bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2022–06–05
nineteen papers selected by
Connor Rogerson, University of Cambridge
  1. JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation.
  2. EPIXplorer: A web server for prediction, analysis and visualization of enhancer-promoter interactions.
  3. Identifying synergistic high-order 3D chromatin conformations from genome-scale nanopore concatemer sequencing.
  4. Enhancer methylation dynamics drive core transcriptional regulatory circuitry in pan-cancer.
  5. Polycomb repressive complex 2 shields naïve human pluripotent cells from trophectoderm differentiation.
  6. DIRECT-NET: An efficient method to discover cis-regulatory elements and construct regulatory networks from single-cell multiomics data.
  7. 3D genome organization in the epithelial-mesenchymal transition spectrum.
  8. DeepLUCIA: predicting tissue-specific chromatin loops using Deep Learning-based Universal Chromatin Interaction Annotator.
  9. Ccr4-Not complex reduces transcription efficiency in heterochromatin.
  10. FABIAN-variant: predicting the effects of DNA variants on transcription factor binding.
  11. Detecting critical transition signals from single-cell transcriptomes to infer lineage-determining transcription factors.
  12. Differential cofactor dependencies define distinct types of human enhancers.
  13. Differential Etv2 threshold requirement for endothelial and erythropoietic development.
  14. Enhanced transcriptional heterogeneity mediated by NF-κB super-enhancers.
  15. BRD4 promotes resection and homology-directed repair of DNA double-strand breaks.
  16. NT-seq: a chemical-based sequencing method for genomic methylome profiling.
  17. YAP inhibits ERα and ER+ breast cancer growth by disrupting a TEAD-ERα signaling axis.
  18. Detecting TAD-like domains from RNA-associated interactions.
  19. RNA inhibits dMi-2/CHD4 chromatin binding and nucleosome remodeling.
  1. Cell Rep. 2022 May 31. pii: S2211-1247(22)00664-7. [Epub ahead of print]39(9): 110889
    JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation.
    Manuel Tavares, Garima Khandelwal, Joanne Muter, Keijo Viiri, Manuel Beltran, Jan J Brosens, Richard G Jenner.
      Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 (H3K27me3) to maintain gene repression and is essential for cell differentiation. In low-grade endometrial stromal sarcoma (LG-ESS), the PRC2 subunit SUZ12 is often fused with the NuA4/TIP60 subunit JAZF1. We show that JAZF1-SUZ12 dysregulates PRC2 composition, genome occupancy, histone modification, gene expression, and cell differentiation. Loss of the SUZ12 N terminus in the fusion protein abrogates interaction with specific PRC2 accessory factors, reduces occupancy at PRC2 target genes, and diminishes H3K27me3. Fusion to JAZF1 increases H4Kac at PRC2 target genes and triggers recruitment to JAZF1 binding sites during cell differentiation. In human endometrial stromal cells, JAZF1-SUZ12 upregulated PRC2 target genes normally activated during decidualization while repressing genes associated with immune clearance, and JAZF1-SUZ12-induced genes were also overexpressed in LG-ESS. These results reveal defects in chromatin regulation, gene expression, and cell differentiation caused by JAZF1-SUZ12 that may underlie its role in oncogenesis.
    Keywords:  CP: Molecular biology; cell differentiation; chromatin; decidualization; embryonic stem cell; endometrial stromal sarcoma; endometrium; epigenetics; histone acetylation; histone modification; polycomb
    DOI:  https://doi.org/10.1016/j.celrep.2022.110889
  2. Nucleic Acids Res. 2022 May 25. pii: gkac397. [Epub ahead of print]
    EPIXplorer: A web server for prediction, analysis and visualization of enhancer-promoter interactions.
    Li Tang, Zhizhou Zhong, Yisheng Lin, Yifei Yang, Jun Wang, James F Martin, Min Li.
      Long distance enhancers can physically interact with promoters to regulate gene expression through formation of enhancer-promoter (E-P) interactions. Identification of E-P interactions is also important for profound understanding of normal developmental and disease-associated risk variants. Although the state-of-art predictive computation methods facilitate the identification of E-P interactions to a certain extent, currently there is no efficient method that can meet various requirements of usage. Here we developed EPIXplorer, a user-friendly web server for efficient prediction, analysis and visualization of E-P interactions. EPIXplorer integrates 9 robust predictive algorithms, supports multiple types of 3D contact data and multi-omics data as input. The output from EPIXplorer is scored, fully annotated by regulatory elements and risk single-nucleotide polymorphisms (SNPs). In addition, the Visualization and Downstream module provide further functional analysis, all the output files and high-quality images are available for download. Together, EPIXplorer provides a user-friendly interface to predict the E-P interactions in an acceptable time, as well as understand how the genome-wide association study (GWAS) variants influence disease pathology by altering DNA looping between enhancers and the target gene promoters. EPIXplorer is available at https://www.csuligroup.com/EPIXplorer.
