bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2022‒07‒17
nineteen papers selected by
Connor Rogerson
University of Cambridge
  1. YAP induces an oncogenic transcriptional program through TET1-mediated epigenetic remodeling in liver growth and tumorigenesis.
  2. Kinetic principles underlying pioneer function of GAGA transcription factor in live cells.
  3. Stochastic models of nucleosome dynamics reveal regulatory rules of stimulus-induced epigenome remodeling.
  4. Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA.
  5. In vivo dissection of a clustered-CTCF domain boundary reveals developmental principles of regulatory insulation.
  6. Mesp1 controls the chromatin and enhancer landscapes essential for spatiotemporal patterning of early cardiovascular progenitors.
  7. Generating specificity in genome regulation through transcription factor sensitivity to chromatin.
  8. PHF20 is crucial for epigenetic control of starvation-induced autophagy through enhancer activation.
  9. Temporally dynamic antagonism between transcription and chromatin compaction controls stochastic photoreceptor specification in flies.
  10. A sequence-based global map of regulatory activity for deciphering human genetics.
  11. DeepLoop robustly maps chromatin interactions from sparse allele-resolved or single-cell Hi-C data at kilobase resolution.
  12. Functional analysis of Vsx2 super-enhancer uncovers distinct cis-regulatory circuits controlling Vsx2 expression during retinogenesis.
  13. Distinct p53 isoforms code for opposing transcriptional outcomes.
  14. Repetitive DNA symmetry elements negatively regulate gene expression in embryonic stem cells.
  15. NURF301 contributes to gypsy chromatin insulator-mediated nuclear organization.
  16. FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma.
  17. A non-transcriptional function of Yap regulates the DNA replication program.
  18. NucleoMap: A computational tool for identifying nucleosomes in ultra-high resolution contact maps.
  19. A SOX17-PDGFB signaling axis regulates aortic root development.
  1. Nat Genet. 2022 Jul 14.
    YAP induces an oncogenic transcriptional program through TET1-mediated epigenetic remodeling in liver growth and tumorigenesis.
    Bo-Kuan Wu, Szu-Chieh Mei, Elizabeth H Chen, Yonggang Zheng, Duojia Pan.
      Epigenetic remodeling is essential for oncogene-induced cellular transformation and malignancy. In contrast to histone post-translational modifications, how DNA methylation is remodeled by oncogenic signaling remains poorly understood. The oncoprotein YAP, a coactivator of the TEAD transcription factors mediating Hippo signaling, is widely activated in human cancers. Here, we identify the 5-methylcytosine dioxygenase TET1 as a direct YAP target and a master regulator that coordinates the genome-wide epigenetic and transcriptional reprogramming of YAP target genes in the liver. YAP activation induces the expression of TET1, which physically interacts with TEAD to cause regional DNA demethylation, histone H3K27 acetylation and chromatin opening in YAP target genes to facilitate transcriptional activation. Loss of TET1 not only reverses YAP-induced epigenetic and transcriptional changes but also suppresses YAP-induced hepatomegaly and tumorigenesis. These findings exemplify how oncogenic signaling regulates the site specificity of DNA demethylation to promote tumorigenesis and implicate TET1 as a potential target for modulating YAP signaling in physiology and disease.
    DOI:  https://doi.org/10.1038/s41588-022-01119-7
  2. Nat Struct Mol Biol. 2022 Jul;29(7): 665-676
    Kinetic principles underlying pioneer function of GAGA transcription factor in live cells.
    Xiaona Tang, Taibo Li, Sheng Liu, Jan Wisniewski, Qinsi Zheng, Yikang Rong, Luke D Lavis, Carl Wu.
