bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2022‒07‒03
eighteen papers selected by
Connor Rogerson
University of Cambridge
  1. Developmental and evolutionary comparative analysis of a regulatory landscape in mouse and chicken.
  2. The Arabidopsis DREAM complex antagonizes WDR5A to modulate histone H3K4me2/3 deposition for a subset of genome repression.
  3. Synthetic regulatory reconstitution reveals principles of mammalian Hox cluster regulation.
  4. Single-cell specific and interpretable machine learning models for sparse scChIP-seq data imputation.
  5. Topoisomerase VI participates in an insulator-like function that prevents H3K9me2 spreading.
  6. OCT4 activates a Suv39h1-repressive antisense lncRNA to couple histone H3 Lysine 9 methylation to pluripotency.
  7. Machine-learning-optimized Cas12a barcoding enables the recovery of single-cell lineages and transcriptional profiles.
  8. Histone H2A ubiquitination resulting from Brap loss of function connects multiple aging hallmarks and accelerates neurodegeneration.
  9. Genetic dissection of the RNA polymerase II transcription cycle.
  10. SETDB1 acts as a topological accessory to Cohesin via an H3K9me3-independent, genomic shunt for regulating cell fates.
  11. Senescent cells limit p53 activity via multiple mechanisms to remain viable.
  12. Structural basis for binding diversity of acetyltransferase p300 to the nucleosome.
  13. Transcription factor paralogs orchestrate alternative gene regulatory networks by context-dependent cooperation with multiple cofactors.
  14. scDART: integrating unmatched scRNA-seq and scATAC-seq data and learning cross-modality relationship simultaneously.
  15. MeConcord: a new metric to quantitatively characterize DNA methylation heterogeneity across reads and CpG sites.
  16. Inactivation of the Hippo tumor suppressor pathway promotes melanoma.
  17. Hepatocellular carcinoma evades RB1-induced senescence by activating the FOXM1-FOXO1 axis.
  18. Widespread redundancy in -omics profiles of cancer mutation states.
  1. Development. 2022 Jun 15. pii: dev200594. [Epub ahead of print]149(12):
    Developmental and evolutionary comparative analysis of a regulatory landscape in mouse and chicken.
    Aurélie Hintermann, Isabel Guerreiro, Lucille Lopez-Delisle, Christopher Chase Bolt, Sandra Gitto, Denis Duboule, Leonardo Beccari.
      Modifications in gene regulation are driving forces in the evolution of organisms. Part of these changes involve cis-regulatory elements (CREs), which contact their target genes through higher-order chromatin structures. However, how such architectures and variations in CREs contribute to transcriptional evolvability remains elusive. We use Hoxd genes as a paradigm for the emergence of regulatory innovations, as many relevant enhancers are located in a regulatory landscape highly conserved in amniotes. Here, we analysed their regulation in murine vibrissae and chicken feather primordia, two skin appendages expressing different Hoxd gene subsets, and compared the regulation of these genes in these appendages with that in the elongation of the posterior trunk. In the two former structures, distinct subsets of Hoxd genes are contacted by different lineage-specific enhancers, probably as a result of using an ancestral chromatin topology as an evolutionary playground, whereas the gene regulation that occurs in the mouse and chicken embryonic trunk partially relies on conserved CREs. A high proportion of these non-coding sequences active in the trunk have functionally diverged between species, suggesting that transcriptional robustness is maintained, despite considerable divergence in enhancer sequences.
    Keywords:  Chromatin topology; Development; Enhancers; Evolution; Gene regulation; Placodes; TADs; Teguments
    DOI:  https://doi.org/10.1242/dev.200594
  2. Proc Natl Acad Sci U S A. 2022 Jul 05. 119(27): e2206075119
    The Arabidopsis DREAM complex antagonizes WDR5A to modulate histone H3K4me2/3 deposition for a subset of genome repression.
    Yuqiu Wang, Yangyang Fan, De Fan, Yubo Zhang, Xiaoli Zhou, Ruikai Zhang, Yao Wang, Yujie Sun, Wei Zhang, Yuehui He, Xing Wang Deng, Danmeng Zhu.
