bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2022–03–27
sixteen papers selected by
Connor Rogerson, University of Cambridge, MRC Cancer Unit
  1. Unveiling RCOR1 as a rheostat at transcriptionally permissive chromatin.
  2. Pan-cancer predictions of transcription factors mediating aberrant DNA methylation.
  3. ChIP-Atlas 2021 update: a data-mining suite for exploring epigenomic landscapes by fully integrating ChIP-seq, ATAC-seq and Bisulfite-seq data.
  4. Massively parallel reporter perturbation assays uncover temporal regulatory architecture during neural differentiation.
  5. HiCuT: An efficient and low input method to identify protein-directed chromatin interactions.
  6. Nuclear receptor activation shapes spatial genome organization essential for gene expression control: lessons learned from the vitamin D receptor.
  7. Optogenetic control of the Bicoid morphogen reveals fast and slow modes of gap gene regulation.
  8. Characterizing cellular heterogeneity in chromatin state with scCUT&Tag-pro.
  9. Genome-wide screening identifies Polycomb repressive complex 1.3 as an essential regulator of human naïve pluripotent cell reprogramming.
  10. AP-2α and AP-2β cooperatively function in the craniofacial surface ectoderm to regulate chromatin and gene expression dynamics during facial development.
  11. The mTOR chromatin-bound interactome in prostate cancer.
  12. Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation.
  13. Shear stress switches the association of endothelial enhancers from ETV/ETS to KLF transcription factor binding sites.
  14. H3K56 deacetylation and H2A.Z deposition are required for aberrant heterochromatin spreading.
  15. Wt1 transcription factor impairs cardiomyocyte specification and drives a phenotypic switch from myocardium to epicardium.
  16. Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors.
  1. Nat Commun. 2022 Mar 23. 13(1): 1550
    Unveiling RCOR1 as a rheostat at transcriptionally permissive chromatin.
    Carlos Rivera, Hun-Goo Lee, Anna Lappala, Danni Wang, Verónica Noches, Montserrat Olivares-Costa, Marcela Sjöberg-Herrera, Jeannie T Lee, María Estela Andrés.
      RCOR1 is a known transcription repressor that recruits and positions LSD1 and HDAC1/2 on chromatin to erase histone methylation and acetylation. However, there is currently an incomplete understanding of RCOR1's range of localization and function. Here, we probe RCOR1's distribution on a genome-wide scale and unexpectedly find that RCOR1 is predominantly associated with transcriptionally active genes. Biochemical analysis reveals that RCOR1 associates with RNA Polymerase II (POL-II) during transcription and deacetylates its carboxy-terminal domain (CTD) at lysine 7. We provide evidence that this non-canonical RCOR1 activity is linked to dampening of POL-II productive elongation at actively transcribing genes. Thus, RCOR1 represses transcription in two ways-first, via a canonical mechanism by erasing transcriptionally permissive histone modifications through associating with HDACs and, second, via a non-canonical mechanism that deacetylates RNA POL-II's CTD to inhibit productive elongation. We conclude that RCOR1 is a transcription rheostat.
    DOI:  https://doi.org/10.1038/s41467-022-29261-0
  2. Epigenetics Chromatin. 2022 Mar 24. 15(1): 10
    Pan-cancer predictions of transcription factors mediating aberrant DNA methylation.
    Dylane Detilleux, Yannick G Spill, Delphine Balaramane, Michaël Weber, Anaïs Flore Bardet.
       BACKGROUND: Aberrant DNA methylation is a hallmark of cancer cells. However, the mechanisms underlying changes in DNA methylation remain elusive. Transcription factors initially thought to be repressed from binding by DNA methylation, have recently emerged as being able to shape DNA methylation patterns.
    RESULTS: Here, we integrated the massive amount of data available from The Cancer Genome Atlas to predict transcription factors driving aberrant DNA methylation in 13 cancer types. We identified differentially methylated regions between cancer and matching healthy samples, searched for transcription factor motifs enriched in those regions and selected transcription factors with corresponding changes in gene expression. We predict transcription factors known to be involved in cancer as well as novel candidates to drive hypo-methylated regions such as FOXA1 and GATA3 in breast cancer, FOXA1 and TWIST1 in prostate cancer and NFE2L2 in lung cancer. We also predict transcription factors that lead to hyper-methylated regions upon transcription factor loss such as EGR1 in several cancer types. Finally, we validate that FOXA1 and GATA3 mediate hypo-methylated regions in breast cancer cells.
