bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2023–05–28
twenty papers selected by
Connor Rogerson, University of Cambridge
  1. Multimodal single cell analysis infers widespread enhancer co-activity in a lymphoblastoid cell line.
  2. SeATAC: a tool for exploring the chromatin landscape and the role of pioneer factors.
  3. Histone modifications regulate pioneer transcription factor cooperativity.
  4. Mitotic bookmarking by SWI/SNF subunits.
  5. Heat shock factor 1 (HSF1) specifically potentiates c-MYC-mediated transcription independently of the canonical heat shock response.
  6. MAF functions as a pioneer transcription factor that initiates and sustains myelomagenesis.
  7. A generalizable framework to comprehensively predict epigenome, chromatin organization, and transcriptome.
  8. Mechanoepigenetic regulation of extracellular matrix homeostasis via Yap and Taz.
  9. Dictionary learning for integrative, multimodal and scalable single-cell analysis.
  10. Intrinsic mesoscale properties of a Polycomb protein underpin heterochromatin fidelity.
  11. Resolution of structural variation in diverse mouse genomes reveals chromatin remodeling due to transposable elements.
  12. Simultaneous profiling of spatial gene expression and chromatin accessibility during mouse brain development.
  13. Variation in histone configurations correlates with gene expression across nine inbred strains of mice.
  14. Unsupervised contrastive peak caller for ATAC-seq.
  15. Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss.
  16. Chemical-induced epigenome resetting for regeneration program activation in human cells.
  17. The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis.
  18. RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia.
  19. FOXK1 promotes nonalcoholic fatty liver disease by mediating mTORC1-dependent inhibition of hepatic fatty acid oxidation.
  20. Base editing-mediated one-step inactivation of the Dnmt gene family reveals critical roles of DNA methylation during mouse gastrulation.
  1. Commun Biol. 2023 May 26. 6(1): 563
    Multimodal single cell analysis infers widespread enhancer co-activity in a lymphoblastoid cell line.
    Chaymae Ziyani, Olivier Delaneau, Diogo M Ribeiro.
      Non-coding regulatory elements such as enhancers are key in controlling the cell-type specificity and spatio-temporal expression of genes. To drive stable and precise gene transcription robust to genetic variation and environmental stress, genes are often targeted by multiple enhancers with redundant action. However, it is unknown whether enhancers targeting the same gene display simultaneous activity or whether some enhancer combinations are more often co-active than others. Here, we take advantage of recent developments in single cell technology that permit assessing chromatin status (scATAC-seq) and gene expression (scRNA-seq) in the same single cells to correlate gene expression to the activity of multiple enhancers. Measuring activity patterns across 24,844 human lymphoblastoid single cells, we find that the majority of enhancers associated with the same gene display significant correlation in their chromatin profiles. For 6944 expressed genes associated with enhancers, we predict 89,885 significant enhancer-enhancer associations between nearby enhancers. We find that associated enhancers share similar transcription factor binding profiles and that gene essentiality is linked with higher enhancer co-activity. We provide a set of predicted enhancer-enhancer associations based on correlation derived from a single cell line, which can be further investigated for functional relevance.
    DOI:  https://doi.org/10.1038/s42003-023-04954-4
  2. Genome Biol. 2023 05 22. 24(1): 125
    SeATAC: a tool for exploring the chromatin landscape and the role of pioneer factors.
    Wuming Gong, Nikita Dsouza, Daniel J Garry.
      Assay for Transposase-Accessible Chromatin with sequencing (ATAC-seq) reveals chromatin accessibility across the genome. Currently, no method specifically detects differential chromatin accessibility. Here, SeATAC uses a conditional variational autoencoder model to learn the latent representation of ATAC-seq V-plots and outperforms MACS2 and NucleoATAC on six separate tasks. Applying SeATAC to several pioneer factor-induced differentiation or reprogramming ATAC-seq datasets suggests that induction of these factors not only relaxes the closed chromatin but also decreases chromatin accessibility of 20% to 30% of their target sites. SeATAC is a novel tool to accurately reveal genomic regions with differential chromatin accessibility from ATAC-seq data.