      The master transcriptional repressor DREAM (dimerization partner, RB-like, E2F and multivulval class B) complex regulates the cell cycle in eukaryotes, but much remains unknown about how it transmits repressive signals on chromatin to the primary transcriptional machinery (e.g., RNA polymerase II [Pol II]). Through a forward genetic screen, we identified BTE1 (barrier of transcription elongation 1), a plant-specific component of the DREAM complex. The subsequent characterization demonstrated that DREAM complex containing BTE1 antagonizes the activity of Complex Proteins Associated with Set1 (COMPASS)-like complex to repress H3K4me3 occupancy and inhibits Pol II elongation at DREAM target genes. We showed that BTE1 is recruited to chromatin at the promoter-proximal regions of target genes by E2F transcription factors. DREAM target genes exhibit characteristic enrichment of H2A.Z and H3K4me2 modification on chromatin. We further showed that BTE1 directly interacts with WDR5A, a core component of COMPASS-like complex, repressing WDR5A chromatin binding and the elongation of transcription on DREAM target genes. H3K4me3 is known to correlate with the Pol II transcription activation and promotes efficient elongation. Thus, our study illustrates a transcriptional repression mechanism by which the DREAM complex dampens H3K4me3 deposition at a set of genes through its interaction with WDR5A.
    Keywords:  DREAM complex; H3K4 methylation; transcriptional repression
    DOI:  https://doi.org/10.1073/pnas.2206075119
  3. Science. 2022 Jul;377(6601): eabk2820
    Synthetic regulatory reconstitution reveals principles of mammalian Hox cluster regulation.
    Sudarshan Pinglay, Milica Bulajić, Dylan P Rahe, Emily Huang, Ran Brosh, Nicholas E Mamrak, Benjamin R King, Sergei German, John A Cadley, Lila Rieber, Nicole Easo, Timothée Lionnet, Shaun Mahony, Matthew T Maurano, Liam J Holt, Esteban O Mazzoni, Jef D Boeke.
      Precise Hox gene expression is crucial for embryonic patterning. Intra-Hox transcription factor binding and distal enhancer elements have emerged as the major regulatory modules controlling Hox gene expression. However, quantifying their relative contributions has remained elusive. Here, we introduce "synthetic regulatory reconstitution," a conceptual framework for studying gene regulation, and apply it to the HoxA cluster. We synthesized and delivered variant rat HoxA clusters (130 to 170 kilobases) to an ectopic location in the mouse genome. We found that a minimal HoxA cluster recapitulated correct patterns of chromatin remodeling and transcription in response to patterning signals, whereas the addition of distal enhancers was needed for full transcriptional output. Synthetic regulatory reconstitution could provide a generalizable strategy for deciphering the regulatory logic of gene expression in complex genomes.
    DOI:  https://doi.org/10.1126/science.abk2820
  4. PLoS One. 2022 ;17(7): e0270043
    Single-cell specific and interpretable machine learning models for sparse scChIP-seq data imputation.
    Steffen Albrecht, Tommaso Andreani, Miguel A Andrade-Navarro, Jean Fred Fontaine.
      MOTIVATION: Single-cell Chromatin ImmunoPrecipitation DNA-Sequencing (scChIP-seq) analysis is challenging due to data sparsity. High degree of sparsity in biological high-throughput single-cell data is generally handled with imputation methods that complete the data, but specific methods for scChIP-seq are lacking. We present SIMPA, a scChIP-seq data imputation method leveraging predictive information within bulk data from the ENCODE project to impute missing protein-DNA interacting regions of target histone marks or transcription factors.RESULTS: Imputations using machine learning models trained for each single cell, each ChIP protein target, and each genomic region accurately preserve cell type clustering and improve pathway-related gene identification on real human data. Results on bulk data simulating single cells show that the imputations are single-cell specific as the imputed profiles are closer to the simulated cell than to other cells related to the same ChIP protein target and the same cell type. Simulations also show that 100 input genomic regions are already enough to train single-cell specific models for the imputation of thousands of undetected regions. Furthermore, SIMPA enables the interpretation of machine learning models by revealing interaction sites of a given single cell that are most important for the imputation model trained for a specific genomic region. The corresponding feature importance values derived from promoter-interaction profiles of H3K4me3, an activating histone mark, highly correlate with co-expression of genes that are present within the cell-type specific pathways in 2 real human and mouse datasets. The SIMPA's interpretable imputation method allows users to gain a deep understanding of individual cells and, consequently, of sparse scChIP-seq datasets.
    AVAILABILITY AND IMPLEMENTATION: Our interpretable imputation algorithm was implemented in Python and is available at https://github.com/salbrec/SIMPA.