    CONCLUSION: Our work highlights the importance of some transcription factors as upstream regulators shaping DNA methylation patterns in cancer.
    Keywords:  Bioinformatics; Cancer; DNA methylation; Transcription factors
    DOI:  https://doi.org/10.1186/s13072-022-00443-w
  3. Nucleic Acids Res. 2022 Mar 24. pii: gkac199. [Epub ahead of print]
    ChIP-Atlas 2021 update: a data-mining suite for exploring epigenomic landscapes by fully integrating ChIP-seq, ATAC-seq and Bisulfite-seq data.
    Zhaonan Zou, Tazro Ohta, Fumihito Miura, Shinya Oki.
      ChIP-Atlas (https://chip-atlas.org) is a web service providing both GUI- and API-based data-mining tools to reveal the architecture of the transcription regulatory landscape. ChIP-Atlas is powered by comprehensively integrating all data sets from high-throughput ChIP-seq and DNase-seq, a method for profiling chromatin regions accessible to DNase. In this update, we further collected all the ATAC-seq and whole-genome bisulfite-seq data for six model organisms (human, mouse, rat, fruit fly, nematode, and budding yeast) with the latest genome assemblies. These together with ChIP-seq data can be visualized with the Peak Browser tool and a genome browser to explore the epigenomic landscape of a query genomic locus, such as its chromatin accessibility, DNA methylation status, and protein-genome interactions. This epigenomic landscape can also be characterized for multiple genes and genomic loci by querying with the Enrichment Analysis tool, which, for example, revealed that inflammatory bowel disease-associated SNPs are the most significantly hypo-methylated in neutrophils. Therefore, ChIP-Atlas provides a panoramic view of the whole epigenomic landscape. All datasets are free to download via either a simple button on the web page or an API.
    DOI:  https://doi.org/10.1093/nar/gkac199
  4. Nat Commun. 2022 Mar 21. 13(1): 1504
    Massively parallel reporter perturbation assays uncover temporal regulatory architecture during neural differentiation.
    Anat Kreimer, Tal Ashuach, Fumitaka Inoue, Alex Khodaverdian, Chengyu Deng, Nir Yosef, Nadav Ahituv.
      Gene regulatory elements play a key role in orchestrating gene expression during cellular differentiation, but what determines their function over time remains largely unknown. Here, we perform perturbation-based massively parallel reporter assays at seven early time points of neural differentiation to systematically characterize how regulatory elements and motifs within them guide cellular differentiation. By perturbing over 2,000 putative DNA binding motifs in active regulatory regions, we delineate four categories of functional elements, and observe that activity direction is mostly determined by the sequence itself, while the magnitude of effect depends on the cellular environment. We also find that fine-tuning transcription rates is often achieved by a combined activity of adjacent activating and repressing elements. Our work provides a blueprint for the sequence components needed to induce different transcriptional patterns in general and specifically during neural differentiation.
    DOI:  https://doi.org/10.1038/s41467-022-28659-0
  5. PLoS Genet. 2022 Mar 23. 18(3): e1010121
    HiCuT: An efficient and low input method to identify protein-directed chromatin interactions.
    Satish Sati, Parker Jones, Hali S Kim, Linda A Zhou, Emmanuel Rapp-Reyes, Thomas H Leung.
      3D genome organization regulates gene expression, and disruption of these long-range (>20kB) DNA-protein interactions results in pathogenic phenotypes. Chromosome conformation methods in conjunction with chromatin immunoprecipitation were used to decipher protein-directed chromatin interactions. However, these methods required abundant starting material (>500,000 cells), sizable number of sequencing reads (>100 million reads), and elaborate data processing methods to reduce background noise, which limited their use in primary cells. Hi-C Coupled chromatin cleavage and Tagmentation (HiCuT) is a new transposase-assisted tagmentation method that generates high-resolution protein directed long-range chromatin interactions as efficiently as existing methods, HiChIP and ChIA-PET, despite using 100,000 cells (5-fold less) and 12 million sequencing reads (8-fold fewer). Moreover, HiCuT generates high resolution fragment libraries with low background signal that are easily interpreted with minimal computational processing. We used HiCuT in human primary skin cells to link previously identified single nucleotide polymorphisms (SNPs) in skin disease to candidate genes and to identify functionally relevant transcription factors in an unbiased manner. HiCuT broadens the capacity for genomic profiling in systems previously unmeasurable, including primary cells, human tissue samples, and rare cell populations, and may be a useful tool for all investigators studying human genetics and personalized epigenomics.