    Keywords:  Ascl1; Etv2; Klf4; Nucleosomal DNA; Oct4; Pioneer factors; Sox2
    DOI:  https://doi.org/10.1186/s13059-023-02954-5
  3. Nature. 2023 May 24.
    Histone modifications regulate pioneer transcription factor cooperativity.
    Kalyan K Sinha, Silvija Bilokapic, Yongming Du, Deepshikha Malik, Mario Halic.
      Pioneer transcription factors have the ability to access DNA in compacted chromatin1. Multiple transcription factors can bind together to a regulatory element in a cooperative way, and cooperation between the pioneer transcription factors OCT4 (also known as POU5F1) and SOX2 is important for pluripotency and reprogramming2-4. However, the molecular mechanisms by which pioneer transcription factors function and cooperate on chromatin remain unclear. Here we present cryo-electron microscopy structures of human OCT4 bound to a nucleosome containing human LIN28B or nMATN1 DNA sequences, both of which bear multiple binding sites for OCT4. Our structural and biochemistry data reveal that binding of OCT4 induces changes to the nucleosome structure, repositions the nucleosomal DNA and facilitates cooperative binding of additional OCT4 and of SOX2 to their internal binding sites. The flexible activation domain of OCT4 contacts the N-terminal tail of histone H4, altering its conformation and thus promoting chromatin decompaction. Moreover, the DNA-binding domain of OCT4 engages with the N-terminal tail of histone H3, and post-translational modifications at H3K27 modulate DNA positioning and affect transcription factor cooperativity. Thus, our findings suggest that the epigenetic landscape could regulate OCT4 activity to ensure proper cell programming.
    DOI:  https://doi.org/10.1038/s41586-023-06112-6
  4. Nature. 2023 May 24.
    Mitotic bookmarking by SWI/SNF subunits.
    Zhexin Zhu, Xiaolong Chen, Ao Guo, Trishabelle Manzano, Patrick J Walsh, Kendall M Wills, Rebecca Halliburton, Sandi Radko-Juettner, Raymond D Carter, Janet F Partridge, Douglas R Green, Jinghui Zhang, Charles W M Roberts.
      For cells to initiate and sustain a differentiated state, it is necessary that a 'memory' of this state is transmitted through mitosis to the daughter cells1-3. Mammalian switch/sucrose non-fermentable (SWI/SNF) complexes (also known as Brg1/Brg-associated factors, or BAF) control cell identity by modulating chromatin architecture to regulate gene expression4-7, but whether they participate in cell fate memory is unclear. Here we provide evidence that subunits of SWI/SNF act as mitotic bookmarks to safeguard cell identity during cell division. The SWI/SNF core subunits SMARCE1 and SMARCB1 are displaced from enhancers but are bound to promoters during mitosis, and we show that this binding is required for appropriate reactivation of bound genes after mitotic exit. Ablation of SMARCE1 during a single mitosis in mouse embryonic stem cells is sufficient to disrupt gene expression, impair the occupancy of several established bookmarks at a subset of their targets and cause aberrant neural differentiation. Thus, SWI/SNF subunit SMARCE1 has a mitotic bookmarking role and is essential for heritable epigenetic fidelity during transcriptional reprogramming.
    DOI:  https://doi.org/10.1038/s41586-023-06085-6
  5. Cell Rep. 2023 May 23. pii: S2211-1247(23)00568-5. [Epub ahead of print]42(6): 112557
    Heat shock factor 1 (HSF1) specifically potentiates c-MYC-mediated transcription independently of the canonical heat shock response.
    Meng Xu, Ling Lin, Babul Moni Ram, Omprakash Shriwas, Kun-Han Chuang, Siyuan Dai, Kuo-Hui Su, Zijian Tang, Chengkai Dai.