      How pioneer factors interface with chromatin to promote accessibility for transcription control is poorly understood in vivo. Here, we directly visualize chromatin association by the prototypical GAGA pioneer factor (GAF) in live Drosophila hemocytes. Single-particle tracking reveals that most GAF is chromatin bound, with a stable-binding fraction showing nucleosome-like confinement residing on chromatin for more than 2 min, far longer than the dynamic range of most transcription factors. These kinetic properties require the full complement of GAF's DNA-binding, multimerization and intrinsically disordered domains, and are autonomous from recruited chromatin remodelers NURF and PBAP, whose activities primarily benefit GAF's neighbors such as Heat Shock Factor. Evaluation of GAF kinetics together with its endogenous abundance indicates that, despite on-off dynamics, GAF constitutively and fully occupies major chromatin targets, thereby providing a temporal mechanism that sustains open chromatin for transcriptional responses to homeostatic, environmental and developmental signals.
    DOI:  https://doi.org/10.1038/s41594-022-00800-z
  3. Cell Rep. 2022 Jul 12. pii: S2211-1247(22)00874-9. [Epub ahead of print]40(2): 111076
    Stochastic models of nucleosome dynamics reveal regulatory rules of stimulus-induced epigenome remodeling.
    Jinsu Kim, Katherine M Sheu, Quen J Cheng, Alexander Hoffmann, German Enciso.
      The genomic positions of nucleosomes are a defining feature of the cell's epigenomic state, but signal-dependent transcription factors (SDTFs), upon activation, bind to specific genomic locations and modify nucleosome positioning. Here we leverage SDTFs as perturbation probes to learn about nucleosome dynamics in living cells. We develop Markov models of nucleosome dynamics and fit them to time course sequencing data of DNA accessibility. We find that (1) the dynamics of DNA unwrapping are significantly slower in cells than reported from cell-free experiments, (2) only models with cooperativity in wrapping and unwrapping fit the available data, (3) SDTF activity produces the highest eviction probability when its binding site is adjacent to but not on the nucleosome dyad, and (4) oscillatory SDTF activity results in high location variability. Our work uncovers the regulatory rules governing SDTF-induced nucleosome dynamics in live cells, which can predict chromatin accessibility alterations during inflammation at single-nucleosome resolution.
    Keywords:  ATAC-seq; CP: Molecular biology; NF-κB; cooperativity; histone eviction; nucleosome dynamics; random walk; signal-dependent transcription factor; stochastic model; time-dependent Markov model
    DOI:  https://doi.org/10.1016/j.celrep.2022.111076
  4. Nat Commun. 2022 Jul 09. 13(1): 3988
    Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA.
    Tuan Nguyen, Sai Li, Jeremy T-H Chang, John W Watters, Htet Ng, Adewola Osunsade, Yael David, Shixin Liu.
      Biomolecular condensation constitutes an emerging mechanism for transcriptional regulation. Recent studies suggest that the co-condensation between transcription factors (TFs) and DNA can generate mechanical forces driving genome rearrangements. However, the reported forces generated by protein-DNA co-condensation are typically below one piconewton (pN), questioning its physiological significance. Moreover, the force-generating capacity of these condensates in the chromatin context remains unknown. Here, we show that Sox2, a nucleosome-binding pioneer TF, forms co-condensates with DNA and generates forces up to 7 pN, exerting considerable mechanical tension on DNA strands. We find that the disordered domains of Sox2 are required for maximum force generation but not for condensate formation. Furthermore, we show that nucleosomes dramatically attenuate the mechanical stress exerted by Sox2 by sequestering it from coalescing on bare DNA. Our findings reveal that TF-mediated DNA condensation can exert significant mechanical stress on the genome which can nonetheless be attenuated by the chromatin architecture.
    DOI:  https://doi.org/10.1038/s41467-022-31738-x
  5. Nat Genet. 2022 Jul;54(7): 1026-1036
    In vivo dissection of a clustered-CTCF domain boundary reveals developmental principles of regulatory insulation.
    Chiara Anania, Rafael D Acemel, Johanna Jedamzick, Adriano Bolondi, Giulia Cova, Norbert Brieske, Ralf Kühn, Lars Wittler, Francisca M Real, Darío G Lupiáñez.
