bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2022–05–15
twenty papers selected by
Connor Rogerson, University of Cambridge, MRC Cancer Unit
  1. Inositol polyphosphate multikinase physically binds to the SWI/SNF complex and modulates BRG1 occupancy in mouse embryonic stem cells.
  2. MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets.
  3. Histone chaperone Nucleophosmin regulates transcription of key genes involved in oral tumorigenesis.
  4. Hormone-controlled cooperative binding of transcription factors drives synergistic induction of fasting-regulated genes.
  5. Sox2 levels regulate the chromatin occupancy of WNT mediators in epiblast progenitors responsible for vertebrate body formation.
  6. Human transcription factor protein interaction networks.
  7. Transcription activation is enhanced by multivalent interactions independent of phase separation.
  8. Essential role of Cp190 in physical and regulatory boundary formation.
  9. Sequence-based modeling of three-dimensional genome architecture from kilobase to chromosome scale.
  10. DeepSTARR predicts enhancer activity from DNA sequence and enables the de novo design of synthetic enhancers.
  11. NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition.
  12. ETV2 functions as a pioneer factor to regulate and reprogram the endothelial lineage.
  13. H3K4me3 recognition by the COMPASS complex facilitates the restoration of this histone mark following DNA replication.
  14. Modulating gene regulation function by chemically controlled transcription factor clustering.
  15. The disordered N-terminal domain of DNMT3A recognizes H2AK119ub and is required for postnatal development.
  16. Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions.
  17. Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction.
  18. Paracrine signalling between intestinal epithelial and tumour cells induces a regenerative programme.
  19. RSAT 2022: regulatory sequence analysis tools.
  20. Runx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells.
  1. Elife. 2022 May 12. pii: e73523. [Epub ahead of print]11
    Inositol polyphosphate multikinase physically binds to the SWI/SNF complex and modulates BRG1 occupancy in mouse embryonic stem cells.
    Jiyoon Beon, Sungwook Han, Hyeokjun Yang, Seung Eun Park, Kwangbeom Hyun, Song-Yi Lee, Hyun-Woo Rhee, Jeong Kon Seo, Jaehoon Kim, Seyun Kim, Daeyoup Lee.
      Inositol polyphosphate multikinase (IPMK), a key enzyme in inositol polyphosphate (IP) metabolism, is a pleiotropic signaling factor involved in major biological events, including transcriptional control. In the yeast, IPMK and its IP products promote the activity of the chromatin remodeling complex SWI/SNF, which plays a critical role in gene expression by regulating chromatin accessibility. However, the direct link between IPMK and chromatin remodelers remains unclear, raising the question of how IPMK contributes to transcriptional regulation in mammals. By employing unbiased screening approaches and in vivo/in vitro immunoprecipitation, here we demonstrate that mammalian IPMK physically interacts with the SWI/SNF complex by directly binding to SMARCB1, BRG1, and SMARCC1. Furthermore, we identified the specific domains required for IPMK-SMARCB1 binding. Notably, using CUT&RUN and ATAC-seq assays, we discovered that IPMK co-localizes with BRG1 and regulates BRG1 localization as well as BRG1-mediated chromatin accessibility in a genome-wide manner in mouse embryonic stem cells. Together, these findings show that IPMK regulates the promoter targeting of the SWI/SNF complex, thereby contributing to SWI/SNF-meditated chromatin accessibility, transcription, and differentiation in mouse embryonic stem cells.
    Keywords:  BRG1; IPMK; SMARCB1; SWI/SNF complex; chromatin accessibility; chromosomes; gene expression; human; mouse
    DOI:  https://doi.org/10.7554/eLife.73523
  2. Nat Commun. 2022 May 13. 13(1): 2559
    MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets.
