ahead of print]2022
    TFLink: an integrated gateway to access transcription factor-target gene interactions for multiple species.
    Orsolya Liska, Balázs Bohár, András Hidas, Tamás Korcsmáros, Balázs Papp, Dávid Fazekas, Eszter Ari.
      Analysis of transcriptional regulatory interactions and their comparisons across multiple species are crucial for progress in various fields in biology, from functional genomics to the evolution of signal transduction pathways. However, despite the rapidly growing body of data on regulatory interactions in several eukaryotes, no databases exist to provide curated high-quality information on transcription factor-target gene interactions for multiple species. Here, we address this gap by introducing the TFLink gateway, which uniquely provides experimentally explored and highly accurate information on transcription factor-target gene interactions (∼12 million), nucleotide sequences and genomic locations of transcription factor binding sites (∼9 million) for human and six model organisms: mouse, rat, zebrafish, fruit fly, worm and yeast by integrating 10 resources. TFLink provides user-friendly access to data on transcription factor-target gene interactions, interactive network visualizations and transcription factor binding sites, with cross-links to several other databases. Besides containing accurate information on transcription factors, with a clear labelling of the type/volume of the experiments (small-scale or high-throughput), the source database and the original publications, TFLink also provides a wealth of standardized regulatory data available for download in multiple formats. The database offers easy access to high-quality data for wet-lab researchers, supplies data for gene set enrichment analyses and facilitates systems biology and comparative gene regulation studies. Database URL https://tflink.net/.
    DOI:  https://doi.org/10.1093/database/baac083
  17. iScience. 2022 Sep 16. 25(9): 104978
    Confined migration induces heterochromatin formation and alters chromatin accessibility.
    Chieh-Ren Hsia, Jawuanna McAllister, Ovais Hasan, Julius Judd, Seoyeon Lee, Richa Agrawal, Chao-Yuan Chang, Paul Soloway, Jan Lammerding.
      During migration, cells often squeeze through small constrictions, requiring extensive deformation. We hypothesized that nuclear deformation associated with such confined migration could alter chromatin organization and function. By studying cells migrating through microfluidic devices that mimic interstitial spaces in vivo, we found that confined migration results in increased H3K9me3 and H3K27me3 heterochromatin marks that persist for days. This "confined migration-induced heterochromatin" (CMiH) was distinct from heterochromatin formation during migration initiation. Confined migration decreased chromatin accessibility at intergenic regions near centromeres and telomeres, suggesting heterochromatin spreading from existing sites. Consistent with the overall decrease in accessibility, global transcription was decreased during confined migration. Intriguingly, we also identified increased accessibility at promoter regions of genes linked to chromatin silencing, tumor invasion, and DNA damage response. Inhibiting CMiH reduced migration speed, suggesting that CMiH promotes confined migration. Together, our findings indicate that confined migration induces chromatin changes that regulate cell migration and other functions.
    Keywords:  Cell biology; Chromosome organization; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.104978
  18. J Exp Med. 2022 Dec 05. pii: e20212418. [Epub ahead of print]219(12):
    c-MAF coordinates enterocyte zonation and nutrient uptake transcriptional programs.
    Alejandra González-Loyola, Jeremiah Bernier-Latmani, Irena Roci, Tania Wyss, Jakob Langer, Stephan Durot, Olivia Munoz, Borja Prat-Luri, Mauro Delorenzi, Matthias P Lutolf, Nicola Zamboni, Grégory Verdeil, Tatiana V Petrova.
      Small intestinal villi are structural and functional units present in higher vertebrates and uniquely adapted to nutrient absorption. Villus enterocytes are organized in transcriptional "zones" dedicated to specialized tasks such as absorption of specific nutrients. We report that the transcription factor c-MAF is expressed in differentiated lower and mid-villus enterocytes and is a target of BMP signaling. Maf inactivation perturbed the villus zonation program by increasing carbohydrate-related transcripts while suppressing transcripts linked to amino-acid and lipid absorption. The formation of cytoplasmic lipid droplets, shuttling dietary fat to chylomicrons, was impaired upon Maf loss indicating its role in dietary lipid handling. Maf inactivation under homeostatic conditions expanded tuft cells and led to compensatory gut lengthening, preventing weight loss. However, delayed Maf-/- enterocyte maturation impaired weight recovery after acute intestinal injury, resulting in reduced survival. Our results identify c-MAF as a regulator of the intestinal villus zonation program, while highlighting the importance of coordination between stem/progenitor and differentiation programs for intestinal regeneration.