      Vertebrate genomes organize into topologically associating domains, delimited by boundaries that insulate regulatory elements from nontarget genes. However, how boundary function is established is not well understood. Here, we combine genome-wide analyses and transgenic mouse assays to dissect the regulatory logic of clustered-CCCTC-binding factor (CTCF) boundaries in vivo, interrogating their function at multiple levels: chromatin interactions, transcription and phenotypes. Individual CTCF binding site (CBS) deletions revealed that the characteristics of specific sites can outweigh other factors such as CBS number and orientation. Combined deletions demonstrated that CBSs cooperate redundantly and provide boundary robustness. We show that divergent CBS signatures are not strictly required for effective insulation and that chromatin loops formed by nonconvergently oriented sites could be mediated by a loop interference mechanism. Further, we observe that insulation strength constitutes a quantitative modulator of gene expression and phenotypes. Our results highlight the modular nature of boundaries and their control over developmental processes.
    DOI:  https://doi.org/10.1038/s41588-022-01117-9
  6. Nat Cell Biol. 2022 Jul;24(7): 1114-1128
    Mesp1 controls the chromatin and enhancer landscapes essential for spatiotemporal patterning of early cardiovascular progenitors.
    Xionghui Lin, Benjamin Swedlund, Mai-Linh N Ton, Shila Ghazanfar, Carolina Guibentif, Catherine Paulissen, Elodie Baudelet, Elise Plaindoux, Younes Achouri, Emilie Calonne, Christine Dubois, William Mansfield, Stéphane Zaffran, John C Marioni, Francois Fuks, Berthold Göttgens, Fabienne Lescroart, Cédric Blanpain.
      The mammalian heart arises from various populations of Mesp1-expressing cardiovascular progenitors (CPs) that are specified during the early stages of gastrulation. Mesp1 is a transcription factor that acts as a master regulator of CP specification and differentiation. However, how Mesp1 regulates the chromatin landscape of nascent mesodermal cells to define the temporal and spatial patterning of the distinct populations of CPs remains unknown. Here, by combining ChIP-seq, RNA-seq and ATAC-seq during mouse pluripotent stem cell differentiation, we defined the dynamic remodelling of the chromatin landscape mediated by Mesp1. We identified different enhancers that are temporally regulated to erase the pluripotent state and specify the pools of CPs that mediate heart development. We identified Zic2 and Zic3 as essential cofactors that act with Mesp1 to regulate its transcription-factor activity at key mesodermal enhancers, thereby regulating the chromatin remodelling and gene expression associated with the specification of the different populations of CPs in vivo. Our study identifies the dynamics of the chromatin landscape and enhancer remodelling associated with temporal patterning of early mesodermal cells into the distinct populations of CPs that mediate heart development.
    DOI:  https://doi.org/10.1038/s41556-022-00947-3
  7. Nat Rev Genet. 2022 Jul 12.
    Generating specificity in genome regulation through transcription factor sensitivity to chromatin.
    Luke Isbel, Ralph S Grand, Dirk Schübeler.
      Cell type-specific gene expression relies on transcription factors (TFs) binding DNA sequence motifs embedded in chromatin. Understanding how motifs are accessed in chromatin is crucial to comprehend differential transcriptional responses and the phenotypic impact of sequence variation. Chromatin obstacles to TF binding range from DNA methylation to restriction of DNA access by nucleosomes depending on their position, composition and modification. In vivo and in vitro approaches now enable the study of TF binding in chromatin at unprecedented resolution. Emerging insights suggest that TFs vary in their ability to navigate chromatin states. However, it remains challenging to link binding and transcriptional outcomes to molecular characteristics of TFs or the local chromatin substrate. Here, we discuss our current understanding of how TFs access DNA in chromatin and novel techniques and directions towards a better understanding of this critical step in genome regulation.