    Xintao Qiu, Nadia Boufaied, Tarek Hallal, Avery Feit, Anna de Polo, Adrienne M Luoma, Walaa Alahmadi, Janie Larocque, Giorgia Zadra, Yingtian Xie, Shengqing Gu, Qin Tang, Yi Zhang, Sudeepa Syamala, Ji-Heui Seo, Connor Bell, Edward O'Connor, Yang Liu, Edward M Schaeffer, R Jeffrey Karnes, Sheila Weinmann, Elai Davicioni, Colm Morrissey, Paloma Cejas, Leigh Ellis, Massimo Loda, Kai W Wucherpfennig, Mark M Pomerantz, Daniel E Spratt, Eva Corey, Matthew L Freedman, X Shirley Liu, Myles Brown, Henry W Long, David P Labbé.
      c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.
    DOI:  https://doi.org/10.1038/s41467-022-30257-z
  3. FASEB J. 2022 May;36 Suppl 1
    Histone chaperone Nucleophosmin regulates transcription of key genes involved in oral tumorigenesis.
    Tapas K Kundu, Parijat Senapati, Aditya Bhattacharya, Sadhan Das, Suchismita Dey, Deepthi Sudarshan, G Shyla, Jyoti Vishwakarma, Surabhi Sudevan, Ravishankar Ramachandran, Tessy T Maliekal.
      Nucleophosmin (NPM1) is a multifunctional histone chaperone that can activate acetylation-dependent transcription from chromatin templates in vitro. Acetylation of NPM1 by p300 has been shown to further enhance its transcription activation potential. Moreover, its total and acetylated pools are increased in oral squamous cell carcinoma. However, the role of NPM1 or its acetylated form (AcNPM1) in transcriptional regulation in cells and oral tumorigenesis is not fully elucidated. Using ChIP-seq analyses, we provide the first genome-wide profile of AcNPM1 and show that AcNPM1 is enriched at transcriptional regulatory elements. AcNPM1 co-occupies marks of active transcription at promoters and DNase I hypersensitive sites at enhancers. In addition, using a high-throughput protein interaction profiling approach, we show that NPM1 interacts with RNA Pol II, general transcription factors, mediator subunits, histone acetyltransferase complexes, and chromatin remodelers. NPM1 histone chaperone activity also contributes to its transcription activation potential. Further, NPM1 depletion leads to decreased AcNPM1 occupancy and reduced expression of genes required for proliferative, migratory and invasive potential of oral cancer cells. NPM1 depletion also abrogates the growth of orthotopic tumors in mice. Collectively, these results establish that AcNPM1 functions as a coactivator during during RNA polymerase II-driven transcription and regulates the expression of genes that promote oral tumorigenesis.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R4402
  4. Nucleic Acids Res. 2022 May 12. pii: gkac358. [Epub ahead of print]
    Hormone-controlled cooperative binding of transcription factors drives synergistic induction of fasting-regulated genes.
    Dana Goldberg, Meital Charni-Natan, Nufar Buchshtab, Meirav Bar-Shimon, Ido Goldstein.
      During fasting, hepatocytes produce glucose in response to hormonal signals. Glucagon and glucocorticoids are principal fasting hormones that cooperate in regulating glucose production via gluconeogenesis. However, how these hormone signals are integrated and interpreted to a biological output is unknown. Here, we use genome-wide profiling of gene expression, enhancer dynamics and transcription factor (TF) binding in primary mouse hepatocytes to uncover the mode of cooperation between glucagon and glucocorticoids. We found that compared to a single treatment with each hormone, a dual treatment directs hepatocytes to a pro-gluconeogenic gene program by synergistically inducing gluconeogenic genes. The cooperative mechanism driving synergistic gene expression is based on 'assisted loading' whereby a glucagon-activated TF (cAMP responsive element binding protein; CREB) leads to enhancer activation which facilitates binding of the glucocorticoid receptor (GR) upon glucocorticoid stimulation. Glucagon does not only activate single enhancers but also activates enhancer clusters, thereby assisting the loading of GR also across enhancer units within the cluster. In summary, we show that cells integrate extracellular signals by an enhancer-specific mechanism: one hormone-activated TF activates enhancers, thereby assisting the loading of a TF stimulated by a second hormone, leading to synergistic gene induction and a tailored transcriptional response to fasting.