    DOI:  https://doi.org/10.1093/nar/gkac397
  3. Nat Biotechnol. 2022 May 30.
    Identifying synergistic high-order 3D chromatin conformations from genome-scale nanopore concatemer sequencing.
    Aditya S Deshpande, Netha Ulahannan, Matthew Pendleton, Xiaoguang Dai, Lynn Ly, Julie M Behr, Stefan Schwenk, Will Liao, Michael A Augello, Carly Tyer, Priyesh Rughani, Sarah Kudman, Huasong Tian, Hannah G Otis, Emily Adney, David Wilkes, Juan Miguel Mosquera, Christopher E Barbieri, Ari Melnick, David Stoddart, Daniel J Turner, Sissel Juul, Eoghan Harrington, Marcin Imieliński.
      High-order three-dimensional (3D) interactions between more than two genomic loci are common in human chromatin, but their role in gene regulation is unclear. Previous high-order 3D chromatin assays either measure distant interactions across the genome or proximal interactions at selected targets. To address this gap, we developed Pore-C, which combines chromatin conformation capture with nanopore sequencing of concatemers to profile proximal high-order chromatin contacts at the genome scale. We also developed the statistical method Chromunity to identify sets of genomic loci with frequencies of high-order contacts significantly higher than background ('synergies'). Applying these methods to human cell lines, we found that synergies were enriched in enhancers and promoters in active chromatin and in highly transcribed and lineage-defining genes. In prostate cancer cells, these included binding sites of androgen-driven transcription factors and the promoters of androgen-regulated genes. Concatemers of high-order contacts in highly expressed genes were demethylated relative to pairwise contacts at the same loci. Synergies in breast cancer cells were associated with tyfonas, a class of complex DNA amplicons. These results rigorously link genome-wide high-order 3D interactions to lineage-defining transcriptional programs and establish Pore-C and Chromunity as scalable approaches to assess high-order genome structure.
    DOI:  https://doi.org/10.1038/s41587-022-01289-z
  4. Oncogene. 2022 Jun 02.
    Enhancer methylation dynamics drive core transcriptional regulatory circuitry in pan-cancer.
    Xu Pan, Xin Li, Jie Sun, Zhiying Xiong, Haoyu Hu, Shangwei Ning, Hui Zhi.
      Accumulating evidence has demonstrated that enhancer methylation has strong and dynamic regulatory effects on gene expression. Some transcription factors (TFs) can auto- and cross-regulate in a feed-forward manner, and cooperate with their enhancers to form core transcriptional regulatory circuitries (CRCs). However, the elaborated regulatory mechanism between enhancer methylation and CRC remains the tip of the iceberg. Here, we revealed that DNA methylation could drive the tissue-specific enhancer basal transcription and target gene expression in human cancers. By integrating methylome, transcriptome, and 3D genomic data, we identified enhancer methylation triplets (enhancer methylation-enhancer transcription-target gene expression) and dissected potential regulatory patterns within them. Moreover, we observed that cancer-specific core TFs regulated by enhancers were able to shape their enhancer methylation forming the enhancer methylation-driven CRCs (emCRCs). Further parsing of clinical implications showed rewired emCRCs could serve as druggable targets and prognostic risk markers. In summary, the integrative analysis of enhancer methylation regulome would facilitate portraying the cancer epigenomics landscape and developing the epigenetic anti-cancer approaches.
    DOI:  https://doi.org/10.1038/s41388-022-02359-x
  5. Nat Cell Biol. 2022 May 30.
    Polycomb repressive complex 2 shields naïve human pluripotent cells from trophectoderm differentiation.
    Banushree Kumar, Carmen Navarro, Nerges Winblad, John P Schell, Cheng Zhao, Jere Weltner, Laura Baqué-Vidal, Angelo Salazar Mantero, Sophie Petropoulos, Fredrik Lanner, Simon J Elsässer.