      Despite its pivotal roles in biology, how the transcriptional activity of c-MYC is tuned quantitatively remains poorly defined. Here, we show that heat shock factor 1 (HSF1), the master transcriptional regulator of the heat shock response, acts as a prime modifier of the c-MYC-mediated transcription. HSF1 deficiency diminishes c-MYC DNA binding and dampens its transcriptional activity genome wide. Mechanistically, c-MYC, MAX, and HSF1 assemble into a transcription factor complex on genomic DNAs, and surprisingly, the DNA binding of HSF1 is dispensable. Instead, HSF1 physically recruits the histone acetyltransferase general control nonderepressible 5 (GCN5), promoting histone acetylation and augmenting c-MYC transcriptional activity. Thus, we find that HSF1 specifically potentiates the c-MYC-mediated transcription, discrete from its canonical role in countering proteotoxic stress. Importantly, this mechanism of action engenders two distinct c-MYC activation states, primary and advanced, which may be important to accommodate diverse physiological and pathological conditions.
    Keywords:  CP: Molecular biology; CUT&RUN-seq; GCN5; HSF1; c-MYC; transcription factor complex
    DOI:  https://doi.org/10.1016/j.celrep.2023.112557
  6. Blood Adv. 2023 May 24. pii: bloodadvances.2023009772. [Epub ahead of print]
    MAF functions as a pioneer transcription factor that initiates and sustains myelomagenesis.
    Alexia Katsarou, Nikolaos Trasanidis, Kanagaraju Ponnusamy, Ioannis V Kostopoulos, Jaime Alvarez-Benayas, Foteini Papaleonidopoulou, Keren Keren, Pierangela Mr Sabbattini, Niklas Feldhahn, Maria Papaioannou, Evdoxia Hatjiharissi, Ian M Sudbery, Aristeidis Chaidos, Valentina S Caputo, Anastasios Karadimitris.
      Deregulated expression of lineage-affiliated transcription factors is a major mechanism of oncogenesis. However, how deregulation of non-lineage affiliated TF impacts chromatin to initiate oncogenic transcriptional programmes is not well known. To address this, we studied the chromatin effects imposed by oncogenic MAF as the cancer-initiating driver in the plasma cell cancer multiple myeloma. We found that the ectopically expressed MAF endows myeloma plasma cells with migratory and proliferative transcriptional potential. This potential is regulated by activation of enhancers and super-enhancers, previously inactive in normal B cells and plasma cells, and in co-operation of MAF with the plasma cell-defining TF IRF4. Forced ectopic MAF expression confirms the de novo ability of oncogenic MAF to convert transcriptionally inert chromatin to active chromatin with features of super-enhancers, leading to activation of the MAF-specific oncogenic transcriptome and acquisition of cancer-related cellular phenotypes such as CCR1-dependent cell migration. These findings establish oncogenic MAF as a pioneer transcription factor that can initiate as well as sustain oncogenic transcriptomes and cancer phenotypes. However, despite its pioneer function, myeloma cells remain MAF-dependent thus validating oncogenic MAF as a therapeutic target that would be able to circumvent the challenges of subsequent genetic diversification driving disease relapse and drug resistance.
    DOI:  https://doi.org/10.1182/bloodadvances.2023009772
  7. Nucleic Acids Res. 2023 May 24. pii: gkad436. [Epub ahead of print]
    A generalizable framework to comprehensively predict epigenome, chromatin organization, and transcriptome.
    Zhenhao Zhang, Fan Feng, Yiyang Qiu, Jie Liu.
      Many deep learning approaches have been proposed to predict epigenetic profiles, chromatin organization, and transcription activity. While these approaches achieve satisfactory performance in predicting one modality from another, the learned representations are not generalizable across predictive tasks or across cell types. In this paper, we propose a deep learning approach named EPCOT which employs a pre-training and fine-tuning framework, and is able to accurately and comprehensively predict multiple modalities including epigenome, chromatin organization, transcriptome, and enhancer activity for new cell types, by only requiring cell-type specific chromatin accessibility profiles. Many of these predicted modalities, such as Micro-C and ChIA-PET, are quite expensive to get in practice, and the in silico prediction from EPCOT should be quite helpful. Furthermore, this pre-training and fine-tuning framework allows EPCOT to identify generic representations generalizable across different predictive tasks. Interpreting EPCOT models also provides biological insights including mapping between different genomic modalities, identifying TF sequence binding patterns, and analyzing cell-type specific TF impacts on enhancer activity.