    DOI:  https://doi.org/10.1093/nar/gkac358
  5. Nat Cell Biol. 2022 May;24(5): 633-644
    Sox2 levels regulate the chromatin occupancy of WNT mediators in epiblast progenitors responsible for vertebrate body formation.
    Robert Blassberg, Harshil Patel, Thomas Watson, Mina Gouti, Vicki Metzis, M Joaquina Delás, James Briscoe.
      WNT signalling has multiple roles. It maintains pluripotency of embryonic stem cells, assigns posterior identity in the epiblast and induces mesodermal tissue. Here we provide evidence that these distinct functions are conducted by the transcription factor SOX2, which adopts different modes of chromatin interaction and regulatory element selection depending on its level of expression. At high levels, SOX2 displaces nucleosomes from regulatory elements with high-affinity SOX2 binding sites, recruiting the WNT effector TCF/β-catenin and maintaining pluripotent gene expression. Reducing SOX2 levels destabilizes pluripotency and reconfigures SOX2/TCF/β-catenin occupancy to caudal epiblast expressed genes. These contain low-affinity SOX2 sites and are co-occupied by T/Bra and CDX. The loss of SOX2 allows WNT-induced mesodermal differentiation. These findings define a role for Sox2 levels in dictating the chromatin occupancy of TCF/β-catenin and reveal how context-specific responses to a signal are configured by the level of a transcription factor.
    DOI:  https://doi.org/10.1038/s41556-022-00910-2
  6. FASEB J. 2022 May;36 Suppl 1
    Human transcription factor protein interaction networks.
    Markku Varjosalo, Helka Göös, Matias Kinnunen, Kari Salokas, Xiaonan Liu.
      Transcription factors (TFs) interact with several other proteins in the process of transcriptional regulation. Here, we identify 6703 and 1536 protein-protein interactions for 109 different human TFs through proximity-dependent biotinylation (BioID) and affinity purification mass spectrometry (AP-MS), respectively. The BioID analysis identifiesmore high-confidence interactions, highlighting the transient and dynamic nature of many of the TF interactions. By performing clustering and correlation analyses, we identify subgroups of TFs associated with specific biological functions, such as RNA splicing or chromatin remodeling. We also observe 202 TF-TF interactions, of which 118 are interactions with nuclear factor 1 (NFI) family members, indicating uncharacterized cross-talk between NFI signaling and other TF signaling pathways. Moreover, TF interactions with basal transcription machinery are mainly observed through TFIID and SAGA complexes. This study provides a rich resource of human TF interactions and also act as a starting point for future studies aimed at understanding TF-mediated transcription.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.L7611
  7. Mol Cell. 2022 May 04. pii: S1097-2765(22)00328-8. [Epub ahead of print]
    Transcription activation is enhanced by multivalent interactions independent of phase separation.
    Jorge Trojanowski, Lukas Frank, Anne Rademacher, Norbert Mücke, Pranas Grigaitis, Karsten Rippe.
      Transcription factors (TFs) consist of a DNA-binding domain and an activation domain (AD) that are frequently considered to be independent and exchangeable modules. However, recent studies report that the physicochemical properties of the AD can control TF assembly at chromatin by driving phase separation into transcriptional condensates. Here, we dissected transcription activation by comparing different synthetic TFs at a reporter gene array with real-time single-cell fluorescence microscopy. In these experiments, binding site occupancy, residence time, and coactivator recruitment in relation to multivalent TF interactions were compared. While phase separation propensity and activation strength of the AD were linked, the actual formation of liquid-like TF droplets had a neutral or inhibitory effect on transcription activation. We conclude that multivalent AD-mediated interactions enhance the transcription activation capacity of a TF by increasing its residence time in the chromatin-bound state and facilitating the recruitment of coactivators independent of phase separation.