    DOI:  https://doi.org/10.1371/journal.pgen.1010121
  6. Nucleic Acids Res. 2022 Mar 23. pii: gkac178. [Epub ahead of print]
    Nuclear receptor activation shapes spatial genome organization essential for gene expression control: lessons learned from the vitamin D receptor.
    Timothy Warwick, Marcel H Schulz, Ralf Gilsbach, Ralf P Brandes, Sabine Seuter.
      Spatial genome organization is tightly controlled by several regulatory mechanisms and is essential for gene expression control. Nuclear receptors are ligand-activated transcription factors that modulate physiological and pathophysiological processes and are primary pharmacological targets. DNA binding of the important loop-forming insulator protein CCCTC-binding factor (CTCF) was modulated by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). We performed CTCF HiChIP assays to produce the first genome-wide dataset of CTCF long-range interactions in 1,25(OH)2D3-treated cells, and to determine whether dynamic changes of spatial chromatin interactions are essential for fine-tuning of nuclear receptor signaling. We detected changes in 3D chromatin organization upon vitamin D receptor (VDR) activation at 3.1% of all observed CTCF interactions. VDR binding was enriched at both differential loop anchors and within differential loops. Differential loops were observed in several putative functional roles including TAD border formation, promoter-enhancer looping, and establishment of VDR-responsive insulated neighborhoods. Vitamin D target genes were enriched in differential loops and at their anchors. Secondary vitamin D effects related to dynamic chromatin domain changes were linked to location of downstream transcription factors in differential loops. CRISPR interference and loop anchor deletion experiments confirmed the functional relevance of nuclear receptor ligand-induced adjustments of the chromatin 3D structure for gene expression regulation.
    DOI:  https://doi.org/10.1093/nar/gkac178
  7. Cell Rep. 2022 Mar 22. pii: S2211-1247(22)00284-4. [Epub ahead of print]38(12): 110543
    Optogenetic control of the Bicoid morphogen reveals fast and slow modes of gap gene regulation.
    Anand P Singh, Ping Wu, Sergey Ryabichko, João Raimundo, Michael Swan, Eric Wieschaus, Thomas Gregor, Jared E Toettcher.
      Developmental patterning networks are regulated by multiple inputs and feedback connections that rapidly reshape gene expression, limiting the information that can be gained solely from slow genetic perturbations. Here we show that fast optogenetic stimuli, real-time transcriptional reporters, and a simplified genetic background can be combined to reveal the kinetics of gene expression downstream of a developmental transcription factor in vivo. We engineer light-controlled versions of the Bicoid transcription factor and study their effects on downstream gap genes in embryos. Our results recapitulate known relationships, including rapid Bicoid-dependent transcription of giant and hunchback and delayed repression of Krüppel. In addition, we find that the posterior pattern of knirps exhibits a quick but inverted response to Bicoid perturbation, suggesting a noncanonical role for Bicoid in directly suppressing knirps transcription. Acute modulation of transcription factor concentration while recording output gene activity represents a powerful approach for studying developmental gene networks in vivo.
    Keywords:  Bicoid; CP: Cell Biology; Drosophila development; gap gene network; kinetics; live imaging; optogenetics; transcription
    DOI:  https://doi.org/10.1016/j.celrep.2022.110543
  8. Nat Biotechnol. 2022 Mar 24.
    Characterizing cellular heterogeneity in chromatin state with scCUT&Tag-pro.
    Bingjie Zhang, Avi Srivastava, Eleni Mimitou, Tim Stuart, Ivan Raimondi, Yuhan Hao, Peter Smibert, Rahul Satija.
      Technologies that profile chromatin modifications at single-cell resolution offer enormous promise for functional genomic characterization, but the sparsity of the measurements and integrating multiple binding maps represent substantial challenges. Here we introduce single-cell (sc)CUT&Tag-pro, a multimodal assay for profiling protein-DNA interactions coupled with the abundance of surface proteins in single cells. In addition, we introduce single-cell ChromHMM, which integrates data from multiple experiments to infer and annotate chromatin states based on combinatorial histone modification patterns. We apply these tools to perform an integrated analysis across nine different molecular modalities in circulating human immune cells. We demonstrate how these two approaches can characterize dynamic changes in the function of individual genomic elements across both discrete cell states and continuous developmental trajectories, nominate associated motifs and regulators that establish chromatin states and identify extensive and cell-type-specific regulatory priming. Finally, we demonstrate how our integrated reference can serve as a scaffold to map and improve the interpretation of additional scCUT&Tag datasets.