    DOI:  https://doi.org/10.1093/nar/gkad436
  8. Proc Natl Acad Sci U S A. 2023 05 30. 120(22): e2211947120
    Mechanoepigenetic regulation of extracellular matrix homeostasis via Yap and Taz.
    Dakota L Jones, Grey F Hallström, Xi Jiang, Ryan C Locke, Mary Kate Evans, Edward D Bonnevie, Anjana Srikumar, Thomas P Leahy, Madhura P Nijsure, Joel D Boerckel, Robert L Mauck, Nathaniel A Dyment.
      Cells integrate mechanical cues to direct fate specification to maintain tissue function and homeostasis. While disruption of these cues is known to lead to aberrant cell behavior and chronic diseases, such as tendinopathies, the underlying mechanisms by which mechanical signals maintain cell function are not well understood. Here, we show using a model of tendon de-tensioning that loss of tensile cues in vivo acutely changes nuclear morphology, positioning, and expression of catabolic gene programs, resulting in subsequent weakening of the tendon. In vitro studies using paired ATAC/RNAseq demonstrate that the loss of cellular tension rapidly reduces chromatin accessibility in the vicinity of Yap/Taz genomic targets while also increasing expression of genes involved in matrix catabolism. Concordantly, the depletion of Yap/Taz elevates matrix catabolic expression. Conversely, overexpression of Yap results in a reduction of chromatin accessibility at matrix catabolic gene loci, while also reducing transcriptional levels. The overexpression of Yap not only prevents the induction of this broad catabolic program following a loss of cellular tension, but also preserves the underlying chromatin state from force-induced alterations. Taken together, these results provide novel mechanistic details by which mechanoepigenetic signals regulate tendon cell function through a Yap/Taz axis.
    Keywords:  chromatin; epigenetics; mechanobiology
    DOI:  https://doi.org/10.1073/pnas.2211947120
  9. Nat Biotechnol. 2023 May 25.
    Dictionary learning for integrative, multimodal and scalable single-cell analysis.
    Yuhan Hao, Tim Stuart, Madeline H Kowalski, Saket Choudhary, Paul Hoffman, Austin Hartman, Avi Srivastava, Gesmira Molla, Shaista Madad, Carlos Fernandez-Granda, Rahul Satija.
      Mapping single-cell sequencing profiles to comprehensive reference datasets provides a powerful alternative to unsupervised analysis. However, most reference datasets are constructed from single-cell RNA-sequencing data and cannot be used to annotate datasets that do not measure gene expression. Here we introduce 'bridge integration', a method to integrate single-cell datasets across modalities using a multiomic dataset as a molecular bridge. Each cell in the multiomic dataset constitutes an element in a 'dictionary', which is used to reconstruct unimodal datasets and transform them into a shared space. Our procedure accurately integrates transcriptomic data with independent single-cell measurements of chromatin accessibility, histone modifications, DNA methylation and protein levels. Moreover, we demonstrate how dictionary learning can be combined with sketching techniques to improve computational scalability and harmonize 8.6 million human immune cell profiles from sequencing and mass cytometry experiments. Our approach, implemented in version 5 of our Seurat toolkit ( http://www.satijalab.org/seurat ), broadens the utility of single-cell reference datasets and facilitates comparisons across diverse molecular modalities.
    DOI:  https://doi.org/10.1038/s41587-023-01767-y
  10. Nat Struct Mol Biol. 2023 May 22.
    Intrinsic mesoscale properties of a Polycomb protein underpin heterochromatin fidelity.