    Keywords:  BRD4; LLPS; acetylation; dCas9; gene regulation; kinetic proofreading; multivalent interactions; optogenetics; phase separation; residence time; transcription factor; transcription kinetics
    DOI:  https://doi.org/10.1016/j.molcel.2022.04.017
  8. Sci Adv. 2022 May 13. 8(19): eabl8834
    Essential role of Cp190 in physical and regulatory boundary formation.
    Anjali Kaushal, Julien Dorier, Bihan Wang, Giriram Mohana, Michael Taschner, Pascal Cousin, Patrice Waridel, Christian Iseli, Anastasiia Semenova, Simon Restrepo, Nicolas Guex, Erez Lieberman Aiden, Maria Cristina Gambetta.
      Boundaries in animal genomes delimit contact domains with enhanced internal contact frequencies and have debated functions in limiting regulatory cross-talk between domains and guiding enhancers to target promoters. Most mammalian boundaries form by stalling of chromosomal loop-extruding cohesin by CTCF, but most Drosophila boundaries form CTCF independently. However, how CTCF-independent boundaries form and function remains largely unexplored. Here, we assess genome folding and developmental gene expression in fly embryos lacking the ubiquitous boundary-associated factor Cp190. We find that sequence-specific DNA binding proteins such as CTCF and Su(Hw) directly interact with and recruit Cp190 to form most promoter-distal boundaries. Cp190 is essential for early development and prevents regulatory cross-talk between specific gene loci that pattern the embryo. Cp190 was, in contrast, dispensable for long-range enhancer-promoter communication at tested loci. Cp190 is thus currently the major player in fly boundary formation and function, revealing that diverse mechanisms evolved to partition genomes into independent regulatory domains.
    DOI:  https://doi.org/10.1126/sciadv.abl8834
  9. Nat Genet. 2022 May 12.
    Sequence-based modeling of three-dimensional genome architecture from kilobase to chromosome scale.
    Jian Zhou.
      To learn how genomic sequence influences multiscale three-dimensional (3D) genome architecture, this manuscript presents a sequence-based deep-learning approach, Orca, that predicts directly from sequence the 3D genome architecture from kilobase to whole-chromosome scale. Orca captures the sequence dependencies of structures including chromatin compartments and topologically associating domains, as well as diverse types of interactions from CTCF-mediated to enhancer-promoter interactions and Polycomb-mediated interactions with cell-type specificity. Orca enables various applications including predicting structural variant effects on multiscale genome organization and it recapitulated effects of experimentally studied variants at varying sizes (300 bp to 90 Mb). Moreover, Orca enables in silico virtual screens to probe the sequence basis of 3D genome organization at different scales. At the submegabase scale, it predicted specific transcription factor motifs underlying cell-type-specific genome interactions. At the compartment scale, virtual screens of sequence activities suggest a model for the sequence basis of chromatin compartments with a prominent role of transcription start sites.
    DOI:  https://doi.org/10.1038/s41588-022-01065-4
  10. Nat Genet. 2022 May 12.
    DeepSTARR predicts enhancer activity from DNA sequence and enables the de novo design of synthetic enhancers.
    Bernardo P de Almeida, Franziska Reiter, Michaela Pagani, Alexander Stark.
      Enhancer sequences control gene expression and comprise binding sites (motifs) for different transcription factors (TFs). Despite extensive genetic and computational studies, the relationship between DNA sequence and regulatory activity is poorly understood, and de novo enhancer design has been challenging. Here, we built a deep-learning model, DeepSTARR, to quantitatively predict the activities of thousands of developmental and housekeeping enhancers directly from DNA sequence in Drosophila melanogaster S2 cells. The model learned relevant TF motifs and higher-order syntax rules, including functionally nonequivalent instances of the same TF motif that are determined by motif-flanking sequence and intermotif distances. We validated these rules experimentally and demonstrated that they can be generalized to humans by testing more than 40,000 wildtype and mutant Drosophila and human enhancers. Finally, we designed and functionally validated synthetic enhancers with desired activities de novo.