      The first lineage choice in human embryo development separates trophectoderm from the inner cell mass. Naïve human embryonic stem cells are derived from the inner cell mass and offer possibilities to explore how lineage integrity is maintained. Here, we discover that polycomb repressive complex 2 (PRC2) maintains naïve pluripotency and restricts differentiation to trophectoderm and mesoderm lineages. Through quantitative epigenome profiling, we found that a broad gain of histone H3 lysine 27 trimethylation (H3K27me3) is a distinct feature of naïve pluripotency. We define shared and naïve-specific bivalent promoters featuring PRC2-mediated H3K27me3 concomitant with H3K4me3. Naïve bivalency maintains key trophectoderm and mesoderm transcription factors in a transcriptionally poised state. Inhibition of PRC2 forces naïve human embryonic stem cells into an 'activated' state, characterized by co-expression of pluripotency and lineage-specific transcription factors, followed by differentiation into either trophectoderm or mesoderm lineages. In summary, PRC2-mediated repression provides a highly adaptive mechanism to restrict lineage potential during early human development.
    DOI:  https://doi.org/10.1038/s41556-022-00916-w
  6. Sci Adv. 2022 Jun 03. 8(22): eabl7393
    DIRECT-NET: An efficient method to discover cis-regulatory elements and construct regulatory networks from single-cell multiomics data.
    Lihua Zhang, Jing Zhang, Qing Nie.
      The emergence of single-cell multiomics data provides unprecedented opportunities to scrutinize the transcriptional regulatory mechanisms controlling cell identity. However, how to use those datasets to dissect the cis-regulatory element (CRE)-to-gene relationships at a single-cell level remains a major challenge. Here, we present DIRECT-NET, a machine-learning method based on gradient boosting, to identify genome-wide CREs and their relationship to target genes, either from parallel single-cell gene expression and chromatin accessibility data or from single-cell chromatin accessibility data alone. By extensively evaluating and characterizing DIRECT-NET's predicted CREs using independent functional genomics data, we find that DIRECT-NET substantially improves the accuracy of inferring CRE-to-gene relationships in comparison to existing methods. DIRECT-NET is also capable of revealing cell subpopulation-specific and dynamic regulatory linkages. Overall, DIRECT-NET provides an efficient tool for predicting transcriptional regulation codes from single-cell multiomics data.
    DOI:  https://doi.org/10.1126/sciadv.abl7393
  7. Genome Biol. 2022 May 30. 23(1): 121
    3D genome organization in the epithelial-mesenchymal transition spectrum.
    Qing You Pang, Tuan Zea Tan, Vignesh Sundararajan, Yi-Chia Chiu, Edward Yu Wing Chee, Vin Yee Chung, Mahesh A Choolani, Ruby Yun-Ju Huang.
       BACKGROUND: The plasticity along the epithelial-mesenchymal transition (EMT) spectrum has been shown to be regulated by various epigenetic repertoires. Emerging evidence of local chromatin conformation changes suggests that regulation of EMT may occur at a higher order of three-dimensional genome level.
    RESULTS: We perform Hi-C analysis and combine ChIP-seq data across cancer cell lines representing different EMT states. We demonstrate that the epithelial and mesenchymal genes are regulated distinctively. We find that EMT genes are regulated within their topologically associated domains (TADs), with only a subset of mesenchymal genes being influenced by A/B compartment switches, indicating topological remodeling is required in the transcriptional regulation of these genes. At the TAD level, epithelial and mesenchymal genes are associated with different regulatory trajectories. The epithelial gene-residing TADs are enriched with H3K27me3 marks in the mesenchymal-like states. The mesenchymal gene-residing TADs, which do not show enrichment of H3K27me3 in epithelial-like states, exhibit increased interaction frequencies with regulatory elements in the mesenchymal-like states.
    CONCLUSIONS: We propose a novel workflow coupling immunofluorescence and dielectrophoresis to unravel EMT heterogeneity at single-cell resolution. The predicted three-dimensional structures of chromosome 10, harboring Vimentin, identify cell clusters of different states. Our results pioneer a novel avenue to decipher the complexities underlying the regulation of EMT and may infer the barriers of plasticity in the 3D genome context.
    DOI:  https://doi.org/10.1186/s13059-022-02687-x
  8. Bioinformatics. 2022 May 31. pii: btac373. [Epub ahead of print]
    DeepLUCIA: predicting tissue-specific chromatin loops using Deep Learning-based Universal Chromatin Interaction Annotator.