    DOI:  https://doi.org/10.1038/s41587-022-01250-0
  9. Sci Adv. 2022 Mar 25. 8(12): eabk0013
    Genome-wide screening identifies Polycomb repressive complex 1.3 as an essential regulator of human naïve pluripotent cell reprogramming.
    Amanda J Collier, Adam Bendall, Charlene Fabian, Andrew A Malcolm, Katarzyna Tilgner, Claudia I Semprich, Katarzyna Wojdyla, Paola Serena Nisi, Kamal Kishore, Valar Nila Roamio Franklin, Bahar Mirshekar-Syahkal, Clive D'Santos, Kathrin Plath, Kosuke Yusa, Peter J Rugg-Gunn.
      Uncovering the mechanisms that establish naïve pluripotency in humans is crucial for the future applications of pluripotent stem cells including the production of human blastoids. However, the regulatory pathways that control the establishment of naïve pluripotency by reprogramming are largely unknown. Here, we use genome-wide screening to identify essential regulators as well as major impediments of human primed to naïve pluripotent stem cell reprogramming. We discover that factors essential for cell state change do not typically undergo changes at the level of gene expression but rather are repurposed with new functions. Mechanistically, we establish that the variant Polycomb complex PRC1.3 and PRDM14 jointly repress developmental and gene regulatory factors to ensure naïve cell reprogramming. In addition, small-molecule inhibitors of reprogramming impediments improve naïve cell reprogramming beyond current methods. Collectively, this work defines the principles controlling the establishment of human naïve pluripotency and also provides new insights into mechanisms that destabilize and reconfigure cell identity during cell state transitions.
    DOI:  https://doi.org/10.1126/sciadv.abk0013
  10. Elife. 2022 Mar 25. pii: e70511. [Epub ahead of print]11
    AP-2α and AP-2β cooperatively function in the craniofacial surface ectoderm to regulate chromatin and gene expression dynamics during facial development.
    Eric Van Otterloo, Isaac Milanda, Hamish Pike, Jamie A Thompson, Hong Li, Kenneth L Jones, Trevor Williams.
      The facial surface ectoderm is essential for normal development of the underlying cranial neural crest cell populations, providing signals that direct appropriate growth, patterning, and morphogenesis. Despite the importance of the ectoderm as a signaling center, the molecular cues and genetic programs implemented within this tissue are understudied. Here we show that removal of two members of the AP-2 transcription factor family, AP-2α and AP-2ß, within the early embryonic ectoderm of the mouse leads to major alterations in the craniofacial complex. Significantly, there are clefts in both the upper face and mandible, accompanied by fusion of the upper and lower jaws in the hinge region. Comparison of ATAC-seq and RNA-seq analyses between controls and mutants revealed significant changes in chromatin accessibility and gene expression centered on multiple AP-2 binding motifs associated with enhancer elements within these ectodermal lineages. In particular, loss of these AP-2 proteins affects both skin differentiation as well as multiple signaling pathways, most notably the WNT pathway. We also determined that the mutant clefting phenotypes that correlated with reduced WNT signaling could be rescued by Wnt1 ligand overexpression in the ectoderm. Collectively, these findings highlight a conserved ancestral function for AP-2 transcription factors in ectodermal development and signaling, and provide a framework from which to understand the gene regulatory network operating within this tissue that directs vertebrate craniofacial development.
    Keywords:  chromosomes; developmental biology; gene expression; mouse
    DOI:  https://doi.org/10.7554/eLife.70511
  11. Cell Rep. 2022 Mar 22. pii: S2211-1247(22)00275-3. [Epub ahead of print]38(12): 110534
    The mTOR chromatin-bound interactome in prostate cancer.
    Catherine R Dufour, Charlotte Scholtes, Ming Yan, Yonghong Chen, Lingwei Han, Ting Li, Hui Xia, Qiyun Deng, Mathieu Vernier, Vincent Giguère.