    DOI:  https://doi.org/10.1084/jem.20212418
  19. BMC Bioinformatics. 2022 Sep 19. 23(1): 383
    msPIPE: a pipeline for the analysis and visualization of whole-genome bisulfite sequencing data.
    Heesun Kim, Mikang Sim, Nayoung Park, Kisang Kwon, Junyoung Kim, Jaebum Kim.
      BACKGROUND: DNA methylation is an important epigenetic modification that is known to regulate gene expression. Whole-genome bisulfite sequencing (WGBS) is a powerful method for studying cytosine methylation in a whole genome. However, it is difficult to obtain methylation profiles using the WGBS raw reads and is necessary to be proficient in all types of bioinformatic tools for the study of DNA methylation. In addition, recent end-to-end pipelines for DNA methylation analyses are not sufficient for addressing those difficulties.RESULTS: Here we present msPIPE, a pipeline for DNA methylation analyses with WGBS data seamlessly connecting all the required tasks ranging from data pre-processing to multiple downstream DNA methylation analyses. The msPIPE can generate various methylation profiles to analyze methylation patterns in the given sample, including statistical summaries and methylation levels. Also, the methylation levels in the functional regions of a genome are computed with proper annotation. The results of methylation profiles, hypomethylation, and differential methylation analysis are plotted in publication-quality figures. The msPIPE can be easily and conveniently used with a Docker image, which includes all dependent packages and software related to DNA methylation analyses.
    CONCLUSION: msPIPE is a new end-to-end pipeline designed for methylation calling, profiling, and various types of downstream DNA methylation analyses, leading to the creation of publication-quality figures. msPIPE allows researchers to process and analyze the WGBS data in an easy and convenient way. It is available at https://github.com/jkimlab/msPIPE and https://hub.docker.com/r/jkimlab/mspipe .
    Keywords:  DNA methylation; Next generation sequencing; Pipeline; Whole-genome bisulfite sequencing
    DOI:  https://doi.org/10.1186/s12859-022-04925-2
  20. Nat Genet. 2022 Sep 19.
    The evolutionary dynamics of extrachromosomal DNA in human cancers.
    Joshua T Lange, John C Rose, Celine Y Chen, Yuriy Pichugin, Liangqi Xie, Jun Tang, King L Hung, Kathryn E Yost, Quanming Shi, Marcella L Erb, Utkrisht Rajkumar, Sihan Wu, Sabine Taschner-Mandl, Marie Bernkopf, Charles Swanton, Zhe Liu, Weini Huang, Howard Y Chang, Vineet Bafna, Anton G Henssen, Benjamin Werner, Paul S Mischel.
      Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance-random identity by descent-is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.
    DOI:  https://doi.org/10.1038/s41588-022-01177-x
  21. Commun Biol. 2022 Sep 19. 5(1): 953
    Asymmetric chromatin retention and nuclear envelopes separate chromosomes in fused cells in vivo.
    Bharath Sunchu, Nicole MynYi Lee, Jennifer A Taylor, Roberto Carlos Segura, Chantal Roubinet, Clemens Cabernard.
      Hybrid cells derived through fertilization or somatic cell fusion recognize and separate chromosomes of different origins. The underlying mechanisms are unknown but could prevent aneuploidy and tumor formation. Here, we acutely induce fusion between Drosophila neural stem cells (neuroblasts; NBs) and differentiating ganglion mother cells (GMCs) in vivo to define how epigenetically distinct chromatin is recognized and segregated. We find that NB-GMC hybrid cells align both endogenous (neuroblast-origin) and ectopic (GMC-origin) chromosomes at the metaphase plate through centrosome derived dual-spindles. Physical separation of endogenous and ectopic chromatin is achieved through asymmetric, microtubule-dependent chromatin retention in interphase and physical boundaries imposed by nuclear envelopes. The chromatin separation mechanisms described here could apply to the first zygotic division in insects, arthropods, and vertebrates or potentially inform biased chromatid segregation in stem cells.
    DOI:  https://doi.org/10.1038/s42003-022-03874-z
  22. Nat Commun. 2022 Sep 19. 13(1): 5478
    ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer.