    Dongchan Yang, Taesu Chung, Dongsup Kim.
       MOTIVATION: The importance of chromatin loops in gene regulation is broadly accepted. There are mainly two approaches to predict chromatin loops: transcription factor (TF) binding-dependent approach and genomic variation-based approach. However, neither of these approaches provides an adequate understanding of gene regulation in human tissues. To address this issue, we developed a deep learning-based chromatin loop prediction model called DeepLUCIA (Deep Learning-based Universal Chromatin Interaction Annotator).
    RESULTS: Although DeepLUCIA does not use TF binding profile data which previous TF binding-dependent methods critically rely on, its prediction accuracies are comparable to those of the previous TF binding-dependent methods. More importantly, DeepLUCIA enables the tissue-specific chromatin loop predictions from tissue-specific epigenomes that cannot be handled by genomic variation-based approach. We demonstrated the utility of the DeepLUCIA by predicting several novel target genes of SNPs identified in genome-wide association studies targeting Brugada syndrome, COVID-19 severity, and age-related macular degeneration.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btac373
  9. Nucleic Acids Res. 2022 May 30. pii: gkac403. [Epub ahead of print]
    Ccr4-Not complex reduces transcription efficiency in heterochromatin.
    Pablo Monteagudo-Mesas, Cornelia Brönner, Parastou Kohvaei, Haris Amedi, Stefan Canzar, Mario Halic.
      Heterochromatic silencing is thought to occur through a combination of transcriptional silencing and RNA degradation, but the relative contribution of each pathway is not known. In this study, we analyzed RNA Polymerase II (RNA Pol II) occupancy and levels of nascent and steady-state RNA in different mutants of Schizosaccharomyces pombe, in order to quantify the contribution of each pathway to heterochromatic silencing. We found that transcriptional silencing consists of two components, reduced RNA Pol II accessibility and, unexpectedly, reduced transcriptional efficiency. Heterochromatic loci showed lower transcriptional output compared to euchromatic loci, even when comparable amounts of RNA Pol II were present in both types of regions. We determined that the Ccr4-Not complex and H3K9 methylation are required for reduced transcriptional efficiency in heterochromatin and that a subset of heterochromatic RNA is degraded more rapidly than euchromatic RNA. Finally, we quantified the contribution of different chromatin modifiers, RNAi and RNA degradation to each silencing pathway. Our data show that several pathways contribute to heterochromatic silencing in a locus-specific manner and reveal transcriptional efficiency as a new mechanism of silencing.
    DOI:  https://doi.org/10.1093/nar/gkac403
  10. Nucleic Acids Res. 2022 May 26. pii: gkac393. [Epub ahead of print]
    FABIAN-variant: predicting the effects of DNA variants on transcription factor binding.
    Robin Steinhaus, Peter N Robinson, Dominik Seelow.
      While great advances in predicting the effects of coding variants have been made, the assessment of non-coding variants remains challenging. This is especially problematic for variants within promoter regions which can lead to over-expression of a gene or reduce or even abolish its expression. The binding of transcription factors to the DNA can be predicted using position weight matrices (PWMs). More recently, transcription factor flexible models (TFFMs) have been introduced and shown to be more accurate than PWMs. TFFMs are based on hidden Markov models and can account for complex positional dependencies. Our new web-based application FABIAN-variant uses 1224 TFFMs and 3790 PWMs to predict whether and to which degree DNA variants affect the binding of 1387 different human transcription factors. For each variant and transcription factor, the software combines the results of different models for a final prediction of the resulting binding-affinity change. The software is written in C++ for speed but variants can be entered through a web interface. Alternatively, a VCF file can be uploaded to assess variants identified by high-throughput sequencing. The search can be restricted to variants in the vicinity of candidate genes. FABIAN-variant is available freely at https://www.genecascade.org/fabian/.
    DOI:  https://doi.org/10.1093/nar/gkac393
  11. Nucleic Acids Res. 2022 May 30. pii: gkac452. [Epub ahead of print]
    Detecting critical transition signals from single-cell transcriptomes to infer lineage-determining transcription factors.
    Xinan H Yang, Andrew Goldstein, Yuxi Sun, Zhezhen Wang, Megan Wei, Ivan P Moskowitz, John M Cunningham.