    Sujin Lee, Stephen Abini-Agbomson, Daniela S Perry, Allen Goodman, Beiduo Rao, Manning Y Huang, Jolene K Diedrich, James J Moresco, John R Yates, Karim-Jean Armache, Hiten D Madhani.
      Little is understood about how the two major types of heterochromatin domains (HP1 and Polycomb) are kept separate. In the yeast Cryptococcus neoformans, the Polycomb-like protein Ccc1 prevents deposition of H3K27me3 at HP1 domains. Here we show that phase separation propensity underpins Ccc1 function. Mutations of the two basic clusters in the intrinsically disordered region or deletion of the coiled-coil dimerization domain alter phase separation behavior of Ccc1 in vitro and have commensurate effects on formation of Ccc1 condensates in vivo, which are enriched for PRC2. Notably, mutations that alter phase separation trigger ectopic H3K27me3 at HP1 domains. Supporting a direct condensate-driven mechanism for fidelity, Ccc1 droplets efficiently concentrate recombinant C. neoformans PRC2 in vitro whereas HP1 droplets do so only weakly. These studies establish a biochemical basis for chromatin regulation in which mesoscale biophysical properties play a key functional role.
    DOI:  https://doi.org/10.1038/s41594-023-01000-z
  11. Cell Genom. 2023 May 10. 3(5): 100291
    Resolution of structural variation in diverse mouse genomes reveals chromatin remodeling due to transposable elements.
    Ardian Ferraj, Peter A Audano, Parithi Balachandran, Anne Czechanski, Jacob I Flores, Alexander A Radecki, Varun Mosur, David S Gordon, Isha A Walawalkar, Evan E Eichler, Laura G Reinholdt, Christine R Beck.
      Diverse inbred mouse strains are important biomedical research models, yet genome characterization of many strains is fundamentally lacking in comparison with humans. In particular, catalogs of structural variants (SVs) (variants ≥ 50 bp) are incomplete, limiting the discovery of causative alleles for phenotypic variation. Here, we resolve genome-wide SVs in 20 genetically distinct inbred mice with long-read sequencing. We report 413,758 site-specific SVs affecting 13% (356 Mbp) of the mouse reference assembly, including 510 previously unannotated coding variants. We substantially improve the Mus musculus transposable element (TE) callset, and we find that TEs comprise 39% of SVs and account for 75% of altered bases. We further utilize this callset to investigate how TE heterogeneity affects mouse embryonic stem cells and find multiple TE classes that influence chromatin accessibility. Our work provides a comprehensive analysis of SVs found in diverse mouse genomes and illustrates the role of TEs in epigenetic differences.
    Keywords:  chromatin accessibility; collaborative cross; effects of structural variation; embryonic stem cells; inbred micetransposable elements; long read sequencing; mouse genomics; structural variation; whole genome assembly
    DOI:  https://doi.org/10.1016/j.xgen.2023.100291
  12. Nat Methods. 2023 May 25.
    Simultaneous profiling of spatial gene expression and chromatin accessibility during mouse brain development.
    Fuqing Jiang, Xin Zhou, Yingying Qian, Miao Zhu, Li Wang, Zhuxia Li, Qingmei Shen, Minhan Wang, Fangfang Qu, Guizhong Cui, Kai Chen, Guangdun Peng.
      The brain is a complex tissue whose function relies on coordinated anatomical and molecular features. However, the molecular annotation of the spatial organization of the brain is currently insufficient. Here, we describe microfluidic indexing-based spatial assay for transposase-accessible chromatin and RNA-sequencing (MISAR-seq), a method for spatially resolved joint profiling of chromatin accessibility and gene expression. By applying MISAR-seq to the developing mouse brain, we study tissue organization and spatiotemporal regulatory logics during mouse brain development.
    DOI:  https://doi.org/10.1038/s41592-023-01884-1
  13. Genome Res. 2023 May 22. pii: gr.277467.122. [Epub ahead of print]
    Variation in histone configurations correlates with gene expression across nine inbred strains of mice.