    DOI:  https://doi.org/10.1038/s41576-022-00512-6
  8. Nucleic Acids Res. 2022 Jul 13. pii: gkac584. [Epub ahead of print]
    PHF20 is crucial for epigenetic control of starvation-induced autophagy through enhancer activation.
    Se Won Park, Jaehoon Kim, Sungryong Oh, Jeongyoon Lee, Joowon Cha, Hyun Sik Lee, Keun Il Kim, Daechan Park, Sung Hee Baek.
      Autophagy is a catabolic pathway that maintains cellular homeostasis under various stress conditions, including conditions of nutrient deprivation. To elevate autophagic flux to a sufficient level under stress conditions, transcriptional activation of autophagy genes occurs to replenish autophagy components. Thus, the transcriptional and epigenetic control of the genes regulating autophagy is essential for cellular homeostasis. Here, we applied integrated transcriptomic and epigenomic profiling to reveal the roles of plant homeodomain finger protein 20 (PHF20), which is an epigenetic reader possessing methyl binding activity, in controlling the expression of autophagy genes. Phf20 deficiency led to impaired autophagic flux and autophagy gene expression under glucose starvation. Interestingly, the genome-wide characterization of chromatin states by Assay for Transposase-Accessible Chromatin (ATAC)-sequencing revealed that the PHF20-dependent chromatin remodelling occurs in enhancers that are co-occupied by dimethylated lysine 36 on histone H3 (H3K36me2). Importantly, the recognition of H3K36me2 by PHF20 was found to be highly correlated with increased levels of H3K4me1/2 at the enhancer regions. Collectively, these results indicate that PHF20 regulates autophagy genes through enhancer activation via H3K36me2 recognition as an epigenetic reader. Our findings emphasize the importance of nuclear events in the regulation of autophagy.
    DOI:  https://doi.org/10.1093/nar/gkac584
  9. Dev Cell. 2022 Jul 12. pii: S1534-5807(22)00457-9. [Epub ahead of print]
    Temporally dynamic antagonism between transcription and chromatin compaction controls stochastic photoreceptor specification in flies.
    Lukas Voortman, Caitlin Anderson, Elizabeth Urban, Rongxin Yuan, Sang Tran, Alexandra Neuhaus-Follini, Josh Derrick, Thomas Gregor, Robert J Johnston.
      Stochastic mechanisms diversify cell fates during development. How cells randomly choose between two or more fates remains poorly understood. In the Drosophila eye, the random mosaic of two R7 photoreceptor subtypes is determined by expression of the transcription factor Spineless (Ss). We investigated how cis-regulatory elements and trans factors regulate nascent transcriptional activity and chromatin compaction at the ss gene locus during R7 development. The ss locus is in a compact state in undifferentiated cells. An early enhancer drives transcription in all R7 precursors, and the locus opens. In differentiating cells, transcription ceases and the ss locus stochastically remains open or compacts. In SsON R7s, ss is open and competent for activation by a late enhancer, whereas in SsOFF R7s, ss is compact, and repression prevents expression. Our results suggest that a temporally dynamic antagonism, in which transcription drives large-scale decompaction and then compaction represses transcription, controls stochastic fate specification.
    Keywords:  Ash2; Drosophila; Klumpfuss; Lid; Spineless; chromatin; enhancer; photoreceptor; retina; stochastic
    DOI:  https://doi.org/10.1016/j.devcel.2022.06.016
  10. Nat Genet. 2022 Jul;54(7): 940-949
    A sequence-based global map of regulatory activity for deciphering human genetics.
    Kathleen M Chen, Aaron K Wong, Olga G Troyanskaya, Jian Zhou.