    DOI:  https://doi.org/10.1371/journal.pone.0270043
  5. Proc Natl Acad Sci U S A. 2022 Jul 05. 119(27): e2001290119
    Topoisomerase VI participates in an insulator-like function that prevents H3K9me2 spreading.
    Louis-Valentin Méteignier, Cécile Lecampion, Florent Velay, Cécile Vriet, Laura Dimnet, Martin Rougée, Christian Breuer, Ludivine Soubigou-Taconnat, Keiko Sugimoto, Fredy Barneche, Christophe Laloi.
      The organization of the genome into transcriptionally active and inactive chromatin domains requires well-delineated chromatin boundaries and insulator functions in order to maintain the identity of adjacent genomic loci with antagonistic chromatin marks and functionality. In plants that lack known chromatin insulators, the mechanisms that prevent heterochromatin spreading into euchromatin remain to be identified. Here, we show that DNA Topoisomerase VI participates in a chromatin boundary function that safeguards the expression of genes in euchromatin islands within silenced heterochromatin regions. While some transposable elements are reactivated in mutants of the Topoisomerase VI complex, genes insulated in euchromatin islands within heterochromatic regions of the Arabidopsis thaliana genome are specifically down-regulated. H3K9me2 levels consistently increase at euchromatin island loci and decrease at some transposable element loci. We further show that Topoisomerase VI physically interacts with S-adenosylmethionine synthase methionine adenosyl transferase 3 (MAT3), which is required for H3K9me2. A Topoisomerase VI defect affects MAT3 occupancy on heterochromatic elements and its exclusion from euchromatic islands, thereby providing a possible mechanistic explanation to the essential role of Topoisomerase VI in the delimitation of chromatin domains.
    Keywords:  euchromatin islands; heterochromatin spreading; insulator; methionine adenosyltransferase; topoisomerase VI
    DOI:  https://doi.org/10.1073/pnas.2001290119
  6. Nucleic Acids Res. 2022 Jun 28. pii: gkac550. [Epub ahead of print]
    OCT4 activates a Suv39h1-repressive antisense lncRNA to couple histone H3 Lysine 9 methylation to pluripotency.
    Laure D Bernard, Agnès Dubois, Victor Heurtier, Véronique Fischer, Inma Gonzalez, Almira Chervova, Alexandra Tachtsidi, Noa Gil, Nick Owens, Lawrence E Bates, Sandrine Vandormael-Pournin, José C R Silva, Igor Ulitsky, Michel Cohen-Tannoudji, Pablo Navarro.
      Histone H3 Lysine 9 (H3K9) methylation, a characteristic mark of heterochromatin, is progressively implemented during development to contribute to cell fate restriction as differentiation proceeds. Accordingly, in undifferentiated and pluripotent mouse Embryonic Stem (ES) cells the global levels of H3K9 methylation are rather low and increase only upon differentiation. How global H3K9 methylation levels are coupled with the loss of pluripotency remains largely unknown. Here, we identify SUV39H1, a major H3K9 di- and tri-methylase, as an indirect target of the pluripotency network of Transcription Factors (TFs). We find that pluripotency TFs, principally OCT4, activate the expression of Suv39h1as, an antisense long non-coding RNA to Suv39h1. In turn, Suv39h1as downregulates Suv39h1 transcription in cis via a mechanism involving the modulation of the chromatin status of the locus. The targeted deletion of the Suv39h1as promoter region triggers increased SUV39H1 expression and H3K9me2 and H3K9me3 levels, affecting all heterochromatic regions, particularly peri-centromeric major satellites and retrotransposons. This increase in heterochromatinization efficiency leads to accelerated and more efficient commitment into differentiation. We report, therefore, a simple genetic circuitry coupling the genetic control of pluripotency with the global efficiency of H3K9 methylation associated with a major cell fate restriction, the irreversible loss of pluripotency.
    DOI:  https://doi.org/10.1093/nar/gkac550
  7. Mol Cell. 2022 Jun 22. pii: S1097-2765(22)00537-8. [Epub ahead of print]
    Machine-learning-optimized Cas12a barcoding enables the recovery of single-cell lineages and transcriptional profiles.