    DOI:  https://doi.org/10.1038/s41588-022-01048-5
  11. Mol Cell. 2022 May 04. pii: S1097-2765(22)00326-4. [Epub ahead of print]
    NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition.
    Yiannis Drosos, Jacquelyn A Myers, Beisi Xu, Kaeli M Mathias, Emma C Beane, Sandi Radko-Juettner, Robert J Mobley, Margaret E Larsen, Federica Piccioni, Xiaotu Ma, Jonathan Low, Baranda S Hansen, Samuel T Peters, Natarajan V Bhanu, Sandeep K Dhanda, Taosheng Chen, Santhosh A Upadhyaya, Shondra M Pruett-Miller, David E Root, Benjamin A Garcia, Janet F Partridge, Charles W M Roberts.
      Disruption of antagonism between SWI/SNF chromatin remodelers and polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of the polycomb protein EZH2 was approved for the treatment of a sarcoma mutant in the SWI/SNF subunit SMARCB1, but resistance occurs. Here, we performed CRISPR screens in SMARCB1-mutant rhabdoid tumor cells to identify genetic contributors to SWI/SNF-polycomb antagonism and potential resistance mechanisms. We found that loss of the H3K36 methyltransferase NSD1 caused resistance to EZH2 inhibition. We show that NSD1 antagonizes polycomb via cooperation with SWI/SNF and identify co-occurrence of NSD1 inactivation in SWI/SNF-defective cancers, indicating in vivo relevance. We demonstrate that H3K36me2 itself has an essential role in the activation of polycomb target genes as inhibition of the H3K36me2 demethylase KDM2A restores the efficacy of EZH2 inhibition in SWI/SNF-deficient cells lacking NSD1. Together our data expand the mechanistic understanding of SWI/SNF and polycomb interplay and identify NSD1 as the key for coordinating this transcriptional control.
    Keywords:  BAF; EZH2 inhibition; NSD1; SWI/SNF; chromatin; epigenetics; polycomb; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2022.04.015
  12. Nat Cell Biol. 2022 May;24(5): 672-684
    ETV2 functions as a pioneer factor to regulate and reprogram the endothelial lineage.
    Wuming Gong, Satyabrata Das, Javier E Sierra-Pagan, Erik Skie, Nikita Dsouza, Thijs A Larson, Mary G Garry, Edgar Luzete-Monteiro, Kenneth S Zaret, Daniel J Garry.
      The vasculature is an essential organ for the delivery of blood and oxygen to all tissues of the body and is thus relevant to the treatment of ischaemic diseases, injury-induced regeneration and solid tumour growth. Previously, we demonstrated that ETV2 is an essential transcription factor for the development of cardiac, endothelial and haematopoietic lineages. Here we report that ETV2 functions as a pioneer factor that relaxes closed chromatin and regulates endothelial development. By comparing engineered embryonic stem cell differentiation and reprogramming models with multi-omics techniques, we demonstrated that ETV2 was able to bind nucleosomal DNA and recruit BRG1. BRG1 recruitment remodelled chromatin around endothelial genes and helped to maintain an open configuration, resulting in increased H3K27ac deposition. Collectively, these results will serve as a platform for the development of therapeutic initiatives directed towards cardiovascular diseases and solid tumours.
    DOI:  https://doi.org/10.1038/s41556-022-00901-3
  13. Sci Adv. 2022 May 06. 8(18): eabm6246
    H3K4me3 recognition by the COMPASS complex facilitates the restoration of this histone mark following DNA replication.
    Albert Serra-Cardona, Shoufu Duan, Chuanhe Yu, Zhiguo Zhang.