      Epigenomic profiling has enabled large-scale identification of regulatory elements, yet we still lack a systematic mapping from any sequence or variant to regulatory activities. We address this challenge with Sei, a framework for integrating human genetics data with sequence information to discover the regulatory basis of traits and diseases. Sei learns a vocabulary of regulatory activities, called sequence classes, using a deep learning model that predicts 21,907 chromatin profiles across >1,300 cell lines and tissues. Sequence classes provide a global classification and quantification of sequence and variant effects based on diverse regulatory activities, such as cell type-specific enhancer functions. These predictions are supported by tissue-specific expression, expression quantitative trait loci and evolutionary constraint data. Furthermore, sequence classes enable characterization of the tissue-specific, regulatory architecture of complex traits and generate mechanistic hypotheses for individual regulatory pathogenic mutations. We provide Sei as a resource to elucidate the regulatory basis of human health and disease.
    DOI:  https://doi.org/10.1038/s41588-022-01102-2
  11. Nat Genet. 2022 Jul;54(7): 1013-1025
    DeepLoop robustly maps chromatin interactions from sparse allele-resolved or single-cell Hi-C data at kilobase resolution.
    Shanshan Zhang, Dylan Plummer, Leina Lu, Jian Cui, Wanying Xu, Miao Wang, Xiaoxiao Liu, Nachiketh Prabhakar, Jatin Shrinet, Divyaa Srinivasan, Peter Fraser, Yan Li, Jing Li, Fulai Jin.
      Mapping chromatin loops from noisy Hi-C heatmaps remains a major challenge. Here we present DeepLoop, which performs rigorous bias correction followed by deep-learning-based signal enhancement for robust chromatin interaction mapping from low-depth Hi-C data. DeepLoop enables loop-resolution, single-cell Hi-C analysis. It also achieves a cross-platform convergence between different Hi-C protocols and micrococcal nuclease (micro-C). DeepLoop allowed us to map the genetic and epigenetic determinants of allele-specific chromatin interactions in the human genome. We nominate new loci with allele-specific interactions governed by imprinting or allelic DNA methylation. We also discovered that, in the inactivated X chromosome (Xi), local loops at the DXZ4 'megadomain' boundary escape X-inactivation but the FIRRE 'superloop' locus does not. Importantly, DeepLoop can pinpoint heterozygous single-nucleotide polymorphisms and large structure variants that cause allelic chromatin loops, many of which rewire enhancers with transcription consequences. Taken together, DeepLoop expands the use of Hi-C to provide loop-resolution insights into the genetics of the three-dimensional genome.
    DOI:  https://doi.org/10.1038/s41588-022-01116-w
  12. Development. 2022 Jul 14. pii: dev.200642. [Epub ahead of print]
    Functional analysis of Vsx2 super-enhancer uncovers distinct cis-regulatory circuits controlling Vsx2 expression during retinogenesis.
    Fuyun Bian, Marwa Daghsni, Fangfang Lu, Silvia Liu, Jeffrey M Gross, Issam Aldiri.
      Vsx2 is a transcription factor essential for retinal proliferation and bipolar cell differentiation but the molecular mechanisms underlying its developmental roles are unclear. Here, we profiled VSX2 genomic occupancy during mouse retinogenesis, revealing extensive retinal genetic programs associated with VSX2 during development. VSX2 binds and transactivates its enhancer in association with the transcription factor PAX6. Mice harboring deletions in the Vsx2 regulatory landscape exhibit specific abnormalities in retinal proliferation and bipolar cell differentiation. In one of those deletions, a complete loss of bipolar cells is associated with a bias toward photoreceptor production. VSX2 occupies cis-regulatory elements nearby genes associated with photoreceptor differentiation and homeostasis in the adult mouse and human retina, including a conserved region nearby Prdm1, a factor implicated in the specification of rod photoreceptors and suppression of bipolar cell fate. VSX2 interacts with the transcription factor OTX2 and can act to suppress OTX2-dependent enhancer transactivation of Prdm1 enhancer. Taken together, our analyses indicate that Vsx2 expression can be temporally and spatially uncoupled at the enhancer level and illuminate important mechanistic insights on how VSX2 is engaged with gene regulatory networks essential for retinal proliferation and cell fate acquisition.