    Nicholas W Hughes, Yuanhao Qu, Jiaqi Zhang, Weijing Tang, Justin Pierce, Chengkun Wang, Aditi Agrawal, Maurizio Morri, Norma Neff, Monte M Winslow, Mengdi Wang, Le Cong.
      The development of CRISPR-based barcoding methods creates an exciting opportunity to understand cellular phylogenies. We present a compact, tunable, high-capacity Cas12a barcoding system called dual acting inverted site array (DAISY). We combined high-throughput screening and machine learning to predict and optimize the 60-bp DAISY barcode sequences. After optimization, top-performing barcodes had ∼10-fold increased capacity relative to the best random-screened designs and performed reliably across diverse cell types. DAISY barcode arrays generated ∼12 bits of entropy and ∼66,000 unique barcodes. Thus, DAISY barcodes-at a fraction of the size of Cas9 barcodes-achieved high-capacity barcoding. We coupled DAISY barcoding with single-cell RNA-seq to recover lineages and gene expression profiles from ∼47,000 human melanoma cells. A single DAISY barcode recovered up to ∼700 lineages from one parental cell. This analysis revealed heritable single-cell gene expression and potential epigenetic modulation of memory gene transcription. Overall, Cas12a DAISY barcoding is an efficient tool for investigating cell-state dynamics.
    Keywords:  CRISPR barcoding; Cas12a; PRC2; high throughput screening; lineage tracking; machine learning; melanoma; online learning optimization; single cell genomics; transcriptional memory
    DOI:  https://doi.org/10.1016/j.molcel.2022.06.001
  8. iScience. 2022 Jul 15. 25(7): 104519
    Histone H2A ubiquitination resulting from Brap loss of function connects multiple aging hallmarks and accelerates neurodegeneration.
    Yan Guo, Alison A Chomiak, Ye Hong, Clara C Lowe, Caroline A Kopsidas, Wen-Ching Chan, Jorge Andrade, Hongna Pan, Xiaoming Zhou, Edwin S Monuki, Yuanyi Feng.
      Aging is an intricate process characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. Whereas each of these traits is detrimental at the cellular level, it remains unclear how they are interconnected to cause systemic organ deterioration. Here we show that abrogating Brap, a BRCA1-associated protein essential for neurogenesis, results in persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). These defects extend to cellular senescence and proteasome-mediated histone H2A proteolysis with alterations in cells' proteomic and epigenetic states. Brap deletion in the mouse brain causes neuroinflammation, impaired proteostasis, accelerated neurodegeneration, and substantially shortened the lifespan. We further show the elevation of H2Aub also occurs in human brain tissues with Alzheimer's disease. These data together suggest that chromatin aberrations mediated by H2Aub may act as a nexus of multiple aging hallmarks and promote tissue-wide degeneration.
    Keywords:  Biological sciences; Cell biology; Cellular neuroscience; Functional aspects of cell biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.104519
  9. Elife. 2022 Jul 01. pii: e78458. [Epub ahead of print]11
    Genetic dissection of the RNA polymerase II transcription cycle.
    Shao-Pei Chou, Adriana K Alexander, Edward J Rice, Lauren A Choate, Charles G Danko.
      How DNA sequence affects the dynamics and position of RNA Polymerase II (Pol II) during transcription remains poorly understood. Here we used naturally occurring genetic variation in F1 hybrid mice to explore how DNA sequence differences affect the genome-wide distribution of Pol II. We measured the position and orientation of Pol II in eight organs collected from heterozygous F1 hybrid mice using ChRO-seq. Our data revealed a strong genetic basis for the precise coordinates of transcription initiation and promoter proximal pause, allowing us to redefine molecular models of core transcriptional processes. Our results implicate DNA sequence, including both known and novel DNA sequence motifs, as key determinants of the position of Pol II initiation and pause. We report evidence that initiation site selection follows a stochastic process similar to Brownian motion along the DNA template. We found widespread differences in the position of transcription termination, which impact the primary structure and stability of mature mRNA. Finally, we report evidence that allelic changes in transcription often affect mRNA and ncRNA expression across broad genomic domains. Collectively, we reveal how DNA sequences shape core transcriptional processes at single nucleotide resolution in mammals.
    Keywords:  chromosomes; gene expression; mouse
    DOI:  https://doi.org/10.7554/eLife.78458
  10. Nucleic Acids Res. 2022 Jul 01. pii: gkac531. [Epub ahead of print]
    SETDB1 acts as a topological accessory to Cohesin via an H3K9me3-independent, genomic shunt for regulating cell fates.