      Analyzing single-cell transcriptomes promises to decipher the plasticity, heterogeneity, and rapid switches in developmental cellular state transitions. Such analyses require the identification of gene markers for semi-stable transition states. However, there are nontrivial challenges such as unexplainable stochasticity, variable population sizes, and alternative trajectory constructions. By advancing current tipping-point theory-based models with feature selection, network decomposition, accurate estimation of correlations, and optimization, we developed BioTIP to overcome these challenges. BioTIP identifies a small group of genes, called critical transition signal (CTS), to characterize regulated stochasticity during semi-stable transitions. Although methods rooted in different theories converged at the same transition events in two benchmark datasets, BioTIP is unique in inferring lineage-determining transcription factors governing critical transition. Applying BioTIP to mouse gastrulation data, we identify multiple CTSs from one dataset and validated their significance in another independent dataset. We detect the established regulator Etv2 whose expression change drives the haemato-endothelial bifurcation, and its targets together in CTS across three datasets. After comparing to three current methods using six datasets, we show that BioTIP is accurate, user-friendly, independent of pseudo-temporal trajectory, and captures significantly interconnected and reproducible CTSs. We expect BioTIP to provide great insight into dynamic regulations of lineage-determining factors.
    DOI:  https://doi.org/10.1093/nar/gkac452
  12. Nature. 2022 Jun 01.
    Differential cofactor dependencies define distinct types of human enhancers.
    Christoph Neumayr, Vanja Haberle, Leonid Serebreni, Katharina Karner, Oliver Hendy, Ann Boija, Jonathan E Henninger, Charles H Li, Karel Stejskal, Gen Lin, Katharina Bergauer, Michaela Pagani, Martina Rath, Karl Mechtler, Cosmas D Arnold, Alexander Stark.
      All multicellular organisms rely on differential gene transcription regulated by genomic enhancers, which function through cofactors that are recruited by transcription factors1,2. Emerging evidence suggests that not all cofactors are required at all enhancers3-5, yet whether these observations reflect more general principles or distinct types of enhancers remained unknown. Here we categorized human enhancers by their cofactor dependencies and show that these categories provide a framework to understand the sequence and chromatin diversity of enhancers and their roles in different gene-regulatory programmes. We quantified enhancer activities along the entire human genome using STARR-seq6 in HCT116 cells, following the rapid degradation of eight cofactors. This analysis identified different types of enhancers with distinct cofactor requirements, sequences and chromatin properties. Some enhancers were insensitive to the depletion of the core Mediator subunit MED14 or the bromodomain protein BRD4 and regulated distinct transcriptional programmes. In particular, canonical Mediator7 seemed dispensable for P53-responsive enhancers, and MED14-depleted cells induced endogenous P53 target genes. Similarly, BRD4 was not required for the transcription of genes that bear CCAAT boxes and a TATA box (including histone genes and LTR12 retrotransposons) or for the induction of heat-shock genes. This categorization of enhancers through cofactor dependencies reveals distinct enhancer types that can bypass broadly utilized cofactors, which illustrates how alternative ways to activate transcription separate gene expression programmes and provide a conceptual framework to understand enhancer function and regulatory specificity.
    DOI:  https://doi.org/10.1038/s41586-022-04779-x
  13. Cell Rep. 2022 May 31. pii: S2211-1247(22)00656-8. [Epub ahead of print]39(9): 110881
    Differential Etv2 threshold requirement for endothelial and erythropoietic development.
    Tanvi Sinha, Kelly Lammerts van Bueren, Diane E Dickel, Ivana Zlatanova, Reuben Thomas, Carlos O Lizama, Shan-Mei Xu, Ann C Zovein, Kohta Ikegami, Ivan P Moskowitz, Katherine S Pollard, Len A Pennacchio, Brian L Black.
      Endothelial and erythropoietic lineages arise from a common developmental progenitor. Etv2 is a master transcriptional regulator required for the development of both lineages. However, the mechanisms through which Etv2 initiates the gene-regulatory networks (GRNs) for endothelial and erythropoietic specification and how the two GRNs diverge downstream of Etv2 remain incompletely understood. Here, by analyzing a hypomorphic Etv2 mutant, we demonstrate different threshold requirements for initiation of the downstream GRNs for endothelial and erythropoietic development. We show that Etv2 functions directly in a coherent feedforward transcriptional network for vascular endothelial development, and a low level of Etv2 expression is sufficient to induce and sustain the endothelial GRN. In contrast, Etv2 induces the erythropoietic GRN indirectly via activation of Tal1, which requires a significantly higher threshold of Etv2 to initiate and sustain erythropoietic development. These results provide important mechanistic insight into the divergence of the endothelial and erythropoietic lineages.