    Anna L Tyler, Catrina Spruce, Romy Kursawe, Annat Haber, Robyn L Ball, Wendy A Pitman, Alexander D Fine, Narayanan Raghupathy, Michael Walker, Vivek M Philip, Christopher L Baker, J Matthew Mahoney, Gary A Churchill, Jennifer J Trowbridge, Michael L Stitzel, Kenneth Paigen, Petko M Petkov, Gregory W Carter.
      The diversity outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression, and as such are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), and DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represented a distinct combination of the four histone modifications. We found that the epigenetic landscape was highly variable across the DO founders and was associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice.
    DOI:  https://doi.org/10.1101/gr.277467.122
  14. Genome Res. 2023 May 22. pii: gr.277677.123. [Epub ahead of print]
    Unsupervised contrastive peak caller for ATAC-seq.
    Ha T H Vu, Yudi Zhang, Geetu Tuteja, Karin S Dorman.
      The assay for transposase-accessible chromatin with sequencing (ATAC-seq) is a common assay to identify chromatin accessible regions by using a Tn5 transposase that can access, cut, and ligate adapters to DNA fragments for subsequent amplification and sequencing. These sequenced regions are quantified and tested for enrichment in a process referred to as "peak calling". Most unsupervised peak calling methods are based on simple statistical models and suffer from elevated false positive rates. Newly developed supervised deep learning methods can be successful, but they rely on high quality labeled data for training, which can be difficult to obtain. Moreover, though biological replicates are recognized to be important, there are no established approaches for using replicates in the deep learning tools, and the approaches available for traditional methods either cannot be applied to ATAC-seq, where control samples may be unavailable, or are post-hoc and do not capitalize on potentially complex, but reproducible signal in the read enrichment data. Here, we propose a novel peak caller that uses unsupervised contrastive learning to extract shared signals from multiple replicates. Raw coverage data are encoded to obtain low-dimensional embeddings and optimized to minimize a contrastive loss over biological replicates. These embeddings are passed to another contrastive loss for learning and predicting peaks and decoded to denoised data under an autoencoder loss. We compared our Replicative Contrastive Learner (RCL) method with other existing methods on ATAC-seq data, using annotations from ChromHMM genome and transcription factor ChIP-seq as noisy truth. RCL consistently achieved the best performance.
    DOI:  https://doi.org/10.1101/gr.277677.123
  15. Nat Commun. 2023 May 20. 14(1): 2894
    Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss.
    Xianbing Zhu, Zheng Fu, Shary Y Chen, Dionzie Ong, Giulio Aceto, Rebecca Ho, Jutta Steinberger, Anie Monast, Virginie Pilon, Eunice Li, Monica Ta, Kyle Ching, Bianca N Adams, Gian L Negri, Luc Choiniere, Lili Fu, Kitty Pavlakis, Patrick Pirrotte, Daina Z Avizonis, Jeffrey Trent, Bernard E Weissman, Ramon I Klein Geltink, Gregg B Morin, Morag Park, David G Huntsman, William D Foulkes, Yemin Wang, Sidong Huang.
      SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers.
    DOI:  https://doi.org/10.1038/s41467-023-38594-3
  16. Cell Rep. 2023 May 23. pii: S2211-1247(23)00558-2. [Epub ahead of print]42(6): 112547
    Chemical-induced epigenome resetting for regeneration program activation in human cells.
    Guan Wang, Yanglu Wang, Yulin Lyu, Huanjing He, Shijia Liuyang, Jinlin Wang, Shicheng Sun, Lin Cheng, Yao Fu, Jialiang Zhu, Xinxing Zhong, Zhihan Yang, Qijing Chen, Cheng Li, Jingyang Guan, Hongkui Deng.