    Tushar Warrier, Chadi El Farran, Yingying Zeng, Benedict Shao Quan Ho, Qiuye Bao, Zi Hao Zheng, Xuezhi Bi, Huck Hui Ng, Derrick Sek Tong Ong, Justin Jang Hann Chu, Amartya Sanyal, Melissa Jane Fullwood, James J Collins, Hu Li, Jian Xu, Yuin-Han Loh.
      SETDB1 is a key regulator of lineage-specific genes and endogenous retroviral elements (ERVs) through its deposition of repressive H3K9me3 mark. Apart from its H3K9me3 regulatory role, SETDB1 has seldom been studied in terms of its other potential regulatory roles. To investigate this, a genomic survey of SETDB1 binding in mouse embryonic stem cells across multiple libraries was conducted, leading to the unexpected discovery of regions bereft of common repressive histone marks (H3K9me3, H3K27me3). These regions were enriched with the CTCF motif that is often associated with the topological regulator Cohesin. Further profiling of these non-H3K9me3 regions led to the discovery of a cluster of non-repeat loci that were co-bound by SETDB1 and Cohesin. These regions, which we named DiSCs (domains involving SETDB1 and Cohesin) were seen to be proximal to the gene promoters involved in embryonic stem cell pluripotency and lineage development. Importantly, it was found that SETDB1-Cohesin co-regulate target gene expression and genome topology at these DiSCs. Depletion of SETDB1 led to localized dysregulation of Cohesin binding thereby locally disrupting topological structures. Dysregulated gene expression trends revealed the importance of this cluster in ES cell maintenance as well as at gene 'islands' that drive differentiation to other lineages. The 'unearthing' of the DiSCs thus unravels a unique topological and transcriptional axis of control regulated chiefly by SETDB1.
    DOI:  https://doi.org/10.1093/nar/gkac531
  11. Nat Commun. 2022 Jun 28. 13(1): 3722
    Senescent cells limit p53 activity via multiple mechanisms to remain viable.
    Ines Sturmlechner, Chance C Sine, Karthik B Jeganathan, Cheng Zhang, Raul O Fierro Velasco, Darren J Baker, Hu Li, Jan M van Deursen.
      Super-enhancers regulate genes with important functions in processes that are cell type-specific or define cell identity. Mouse embryonic fibroblasts establish 40 senescence-associated super-enhancers regardless of how they become senescent, with 50 activated genes located in the vicinity of these enhancers. Here we show, through gene knockdown and analysis of three core biological properties of senescent cells that a relatively large number of senescence-associated super-enhancer-regulated genes promote survival of senescent mouse embryonic fibroblasts. Of these, Mdm2, Rnase4, and Ang act by suppressing p53-mediated apoptosis through various mechanisms that are also engaged in response to DNA damage. MDM2 and RNASE4 transcription is also elevated in human senescent fibroblasts to restrain p53 and promote survival. These insights identify key survival mechanisms of senescent cells and provide molecular entry points for the development of targeted therapeutics that eliminate senescent cells at sites of pathology.
    DOI:  https://doi.org/10.1038/s41467-022-31239-x
  12. iScience. 2022 Jul 15. 25(7): 104563
    Structural basis for binding diversity of acetyltransferase p300 to the nucleosome.
    Suguru Hatazawa, Jiuyang Liu, Yoshimasa Takizawa, Mohamad Zandian, Lumi Negishi, Tatiana G Kutateladze, Hitoshi Kurumizaka.
      p300 is a human acetyltransferase that associates with chromatin and mediates vital cellular processes. We now report the cryo-electron microscopy structures of the p300 catalytic core in complex with the nucleosome core particle (NCP). In the most resolved structure, the HAT domain and bromodomain of p300 contact nucleosomal DNA at superhelical locations 2 and 3, and the catalytic site of the HAT domain are positioned near the N-terminal tail of histone H4. Mutations of the p300-DNA interfacial residues of p300 substantially decrease binding to NCP. Three additional classes of p300-NCP complexes show different modes of the p300-NCP complex formation. Our data provide structural details critical to our understanding of the mechanism by which p300 acetylates multiple sites on the nucleosome.