      During DNA replication, parental H3-H4 marked by H3K4me3 are transferred almost equally onto leading and lagging strands of DNA replication forks. Mutations in replicative helicase subunit, Mcm2 (Mcm2-3A), and leading strand DNA polymerase subunit, Dpb3 (dpb3∆), result in asymmetric distributions of H3K4me3 at replicating DNA strands immediately following DNA replication. Here, we show that mcm2-3A and dpb3∆ mutant cells markedly reduce the asymmetric distribution of H3K4me3 during cell cycle progression before mitosis. Furthermore, the restoration of a more symmetric distribution of H3K4me3 at replicating DNA strands in these mutant cells is driven by methylating nucleosomes without H3K4me3 by the H3K4 methyltransferase complex, COMPASS. Last, both gene transcription machinery and the binding of parental H3K4me3 by Spp1 subunit of the COMPASS complex help recruit the enzyme to chromatin for the restoration of the H3K4me3-marked state following DNA replication, shedding light on inheritance of this mark following DNA replication.
    DOI:  https://doi.org/10.1126/sciadv.abm6246
  14. Nat Commun. 2022 May 13. 13(1): 2663
    Modulating gene regulation function by chemically controlled transcription factor clustering.
    Jiegen Wu, Baoqiang Chen, Yadi Liu, Liang Ma, Wen Huang, Yihan Lin.
      Recent studies have suggested that transcriptional protein condensates (or clusters) may play key roles in gene regulation and cell fate determination. However, it remains largely unclear how the gene regulation function is quantitatively tuned by transcription factor (TF) clustering and whether TF clustering may confer emergent behaviors as in cell fate control systems. Here, to address this, we construct synthetic TFs whose clustering behavior can be chemically controlled. Through single-parameter tuning of the system (i.e., TF clustering propensity), we provide lines of evidence supporting the direct transcriptional activation and amplification of target genes by TF clustering. Single-gene imaging suggests that such amplification results from the modulation of transcriptional dynamics. Importantly, TF clustering propensity modulates the gene regulation function by significantly tuning the effective TF binding affinity and to a lesser extent the ultrasensitivity, contributing to bimodality and sustained response behavior that are reminiscent of canonical cell fate control systems. Collectively, these results demonstrate that TF clustering can modulate the gene regulation function to enable emergent behaviors, and highlight the potential applications of chemically controlled protein clustering.
    DOI:  https://doi.org/10.1038/s41467-022-30397-2
  15. Nat Genet. 2022 May 09.
    The disordered N-terminal domain of DNMT3A recognizes H2AK119ub and is required for postnatal development.
    Tianpeng Gu, Dapeng Hao, Junsung Woo, Teng-Wei Huang, Lei Guo, Xueqiu Lin, Anna G Guzman, Ayala Tovy, Carina Rosas, Mira Jeong, Yubin Zhou, Benjamin Deneen, Yun Huang, Wei Li, Margaret A Goodell.
      DNA methyltransferase 3a (DNMT3A) plays a crucial role during mammalian development. Two isoforms of DNMT3A are differentially expressed from stem cells to somatic tissues, but their individual functions remain largely uncharacterized. Here we report that the long isoform DNMT3A1, but not the short DNMT3A2, is essential for mouse postnatal development. DNMT3A1 binds to and regulates bivalent neurodevelopmental genes in the brain. Strikingly, Dnmt3a1 knockout perinatal lethality could be partially rescued by DNMT3A1 restoration in the nervous system. We further show that the intrinsically disordered N terminus of DNMT3A1 is required for normal development and DNA methylation at DNMT3A1-enriched regions. Mechanistically, a ubiquitin-interacting motif embedded in a putative α-helix within the N terminus binds to mono-ubiquitinated histone H2AK119, probably mediating recruitment of DNMT3A1 to Polycomb-regulated regions. These data demonstrate an isoform-specific role for DNMT3A1 in mouse postnatal development and reveal the N terminus as a necessary regulatory domain for DNMT3A1 chromatin occupancy and functions in the nervous system.
    DOI:  https://doi.org/10.1038/s41588-022-01063-6
  16. Mol Cell. 2022 May 04. pii: S1097-2765(22)00382-3. [Epub ahead of print]
    Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions.