    Keywords:  Bipolar cells; Chromatin; Enhancers; Neurogenesis; Retina; Vsx2
    DOI:  https://doi.org/10.1242/dev.200642
  13. Dev Cell. 2022 Jul 05. pii: S1534-5807(22)00456-7. [Epub ahead of print]
    Distinct p53 isoforms code for opposing transcriptional outcomes.
    Annika Wylie, Amanda E Jones, Simanti Das, Wan-Jin Lu, John M Abrams.
      p53 genes are conserved transcriptional activators that respond to stress. These proteins can also downregulate genes, but the mechanisms are not understood and are generally assumed to be indirect. Here, we investigate synthetic and native cis-regulatory elements in Drosophila to examine opposing features of p53-mediated transcriptional control in vivo. We show that transcriptional repression by p53 operates continuously through canonical DNA binding sites that confer p53-dependent transactivation at earlier developmental stages. p53 transrepression is correlated with local H3K9me3 chromatin marks and occurs without the need for stress or Chk2. In sufficiency tests, two p53 isoforms qualify as transrepressors and a third qualifies as a transcriptional activator. Targeted isoform-specific knockouts dissociate these opposing transcriptional activities, highlighting features that are dispensable for transactivation but critical for repression and for proper germ cell formation. Together, these results demonstrate that certain p53 isoforms function as constitutive tissue-specific repressors, raising important implications for tumor suppression by the human counterpart.
    Keywords:  Chk2; DNA binding motif; Drosophila; biosensor; chromatin modifications; corolla; p53; p53 isoforms; transactivation; transrepression
    DOI:  https://doi.org/10.1016/j.devcel.2022.06.015
  14. Biophys J. 2022 Jul 08. pii: S0006-3495(22)00557-4. [Epub ahead of print]
    Repetitive DNA symmetry elements negatively regulate gene expression in embryonic stem cells.
    Meir Mellul, Shlomtzion Lahav, Masahiko Imashimizu, Yuji Tokunaga, David B Lukatsky, Oren Ram.
      Transcription factor (TF) binding to genomic DNA elements constitutes one of the key mechanisms that regulates gene expression program in cells. Both consensus and non-consensus DNA sequence elements influence the recognition specificity of TFs. Based on the analysis of experimentally determined c-Myc binding preferences to genomic DNA, here we statistically predict that certain repetitive, non-consensus DNA symmetry elements can relatively reduce TF-DNA binding preferences. This is in contrast to a different set of repetitive, non-consensus symmetry elements that can increase the strength of TF-DNA binding. Using c-Myc enhancer reporter system containing consensus motif flanked by non-consensus sequences in embryonic stem cells (ESCs), we directly demonstrate that the enrichment in such negatively regulating repetitive symmetry elements is sufficient to reduce the gene expression level as compared with native genomic sequences. Negatively regulating repetitive symmetry elements around consensus c-Myc motif and DNA sequences containing consensus c-Myc motif flanked by entirely randomized sequences show similar expression baseline. A possible explanation for this observation is that rather than complete repression, negatively regulating repetitive symmetry elements play a regulatory role in fine-tuning the reduction of gene expression, most probably by binding TFs other than c-Myc.
    Keywords:  Nonspecific protein-DNA interactions; Protein-DNA interactions; Regulation of gene expression
    DOI:  https://doi.org/10.1016/j.bpj.2022.07.011
  15. Nucleic Acids Res. 2022 Jul 12. pii: gkac600. [Epub ahead of print]
    NURF301 contributes to gypsy chromatin insulator-mediated nuclear organization.
    Shue Chen, Leah F Rosin, Gianluca Pegoraro, Nellie Moshkovich, Patrick J Murphy, Guoyun Yu, Elissa P Lei.