    Keywords:  Biochemistry; Biological sciences; Structural biology
    DOI:  https://doi.org/10.1016/j.isci.2022.104563
  13. Nat Commun. 2022 Jul 01. 13(1): 3808
    Transcription factor paralogs orchestrate alternative gene regulatory networks by context-dependent cooperation with multiple cofactors.
    Siqian Feng, Chaitanya Rastogi, Ryan Loker, William J Glassford, H Tomas Rube, Harmen J Bussemaker, Richard S Mann.
      In eukaryotes, members of transcription factor families often exhibit similar DNA binding properties in vitro, yet orchestrate paralog-specific gene regulatory networks in vivo. The serially homologous first (T1) and third (T3) thoracic legs of Drosophila, which are specified by the Hox proteins Scr and Ubx, respectively, offer a unique opportunity to address this paradox in vivo. Genome-wide analyses using epitope-tagged alleles of both Hox loci in the T1 and T3 leg imaginal discs, the precursors to the adult legs and ventral body regions, show that ~8% of Hox binding is paralog-specific. Binding specificity is mediated by interactions with distinct cofactors in different domains: the Hox cofactor Exd acts in the proximal domain and is necessary for Scr to bind many of its paralog-specific targets, while in the distal leg domain, the homeodomain protein Distal-less (Dll) enhances Scr binding to a different subset of loci. These findings reveal how Hox paralogs, and perhaps paralogs of other transcription factor families, orchestrate alternative downstream gene regulatory networks with the help of multiple, context-specific cofactors.
    DOI:  https://doi.org/10.1038/s41467-022-31501-2
  14. Genome Biol. 2022 Jun 27. 23(1): 139
    scDART: integrating unmatched scRNA-seq and scATAC-seq data and learning cross-modality relationship simultaneously.
    Ziqi Zhang, Chengkai Yang, Xiuwei Zhang.
      It is a challenging task to integrate scRNA-seq and scATAC-seq data obtained from different batches. Existing methods tend to use a pre-defined gene activity matrix to convert the scATAC-seq data into scRNA-seq data. The pre-defined gene activity matrix is often of low quality and does not reflect the dataset-specific relationship between the two data modalities. We propose scDART, a deep learning framework that integrates scRNA-seq and scATAC-seq data and learns cross-modalities relationships simultaneously. Specifically, the design of scDART allows it to preserve cell trajectories in continuous cell populations and can be applied to trajectory inference on integrated data.
    Keywords:  Integrative analysis; Single-cell multiomics; Trajectory inference; scATAC-seq; scRNA-seq
    DOI:  https://doi.org/10.1186/s13059-022-02706-x
  15. Bioinformatics. 2022 06 24. 38(Suppl 1): i307-i315
    MeConcord: a new metric to quantitatively characterize DNA methylation heterogeneity across reads and CpG sites.
    Xianglin Zhang, Xiaowo Wang.
      MOTIVATION: Intermediately methylated regions occupy a significant fraction of the human genome and are closely associated with epigenetic regulations or cell-type deconvolution of bulk data. However, these regions show distinct methylation patterns, corresponding to different biological mechanisms. Although there have been some metrics developed for investigating these regions, the high noise sensitivity limits the utility for distinguishing distinct methylation patterns.RESULTS: We proposed a method named MeConcord to measure local methylation concordance across reads and CpG sites, respectively. MeConcord showed the most stable performance in distinguishing distinct methylation patterns ('identical', 'uniform' and 'disordered') compared with other metrics. Applying MeConcord to the whole genome data across 25 cell lines or primary cells or tissues, we found that distinct methylation patterns were associated with different genomic characteristics, such as CTCF binding or imprinted genes. Further, we showed the differences of CpG island hypermethylation patterns between senescence and tumorigenesis by using MeConcord. MeConcord is a powerful method to study local read-level methylation patterns for both the whole genome and specific regions of interest.
    AVAILABILITY AND IMPLEMENTATION: MeConcord is available at https://github.com/WangLabTHU/MeConcord.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btac248
  16. Nat Commun. 2022 Jun 29. 13(1): 3732
    Inactivation of the Hippo tumor suppressor pathway promotes melanoma.
    Marc A Vittoria, Nathan Kingston, Kristyna Kotynkova, Eric Xia, Rui Hong, Lee Huang, Shayna McDonald, Andrew Tilston-Lunel, Revati Darp, Joshua D Campbell, Deborah Lang, Xiaowei Xu, Craig J Ceol, Xaralabos Varelas, Neil J Ganem.