    Julien Vibert, Olivier Saulnier, Céline Collin, Floriane Petit, Kyra J E Borgman, Jérômine Vigneau, Maud Gautier, Sakina Zaidi, Gaëlle Pierron, Sarah Watson, Nadège Gruel, Clémence Hénon, Sophie Postel-Vinay, Marc Deloger, Virginie Raynal, Sylvain Baulande, Karine Laud-Duval, Véronique Hill, Sandrine Grossetête, Florent Dingli, Damarys Loew, Jacob Torrejon, Olivier Ayrault, Martin F Orth, Thomas G P Grünewald, Didier Surdez, Antoine Coulon, Joshua J Waterfall, Olivier Delattre.
      Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWS::FLI1 in Ewing sarcoma (EwS). Here, we find that EWS::FLI1 induces the robust expression of a specific set of novel spliced and polyadenylated transcripts within otherwise transcriptionally silent regions of the genome. These neogenes (NGs) are virtually undetectable in large collections of normal tissues or non-EwS tumors and can be silenced by CRISPR interference at regulatory EWS::FLI1-bound microsatellites. Ribosome profiling and proteomics further show that some NGs are translated into highly EwS-specific peptides. More generally, we show that hundreds of NGs can be detected in diverse cancers characterized by chimeric TFs. Altogether, this study identifies the transcription, processing, and translation of novel, specific, highly expressed multi-exonic transcripts from otherwise silent regions of the genome as a new activity of aberrant TFs in cancer.
    Keywords:  chimeric transcription factors; long non-coding RNAs; sarcomas; tumor-specific peptides; tumor-specific transcripts
    DOI:  https://doi.org/10.1016/j.molcel.2022.04.019
  17. Cell Rep. 2022 May 10. pii: S2211-1247(22)00565-4. [Epub ahead of print]39(6): 110798
    Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction.
    Fatemeh Safi, Parashar Dhapola, Sarah Warsi, Mikael Sommarin, Eva Erlandsson, Jonas Ungerbäck, Rebecca Warfvinge, Ewa Sitnicka, David Bryder, Charlotta Böiers, Ram Krishna Thakur, Göran Karlsson.
      The emerging notion of hematopoietic stem and progenitor cells (HSPCs) as a low-primed cloud without sharply demarcated gene expression programs raises the question on how cellular-fate options emerge and at which stem-like stage lineage priming is initiated. Here, we investigate single-cell chromatin accessibility of Lineage-, cKit+, and Sca1+ (LSK) HSPCs spanning the early differentiation landscape. Application of a signal-processing algorithm to detect transition points corresponding to massive alterations in accessibility of 571 transcription factor motifs reveals a population of LSK FMS-like tyrosine kinase 3 (Flt3)intCD9high cells that concurrently display stem-like and lineage-affiliated chromatin signatures, pointing to a simultaneous gain of both lympho-myeloid and megakaryocyte-erythroid programs. Molecularly and functionally, these cells position between stem cells and committed progenitors and display multi-lineage capacity in vitro and in vivo but lack self-renewal activity. This integrative molecular analysis resolves the heterogeneity of cells along hematopoietic differentiation and permits investigation of chromatin-mediated transition between multipotency and lineage restriction.
    Keywords:  CD9; CP: Cell biology; CP: Developmental biology; Flt3; hematopoietic stem cells; lineage commitment; single-cell ATAC sequencing; single-cell RNA sequencing; transition state
    DOI:  https://doi.org/10.1016/j.celrep.2022.110798
  18. Elife. 2022 May 11. pii: e76541. [Epub ahead of print]11
    Paracrine signalling between intestinal epithelial and tumour cells induces a regenerative programme.
    Guillaume Jacquemin, Annabelle Wurmser, Mathilde Huyghe, Wenjie Sun, Zeinab Homayed, Candice Merle, Meghan Perkins, Fairouz Qasrawi, Sophie Richon, Florent Dingli, Guillaume Arras, Damarys Loew, Danijela Vignjevic, Julie Pannequin, Silvia Fre.