      Chromatin insulators are DNA-protein complexes that can prevent the spread of repressive chromatin and block communication between enhancers and promoters to regulate gene expression. In Drosophila, the gypsy chromatin insulator complex consists of three core proteins: CP190, Su(Hw), and Mod(mdg4)67.2. These factors concentrate at nuclear foci termed insulator bodies, and changes in insulator body localization have been observed in mutants defective for insulator function. Here, we identified NURF301/E(bx), a nucleosome remodeling factor, as a novel regulator of gypsy insulator body localization through a high-throughput RNAi imaging screen. NURF301 promotes gypsy-dependent insulator barrier activity and physically interacts with gypsy insulator proteins. Using ChIP-seq, we found that NURF301 co-localizes with insulator proteins genome-wide, and NURF301 promotes chromatin association of Su(Hw) and CP190 at gypsy insulator binding sites. These effects correlate with NURF301-dependent nucleosome repositioning. At the same time, CP190 and Su(Hw) both facilitate recruitment of NURF301 to chromatin. Finally, Oligopaint FISH combined with immunofluorescence revealed that NURF301 promotes 3D contact between insulator bodies and gypsy insulator DNA binding sites, and NURF301 is required for proper nuclear positioning of gypsy binding sites. Our data provide new insights into how a nucleosome remodeling factor and insulator proteins cooperatively contribute to nuclear organization.
    DOI:  https://doi.org/10.1093/nar/gkac600
  16. Dev Cell. 2022 Jul 05. pii: S1534-5807(22)00458-0. [Epub ahead of print]
    FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma.
    Grace Orstad, Gabriela Fort, Timothy J Parnell, Alex Jones, Chris Stubben, Brian Lohman, Katherine L Gillis, Walter Orellana, Rushmeen Tariq, Olaf Klingbeil, Klaus Kaestner, Christopher R Vakoc, Benjamin T Spike, Eric L Snyder.
      Changes in cellular identity (also known as histologic transformation or lineage plasticity) can drive malignant progression and resistance to therapy in many cancers, including lung adenocarcinoma (LUAD). The lineage-specifying transcription factors FoxA1 and FoxA2 (FoxA1/2) control identity in NKX2-1/TTF1-negative LUAD. However, their role in NKX2-1-positive LUAD has not been systematically investigated. We find that Foxa1/2 knockout severely impairs tumorigenesis in KRAS-driven genetically engineered mouse models and human cell lines. Loss of FoxA1/2 leads to the collapse of a dual-identity state, marked by co-expression of pulmonary and gastrointestinal transcriptional programs, which has been implicated in LUAD progression. Mechanistically, FoxA1/2 loss leads to aberrant NKX2-1 activity and genomic localization, which in turn actively inhibits tumorigenesis and drives alternative cellular identity programs that are associated with non-proliferative states. This work demonstrates that FoxA1/2 expression is a lineage-specific vulnerability in NKX2-1-positive LUAD and identifies mechanisms of response and resistance to targeting FoxA1/2 in this disease.
    Keywords:  FoxA1; FoxA2; NKX2-1; cellular identity; lineage switching; lung adenocarcinoma
    DOI:  https://doi.org/10.1016/j.devcel.2022.06.017
  17. Elife. 2022 Jul 15. pii: e75741. [Epub ahead of print]11
    A non-transcriptional function of Yap regulates the DNA replication program.
    Rodrigo Meléndez García, Olivier Haccard, Albert Chesneau, Hemalatha Narassimprakash, Jérôme Roger, Muriel Perron, Kathrin Marheineke, Odile Bronchain.