    Radia M Johnson, Xueping Qu, Chu-Fang Lin, Ling-Yuh Huw, Avinashnarayan Venkatanarayan, Ethan Sokol, Fang-Shu Ou, Nnamdi Ihuegbu, Oliver A Zill, Omar Kabbarah, Lisa Wang, Richard Bourgon, Felipe de Sousa E Melo, Chris Bolen, Anneleen Daemen, Alan P Venook, Federico Innocenti, Heinz-Josef Lenz, Carlos Bais.
      Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for emerging ARID1A mutations in CRC patients. In addition, we find that patients with ARID1A mutations, at baseline, are associated with worse outcome when treated with cetuximab- but not bevacizumab-containing therapies; thus, this suggests that ARID1A mutations may provide both an acquired and intrinsic mechanism of resistance to anti-EGFR therapies. We find that, ARID1A and EGFR-pathway genetic alterations are mutually exclusive across lung and colorectal cancers, further supporting a functional connection between these pathways. Our results not only suggest that ARID1A could be potentially used as a predictive biomarker for cetuximab treatment decisions but also provide a rationale for exploring therapeutic MAPK inhibition in an unexpected but genetically defined segment of CRC patients.
    DOI:  https://doi.org/10.1038/s41467-022-33172-5
  23. iScience. 2022 Sep 16. 25(9): 105011
    CTCF DNA-binding domain undergoes dynamic and selective protein-protein interactions.
    Rong Zhou, Kai Tian, Jie Huang, Wenjia Duan, Hongye Fu, Ying Feng, Hui Wang, Yongpeng Jiang, Yuanjun Li, Rui Wang, Jiazhi Hu, Hanhui Ma, Zhi Qi, Xiong Ji.
      CTCF is a predominant insulator protein required for three-dimensional chromatin organization. However, the roles of its insulation of enhancers in a 3D nuclear organization have not been fully explained. Here, we found that the CTCF DNA-binding domain (DBD) forms dynamic self-interacting clusters. Strikingly, CTCF DBD clusters were found to incorporate other insulator proteins but are not coenriched with transcriptional activators in the nucleus. This property is not observed in other domains of CTCF or the DBDs of other transcription factors. Moreover, endogenous CTCF shows a phenotype consistent with the DBD by forming small protein clusters and interacting with CTCF motif arrays that have fewer transcriptional activators bound. Our results reveal an interesting phenomenon in which CTCF DBD interacts with insulator proteins and selectively localizes to nuclear positions with lower concentrations of transcriptional activators, providing insights into the insulation function of CTCF.
    Keywords:  Biological sciences; Molecular biology; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2022.105011
  24. Cell Rep. 2022 Sep 20. pii: S2211-1247(22)01202-5. [Epub ahead of print]40(12): 111370
    Single-cell transcriptomics identifies conserved regulators of neuroglandular lineages.
    Julia Steger, Alison G Cole, Andreas Denner, Tatiana Lebedeva, Grigory Genikhovich, Alexander Ries, Robert Reischl, Elisabeth Taudes, Mark Lassnig, Ulrich Technau.
      Communication in bilaterian nervous systems is mediated by electrical and secreted signals; however, the evolutionary origin and relation of neurons to other secretory cell types has not been elucidated. Here, we use developmental single-cell RNA sequencing in the cnidarian Nematostella vectensis, representing an early evolutionary lineage with a simple nervous system. Validated by transgenics, we demonstrate that neurons, stinging cells, and gland cells arise from a common multipotent progenitor population. We identify the conserved transcription factor gene SoxC as a key upstream regulator of all neuroglandular lineages and demonstrate that SoxC knockdown eliminates both neuronal and secretory cell types. While in vertebrates and many other bilaterians neurogenesis is largely restricted to early developmental stages, we show that in the sea anemone, differentiation of neuroglandular cells is maintained throughout all life stages, and follows the same molecular trajectories from embryo to adulthood, ensuring lifelong homeostasis of neuroglandular cell lineages.
    Keywords:  CP: cell biology; CP: developmental biology; Nanos; Nematostella vectensis; Sox genes; cell type specification; cnidogenesis; homeostasis; neural progenitor cell; neuronal differentiation; neurosecretory cells; scRNA-seq
    DOI:  https://doi.org/10.1016/j.celrep.2022.111370
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