      Tumours are complex ecosystems composed of different types of cells that communicate and influence each other. While the critical role of stromal cells in affecting tumour growth is well established, the impact of mutant cancer cells on healthy surrounding tissues remains poorly defined. Here, using mouse intestinal organoids, we uncover a paracrine mechanism by which intestinal cancer cells reactivate foetal and regenerative YAP-associated transcriptional programmes in neighbouring wildtype epithelial cells, rendering them adapted to thrive in the tumour context. We identify the glycoprotein thrombospondin-1 (THBS1) as the essential factor that mediates non-cell-autonomous morphological and transcriptional responses. Importantly, Thbs1 is associated with bad prognosis in several human cancers. This study reveals the THBS1-YAP axis as the mechanistic link mediating paracrine interactions between epithelial cells in intestinal tumours.
    Keywords:  YAP signalling; cancer biology; colon cancer; mouse; organoids
    DOI:  https://doi.org/10.7554/eLife.76541
  19. Nucleic Acids Res. 2022 May 11. pii: gkac312. [Epub ahead of print]
    RSAT 2022: regulatory sequence analysis tools.
    Walter Santana-Garcia, Jaime A Castro-Mondragon, Mónica Padilla-Gálvez, Nga Thi Thuy Nguyen, Ana Elizondo-Salas, Najla Ksouri, François Gerbes, Denis Thieffry, Pierre Vincens, Bruno Contreras-Moreira, Jacques van Helden, Morgane Thomas-Chollier, Alejandra Medina-Rivera.
      RSAT (Regulatory Sequence Analysis Tools) enables the detection and the analysis of cis-regulatory elements in genomic sequences. This software suite performs (i) de novo motif discovery (including from genome-wide datasets like ChIP-seq/ATAC-seq) (ii) genomic sequences scanning with known motifs, (iii) motif analysis (quality assessment, comparisons and clustering), (iv) analysis of regulatory variations and (v) comparative genomics. RSAT comprises 50 tools. Six public Web servers (including a teaching server) are offered to meet the needs of different biological communities. RSAT philosophy and originality are: (i) a multi-modal access depending on the user needs, through web forms, command-line for local installation and programmatic web services, (ii) a support for virtually any genome (animals, bacteria, plants, totalizing over 10 000 genomes directly accessible). Since the 2018 NAR Web Software Issue, we have developed a large REST API, extended the support for additional genomes and external motif collections, enhanced some tools and Web forms, and developed a novel tool that builds or refine gene regulatory networks using motif scanning (network-interactions). The RSAT website provides extensive documentation, tutorials and published protocols. RSAT code is under open-source license and now hosted in GitHub. RSAT is available at http://www.rsat.eu/.
    DOI:  https://doi.org/10.1093/nar/gkac312
  20. Nat Commun. 2022 May 12. 13(1): 2654
    Runx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells.
    Yoshiki Omatsu, Shota Aiba, Tomonori Maeta, Kei Higaki, Kazunari Aoki, Hitomi Watanabe, Gen Kondoh, Riko Nishimura, Shu Takeda, Ung-Il Chung, Takashi Nagasawa.
      In bone marrow, special microenvironments, known as niches, are essential for the maintenance of hematopoietic stem cells (HSCs). A population of mesenchymal stem cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells or leptin receptor-expressing cells are the major cellular component of HSC niches. The molecular regulation of HSC niche properties is not fully understood. The role of Runx transcription factors, Runx1 and Runx2 in HSC cellular niches remains unclear. Here we show that Runx1 is predominantly expressed in CAR cells and that mice lacking both Runx1 and Runx2 in CAR cells display an increase in fibrosis and bone formation with markedly reduced hematopoietic stem and progenitor cells in bone marrow. In vitro, Runx1 is induced by the transcription factor Foxc1 and decreases fibrotic gene expression in CAR cells. Thus, HSC cellular niches require Runx1 or Runx2 to prevent their fibrotic conversion and maintain HSCs and hematopoiesis in adults.
    DOI:  https://doi.org/10.1038/s41467-022-30266-y
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