      In multicellular eukaryotic organisms, the initiation of DNA replication occurs asynchronously throughout S-phase according to a regulated replication timing program. Here, using Xenopus egg extracts, we showed that Yap (Yes-associated protein 1), a downstream effector of the Hippo signalling pathway, is required for the control of DNA replication dynamics. We found that Yap is recruited to chromatin at the start of DNA replication and identified Rif1, a major regulator of the DNA replication timing program, as a novel Yap binding protein. Furthermore, we show that either Yap or Rif1 depletion accelerates DNA replication dynamics by increasing the number of activated replication origins. In Xenopus embryos, using a Trim-Away approach during cleavage stages devoid of transcription, we found that either Yap or Rif1 depletion triggers an acceleration of cell divisions, suggesting a shorter S-phase by alterations of the replication program. Finally, our data show that Rif1 knockdown leads to defects in the partitioning of early versus late replication foci in retinal stem cells, as we previously showed for Yap. Altogether, our findings unveil a non-transcriptional role for Yap in regulating replication dynamics. We propose that Yap and Rif1 function as breaks to control the DNA replication program in early embryos and post-embryonic stem cells.
    Keywords:  cell biology; developmental biology; xenopus
    DOI:  https://doi.org/10.7554/eLife.75741
  18. PLoS Comput Biol. 2022 Jul 14. 18(7): e1010265
    NucleoMap: A computational tool for identifying nucleosomes in ultra-high resolution contact maps.
    Yuanhao Huang, Bingjiang Wang, Jie Liu.
      Although poorly positioned nucleosomes are ubiquitous in the eukaryotic genome, they are difficult to identify with existing nucleosome identification methods. Recently available enhanced high-throughput chromatin conformation capture techniques such as Micro-C, DNase Hi-C, and Hi-CO characterize nucleosome-level chromatin proximity, probing the positions of mono-nucleosomes and the spacing between nucleosome pairs at the same time, enabling nucleosome profiling in poorly positioned regions. Here we develop a novel computational approach, NucleoMap, to identify nucleosome positioning from ultra-high resolution chromatin contact maps. By integrating nucleosome read density, contact distances, and binding preferences, NucleoMap precisely locates nucleosomes in both prokaryotic and eukaryotic genomes and outperforms existing nucleosome identification methods in both precision and recall. We rigorously characterize genome-wide association in eukaryotes between the spatial organization of mono-nucleosomes and their corresponding histone modifications, protein binding activities, and higher-order chromatin functions. We also find evidence of two tetra-nucleosome folding structures in human embryonic stem cells and analyze their association with multiple structural and functional regions. Based on the identified nucleosomes, nucleosome contact maps are constructed, reflecting the inter-nucleosome distances and preserving the contact distance profiles in original contact maps.
    DOI:  https://doi.org/10.1371/journal.pcbi.1010265
  19. Nat Commun. 2022 Jul 13. 13(1): 4065
    A SOX17-PDGFB signaling axis regulates aortic root development.
    Pengfei Lu, Ping Wang, Bingruo Wu, Yidong Wang, Yang Liu, Wei Cheng, Xuhui Feng, Xinchun Yuan, Miriam M Atteya, Haleigh Ferro, Yukiko Sugi, Grant Rydquist, Mahdi Esmaily, Jonathan T Butcher, Ching-Pin Chang, Jack Lenz, Deyou Zheng, Bin Zhou.
      Developmental etiologies causing complex congenital aortic root abnormalities are unknown. Here we show that deletion of Sox17 in aortic root endothelium in mice causes underdeveloped aortic root leading to a bicuspid aortic valve due to the absence of non-coronary leaflet and mispositioned left coronary ostium. The respective defects are associated with reduced proliferation of non-coronary leaflet mesenchyme and aortic root smooth muscle derived from the second heart field cardiomyocytes. Mechanistically, SOX17 occupies a Pdgfb transcriptional enhancer to promote its transcription and Sox17 deletion inhibits the endothelial Pdgfb transcription and PDGFB growth signaling to the non-coronary leaflet mesenchyme. Restoration of PDGFB in aortic root endothelium rescues the non-coronary leaflet and left coronary ostium defects in Sox17 nulls. These data support a SOX17-PDGFB axis underlying aortic root development that is critical for aortic valve and coronary ostium patterning, thereby informing a potential shared disease mechanism for concurrent anomalous aortic valve and coronary arteries.
    DOI:  https://doi.org/10.1038/s41467-022-31815-1
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