      A growing number of studies support a direct role for nuclear mTOR in gene regulation and chromatin structure. Still, the scarcity of known chromatin-bound mTOR partners limits our understanding of how nuclear mTOR controls transcription. Herein, comprehensive mapping of the mTOR chromatin-bound interactome in both androgen-dependent and -independent cellular models of prostate cancer (PCa) identifies a conserved 67-protein interaction network enriched for chromatin modifiers, transcription factors, and SUMOylation machinery. SUMO2/3 and nuclear pore protein NUP210 are among the strongest interactors, while the androgen receptor (AR) is the dominant androgen-inducible mTOR partner. Further investigation reveals that NUP210 facilitates mTOR nuclear trafficking, that mTOR and AR form a functional transcriptional module with the nucleosome remodeling and deacetylase (NuRD) complex, and that androgens specify mTOR-SUMO2/3 promoter-enhancer association. This work identifies a vast network of mTOR-associated nuclear complexes advocating innovative molecular strategies to modulate mTOR-dependent gene regulation with conceivable implications for PCa and other diseases.
    Keywords:  AR; CP: Cancer; CP: Molecular biology; ChIP-MS; ESRRA; FOXA1; HDAC2; HOXB13; PML; ZNF618
    DOI:  https://doi.org/10.1016/j.celrep.2022.110534
  12. Nat Commun. 2022 Mar 25. 13(1): 1626
    Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation.
    Liang-Jie Wang, Chie-Pein Chen, Yun-Shien Lee, Pui-Sze Ng, Geen-Dong Chang, Yu-Hsuan Pao, Hsiao-Fan Lo, Chao-Hsiang Peng, Mei-Leng Cheong, Hungwen Chen.
      The combination of EGF, CHIR99021, A83-01, SB431542, VPA, and Y27632 (EGF/CASVY) facilitates the derivation of trophoblast stem (TS) cells from human blastocysts and first-trimester, but not term, cytotrophoblasts. The mechanism underlying this chemical induction of TS cells remains elusive. Here we demonstrate that the induction efficiency of cytotrophoblast is determined by functional antagonism of the placental transcription factor GCM1 and the stemness regulator ΔNp63α. ΔNp63α reduces GCM1 transcriptional activity, whereas GCM1 inhibits ΔNp63α oligomerization and autoregulation. EGF/CASVY cocktail activates ΔNp63α, thereby partially inhibiting GCM1 activity and reverting term cytotrophoblasts into stem cells. By applying hypoxia condition, we can further reduce GCM1 activity and successfully induce term cytotrophoblasts into TS cells. Consequently, we identify mitochondrial creatine kinase 1 (CKMT1) as a key GCM1 target crucial for syncytiotrophoblast differentiation and reveal decreased CKMT1 expression in preeclampsia. Our study delineates the molecular underpinnings of trophoblast stemness and differentiation and an efficient method to establish TS cells from term placentas.
    DOI:  https://doi.org/10.1038/s41467-022-29312-6
  13. Sci Rep. 2022 Mar 21. 12(1): 4795
    Shear stress switches the association of endothelial enhancers from ETV/ETS to KLF transcription factor binding sites.
    Roman Tsaryk, Nora Yucel, Elvin V Leonard, Noelia Diaz, Olga Bondareva, Maria Odenthal-Schnittler, Zoltan Arany, Juan M Vaquerizas, Hans Schnittler, Arndt F Siekmann.
      Endothelial cells (ECs) lining blood vessels are exposed to mechanical forces, such as shear stress. These forces control many aspects of EC biology, including vascular tone, cell migration and proliferation. Despite a good understanding of the genes responding to shear stress, our insight into the transcriptional regulation of these genes is much more limited. Here, we set out to study alterations in the chromatin landscape of human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress. To do so, we performed ChIP-Seq for H3K27 acetylation, indicative of active enhancer elements and ATAC-Seq to mark regions of open chromatin in addition to RNA-Seq on HUVEC exposed to 6 h of laminar shear stress. Our results show a correlation of gained and lost enhancers with up and downregulated genes, respectively. DNA motif analysis revealed an over-representation of KLF transcription factor (TF) binding sites in gained enhancers, while lost enhancers contained more ETV/ETS motifs. We validated a subset of flow responsive enhancers using luciferase-based reporter constructs and CRISPR-Cas9 mediated genome editing. Lastly, we characterized the shear stress response in ECs of zebrafish embryos using RNA-Seq. Our results lay the groundwork for the exploration of shear stress responsive elements in controlling EC biology.