      Melanoma is commonly driven by activating mutations in the MAP kinase BRAF; however, oncogenic BRAF alone is insufficient to promote melanomagenesis. Instead, its expression induces a transient proliferative burst that ultimately ceases with the development of benign nevi comprised of growth-arrested melanocytes. The tumor suppressive mechanisms that restrain nevus melanocyte proliferation remain poorly understood. Here we utilize cell and murine models to demonstrate that oncogenic BRAF leads to activation of the Hippo tumor suppressor pathway, both in melanocytes in vitro and nevus melanocytes in vivo. Mechanistically, we show that oncogenic BRAF promotes both ERK-dependent alterations in the actin cytoskeleton and whole-genome doubling events, which independently reduce RhoA activity to promote Hippo activation. We also demonstrate that functional impairment of the Hippo pathway enables oncogenic BRAF-expressing melanocytes to bypass nevus formation and rapidly form melanomas. Our data reveal that the Hippo pathway enforces the stable arrest of nevus melanocytes and represents a critical barrier to melanoma development.
    DOI:  https://doi.org/10.1038/s41467-022-31399-w
  17. Oncogene. 2022 Jun 27.
    Hepatocellular carcinoma evades RB1-induced senescence by activating the FOXM1-FOXO1 axis.
    Vaibhav Chand, Xiubei Liao, Grace Guzman, Elizaveta Benevolenskaya, Pradip Raychaudhuri.
      Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The retinoblastoma protein (RB1), a regulator of cell proliferation, is functionally inactivated in HCC by CYCLIN D/E-mediated phosphorylation. However, the mechanism of RB1-inactivation is unclear because only small percentages of HCCs exhibit amplification of CYCLIN D/E or mutations in the CDK-inhibitory genes. We show that FOXM1, which is overexpressed and critical for HCC, plays essential roles in inactivating RB1 and suppressing RB1-induced senescence of the HCC cells. Mechanistically, FOXM1 binds RB1 and DNMT3B to repress the expression of FOXO1, leading to a decrease in the levels of the CDK-inhibitors, creating an environment for phosphorylation and inactivation of RB1. Consistent with that, inhibition of FOXM1 causes increased expression of FOXO1 with consequent activation of RB1, leading to senescence of the HCC cells, in vitro and in vivo. Also, repression-deficient mutants of FOXM1 induce senescence that is blocked by depletion of RB1 or FOXO1. We provide evidence that human HCCs rely upon this FOXM1-FOXO1 axis for phosphorylation and inactivation of RB1. The observations demonstrate the existence of a new autoregulatory loop of RB1-inactivation in HCC involving a FOXM1-FOXO1 axis that is required for phosphorylation of RB1 and for aggressive progression of HCC.
    DOI:  https://doi.org/10.1038/s41388-022-02394-8
  18. Genome Biol. 2022 Jun 27. 23(1): 137
    Widespread redundancy in -omics profiles of cancer mutation states.
    Jake Crawford, Brock C Christensen, Maria Chikina, Casey S Greene.
      BACKGROUND: In studies of cellular function in cancer, researchers are increasingly able to choose from many -omics assays as functional readouts. Choosing the correct readout for a given study can be difficult, and which layer of cellular function is most suitable to capture the relevant signal remains unclear.RESULTS: We consider prediction of cancer mutation status (presence or absence) from functional -omics data as a representative problem that presents an opportunity to quantify and compare the ability of different -omics readouts to capture signals of dysregulation in cancer. From the TCGA Pan-Cancer Atlas that contains genetic alteration data, we focus on RNA sequencing, DNA methylation arrays, reverse phase protein arrays (RPPA), microRNA, and somatic mutational signatures as -omics readouts. Across a collection of genes recurrently mutated in cancer, RNA sequencing tends to be the most effective predictor of mutation state. We find that one or more other data types for many of the genes are approximately equally effective predictors. Performance is more variable between mutations than that between data types for the same mutation, and there is little difference between the top data types. We also find that combining data types into a single multi-omics model provides little or no improvement in predictive ability over the best individual data type.
    CONCLUSIONS: Based on our results, for the design of studies focused on the functional outcomes of cancer mutations, there are often multiple -omics types that can serve as effective readouts, although gene expression seems to be a reasonable default option.
    DOI:  https://doi.org/10.1186/s13059-022-02705-y
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