    Keywords:  CP: Developmental biology; CP: Molecular biology; Etv2; GRN; Tal1; endothelial development; erythropoiesis; gene regulatory network; hematopoiesis; transcriptional regulation; yolk sac
    DOI:  https://doi.org/10.1016/j.celrep.2022.110881
  14. PLoS Genet. 2022 Jun 01. 18(6): e1010235
    Enhanced transcriptional heterogeneity mediated by NF-κB super-enhancers.
    Johannes N Wibisana, Takehiko Inaba, Hisaaki Shinohara, Noriko Yumoto, Tetsutaro Hayashi, Mana Umeda, Masashi Ebisawa, Itoshi Nikaido, Yasushi Sako, Mariko Okada.
      The transcription factor NF-κB, which plays an important role in cell fate determination, is involved in the activation of super-enhancers (SEs). However, the biological functions of the NF-κB SEs in gene control are not fully elucidated. We investigated the characteristics of NF-κB-mediated SE activity using fluorescence imaging of RelA, single-cell transcriptome and chromatin accessibility analyses in anti-IgM-stimulated B cells. The formation of cell stimulation-induced nuclear RelA foci was abolished in the presence of hexanediol, suggesting an underlying process of liquid-liquid phase separation. The gained SEs induced a switch-like expression and enhanced cell-to-cell variability in transcriptional response. These properties were correlated with the number of gained cis-regulatory interactions, while switch-like gene induction was associated with the number of NF-κB binding sites in SE. Our study suggests that NF-κB SEs have an important role in the transcriptional regulation of B cells possibly through liquid condensate formation consisting of macromolecular interactions.
    DOI:  https://doi.org/10.1371/journal.pgen.1010235
  15. Nat Commun. 2022 May 31. 13(1): 3016
    BRD4 promotes resection and homology-directed repair of DNA double-strand breaks.
    John K Barrows, Baicheng Lin, Colleen E Quaas, George Fullbright, Elizabeth N Wallace, David T Long.
      Double-strand breaks (DSBs) are one of the most toxic forms of DNA damage and represent a major source of genomic instability. Members of the bromodomain and extra-terminal (BET) protein family are characterized as epigenetic readers that regulate gene expression. However, evidence suggests that BET proteins also play a more direct role in DNA repair. Here, we establish a cell-free system using Xenopus egg extracts to elucidate the gene expression-independent functions of BET proteins in DSB repair. We identify the BET protein BRD4 as a critical regulator of homologous recombination and describe its role in stimulating DNA processing through interactions with the SWI/SNF chromatin remodeling complex and resection machinery. These results establish BRD4 as a multifunctional regulator of chromatin binding that links transcriptional activity and homology-directed repair.
    DOI:  https://doi.org/10.1038/s41467-022-30787-6
  16. Genome Biol. 2022 May 30. 23(1): 122
    NT-seq: a chemical-based sequencing method for genomic methylome profiling.
    Xuwen Li, Shiyuan Guo, Yan Cui, Zijian Zhang, Xinlong Luo, Margarita T Angelova, Laura F Landweber, Yinsheng Wang, Tao P Wu.
      DNA methylation plays vital roles in both prokaryotes and eukaryotes. There are three forms of DNA methylation in prokaryotes: N6-methyladenine (6mA), N4-methylcytosine (4mC), and 5-methylcytosine (5mC). Although many sequencing methods have been developed to sequence specific types of methylation, few technologies can be used for efficiently mapping multiple types of methylation. Here, we present NT-seq for mapping all three types of methylation simultaneously. NT-seq reliably detects all known methylation motifs in two bacterial genomes and can be used for identifying de novo methylation motifs. NT-seq provides a simple and efficient solution for detecting multiple types of DNA methylation.
    Keywords:  DNA methylation; Next-generation sequencing; Whole-genome epigenetic profiling
    DOI:  https://doi.org/10.1186/s13059-022-02689-9
  17. Nat Commun. 2022 Jun 02. 13(1): 3075
    YAP inhibits ERα and ER+ breast cancer growth by disrupting a TEAD-ERα signaling axis.