    DOI:  https://doi.org/10.1038/s41598-022-08645-8
  14. Nucleic Acids Res. 2022 Mar 25. pii: gkac196. [Epub ahead of print]
    H3K56 deacetylation and H2A.Z deposition are required for aberrant heterochromatin spreading.
    Chengcheng Zhang, Yuan Tian, Shuang Song, Lu Zhang, Yunkun Dang, Qun He.
      Crucial mechanisms are required to restrict self-propagating heterochromatin spreading within defined boundaries and prevent euchromatic gene silencing. In the filamentous fungus Neurospora crassa, the JmjC domain protein DNA METHYLATION MODULATOR-1 (DMM-1) prevents aberrant spreading of heterochromatin, but the molecular details remain unknown. Here, we revealed that DMM-1 is highly enriched in a well-defined 5-kb heterochromatin domain upstream of the cat-3 gene, hereby called 5H-cat-3 domain, to constrain aberrant heterochromatin spreading. Interestingly, aberrant spreading of the 5H-cat-3 domain observed in the dmm-1KO strain is accompanied by robust deposition of histone variant H2A.Z, and deletion of H2A.Z abolishes aberrant spreading of the 5H-cat-3 domain into adjacent euchromatin. Furthermore, lysine 56 of histone H3 is deacetylated at the expanded heterochromatin regions, and mimicking H3K56 acetylation with an H3K56Q mutation effectively blocks H2A.Z-mediated aberrant spreading of the 5H-cat-3 domain. Importantly, genome-wide analyses demonstrated the general roles of H3K56 deacetylation and H2A.Z deposition in aberrant spreading of heterochromatin. Together, our results illustrate a previously unappreciated regulatory process that mediates aberrant heterochromatin spreading.
    DOI:  https://doi.org/10.1093/nar/gkac196
  15. Development. 2022 Mar 15. pii: dev200375. [Epub ahead of print]149(6):
    Wt1 transcription factor impairs cardiomyocyte specification and drives a phenotypic switch from myocardium to epicardium.
    Ines J Marques, Alexander Ernst, Prateek Arora, Andrej Vianin, Tanja Hetke, Andrés Sanz-Morejón, Uta Naumann, Adolfo Odriozola, Xavier Langa, Laura Andrés-Delgado, Benoît Zuber, Carlos Torroja, Marco Osterwalder, Filipa C Simões, Christoph Englert, Nadia Mercader.
      During development, the heart grows by addition of progenitor cells to the poles of the primordial heart tube. In the zebrafish, Wilms tumor 1 transcription factor a (wt1a) and b (wt1b) genes are expressed in the pericardium, at the venous pole of the heart. From this pericardial layer, the proepicardium emerges. Proepicardial cells are subsequently transferred to the myocardial surface and form the epicardium, covering the myocardium. We found that while wt1a and wt1b expression is maintained in proepicardial cells, it is downregulated in pericardial cells that contributes cardiomyocytes to the developing heart. Sustained wt1b expression in cardiomyocytes reduced chromatin accessibility of specific genomic loci. Strikingly, a subset of wt1a- and wt1b-expressing cardiomyocytes changed their cell-adhesion properties, delaminated from the myocardium and upregulated epicardial gene expression. Thus, wt1a and wt1b act as a break for cardiomyocyte differentiation, and ectopic wt1a and wt1b expression in cardiomyocytes can lead to their transdifferentiation into epicardial-like cells.
    Keywords:   wt1a ; wt1b ; Cardiomyocyte; Cell fate; Epicardium; Heart development; Zebrafish
    DOI:  https://doi.org/10.1242/dev.200375
  16. Nat Commun. 2022 Mar 22. 13(1): 1544
    Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors.
    Monika Graf, Marta Interlandi, Natalia Moreno, Dörthe Holdhof, Carolin Göbel, Viktoria Melcher, Julius Mertins, Thomas K Albert, Dennis Kastrati, Amelie Alfert, Till Holsten, Flavia de Faria, Michael Meisterernst, Claudia Rossig, Monika Warmuth-Metz, Johannes Nowak, Gerd Meyer Zu Hörste, Chloe Mayère, Serge Nef, Pascal Johann, Michael C Frühwald, Martin Dugas, Ulrich Schüller, Kornelius Kerl.
      Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease.
    DOI:  https://doi.org/10.1038/s41467-022-29152-4
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