    Xu Li, Shu Zhuo, Ting Zhuang, Yong Suk Cho, Guojin Wu, Yuchen Liu, Kun Mu, Kai Zhang, Peng Su, Yingzi Yang, Cheng Cheng Zhang, Jian Zhu, Jin Jiang.
      Hippo signaling restricts tissue growth by inhibiting the transcriptional effector YAP. Here we uncover a role of Hippo signaling and a tumor suppressor function of YAP in estrogen receptor positive (ER+) breast cancer. We find that inhibition of Hippo/MST1/2 or activation of YAP blocks the ERα transcriptional program and ER+ breast cancer growth. Mechanistically, the Hippo pathway transcription factor TEAD physically interacts with ERα to increase its promoter/enhancer occupancy whereas YAP inhibits ERα/TEAD interaction, decreases ERα occupancy on its target promoters/enhancers, and promotes ERα degradation by the proteasome. Furthermore, YAP inhibits hormone-independent transcription of ERα gene (ESR1). Consistently, high levels of YAP correlate with good prognosis of ER+ breast cancer patients. Finally, we find that pharmacological inhibition of Hippo/MST1/2 impeded tumor growth driven by hormone therapy resistant ERα mutants, suggesting that targeting the Hippo-YAP-TEAD signaling axis could be a potential therapeutical strategy to overcome endocrine therapy resistance conferred by ERα mutants.
    DOI:  https://doi.org/10.1038/s41467-022-30831-5
  18. Nucleic Acids Res. 2022 May 25. pii: gkac422. [Epub ahead of print]
    Detecting TAD-like domains from RNA-associated interactions.
    Yu Wei Zhang, Lingxi Chen, Shuai Cheng Li.
      Topologically associated domains (TADs) are crucial chromatin structural units. Evidence has illustrated that RNA-chromatin and RNA-RNA spatial interactions, so-called RNA-associated interactions (RAIs), may be associated with TAD-like domains (TLDs). To decode hierarchical TLDs from RAIs, we proposed SuperTLD, a domain detection algorithm incorporating imputation. We applied SuperTLD on four RAI data sets and compared TLDs with the TADs identified from the corresponding Hi-C datasets. The TLDs and TADs share a moderate similarity of hierarchies ≥ 0.5312 and the finest structures ≥ 0.8295. Comparison between boundaries and domains further demonstrated the novelty of TLDs. Enrichment analysis of epigenetic characteristics illustrated that the novel TLDs exhibit an enriched CTCF by 0.6245 fold change and H3 histone marks enriched within domains. GO analysis on the TLD novel boundaries exhibited enriched diverse terms, revealing TLDs' formation mechanism related closely to gene regulation.
    DOI:  https://doi.org/10.1093/nar/gkac422
  19. Cell Rep. 2022 May 31. pii: S2211-1247(22)00670-2. [Epub ahead of print]39(9): 110895
    RNA inhibits dMi-2/CHD4 chromatin binding and nucleosome remodeling.
    Ikram Ullah, Clemens Thölken, Yichen Zhong, Mara John, Oliver Rossbach, Jonathan Lenz, Markus Gößringer, Andrea Nist, Lea Albert, Thorsten Stiewe, Roland Hartmann, Olalla Vázquez, Ho-Ryung Chung, Joel P Mackay, Alexander Brehm.
      The ATP-dependent nucleosome remodeler Mi-2/CHD4 broadly modulates chromatin landscapes to repress transcription and to maintain genome integrity. Here we use individual nucleotide resolution crosslinking and immunoprecipitation (iCLIP) to show that Drosophila Mi-2 associates with thousands of mRNA molecules in vivo. Biochemical data reveal that recombinant dMi-2 preferentially binds to G-rich RNA molecules using two intrinsically disordered regions of unclear function. Pharmacological inhibition of transcription and RNase digestion approaches establish that RNA inhibits the association of dMi-2 with chromatin. We also show that RNA inhibits dMi-2-mediated nucleosome mobilization by competing with the nucleosome substrate. Importantly, this activity is shared by CHD4, the human homolog of dMi-2, strongly suggesting that RNA-mediated regulation of remodeler activity is an evolutionary conserved mechanism. Our data support a model in which RNA serves to protect actively transcribed regions of the genome from dMi-2/CHD4-mediated establishment of repressive chromatin structures.
    Keywords:  ATP-dependent chromatin remodeling; CP: Molecular biology; NuRD; RNA; chromatin; gene regulation; iCLIP
    DOI:  https://doi.org/10.1016/j.celrep.2022.110895
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