      Human somatic cells can be reprogrammed to pluripotent stem cells by small molecules through an intermediate stage with a regeneration signature, but how this regeneration state is induced remains largely unknown. Here, through integrated single-cell analysis of transcriptome, we demonstrate that the pathway of human chemical reprogramming with regeneration state is distinct from that of transcription-factor-mediated reprogramming. Time-course construction of chromatin landscapes unveils hierarchical histone modification remodeling underlying the regeneration program, which involved sequential enhancer recommissioning and mirrored the reversal process of regeneration potential lost in organisms as they mature. In addition, LEF1 is identified as a key upstream regulator for regeneration gene program activation. Furthermore, we reveal that regeneration program activation requires sequential enhancer silencing of somatic and proinflammatory programs. Altogether, chemical reprogramming resets the epigenome through reversal of the loss of natural regeneration, representing a distinct concept for cellular reprogramming and advancing the development of regenerative therapeutic strategies.
    Keywords:  CP: Stem cell research; activation of regeneration-like program; chemical reprogramming; enhancer recommissioning; epigenome remodeling; reboot regeneration potential
    DOI:  https://doi.org/10.1016/j.celrep.2023.112547
  17. Proc Natl Acad Sci U S A. 2023 05 30. 120(22): e2217425120
    The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis.
    Athena Jessica S Ong, Cerys E Bladen, Tara A Tigani, Anthony P Karamalakis, Kimberley J Evason, Kristin K Brown, Andrew G Cox.
      The maintenance of redox and metabolic homeostasis is integral to embryonic development. Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress-induced transcription factor that plays a central role in the regulation of redox balance and cellular metabolism. Under homeostatic conditions, NRF2 is repressed by Kelch-like ECH-associated protein 1 (KEAP1). Here, we demonstrate that Keap1 deficiency induces Nrf2 activation and postdevelopmental lethality. Loss of viability is preceded by severe liver abnormalities characterized by an accumulation of lysosomes. Mechanistically, we demonstrate that loss of Keap1 promotes aberrant activation of transcription factor EB (TFEB)/transcription factor binding to IGHM Enhancer 3 (TFE3)-dependent lysosomal biogenesis. Importantly, we find that NRF2-dependent regulation of lysosomal biogenesis is cell autonomous and evolutionarily conserved. These studies identify a role for the KEAP1-NRF2 pathway in the regulation of lysosomal biogenesis and suggest that maintenance of lysosomal homeostasis is required during embryonic development.
    Keywords:  KEAP1; NRF2; TFEB/TFE3; lysosome; zebrafish
    DOI:  https://doi.org/10.1073/pnas.2217425120
  18. iScience. 2023 Jun 16. 26(6): 106795
    RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia.
    Rashedul Islam, Catherine E Jenkins, Qi Cao, Jasper Wong, Misha Bilenky, Annaïck Carles, Michelle Moksa, Andrew P Weng, Martin Hirst.
      Runt-related transcription factor 1 (RUNX1) is oncogenic in diverse types of leukemia and epithelial cancers where its expression is associated with poor prognosis. Current models suggest that RUNX1 cooperates with other oncogenic factors (e.g., NOTCH1, TAL1) to drive the expression of proto-oncogenes in T cell acute lymphoblastic leukemia (T-ALL) but the molecular mechanisms controlled by RUNX1 and its cooperation with other factors remain unclear. Integrative chromatin and transcriptional analysis following inhibition of RUNX1 and NOTCH1 revealed a surprisingly widespread role of RUNX1 in the establishment of global H3K27ac levels and that RUNX1 is required by NOTCH1 for cooperative transcription activation of key NOTCH1 target genes including MYC, DTX1, HES4, IL7R, and NOTCH3. Super-enhancers were preferentially sensitive to RUNX1 knockdown and RUNX1-dependent super-enhancers were disrupted following the treatment of a pan-BET inhibitor, I-BET151.
    Keywords:  Cancer; Cancer systems biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.106795
  19. Cell Rep. 2023 May 18. pii: S2211-1247(23)00541-7. [Epub ahead of print]42(5): 112530
    FOXK1 promotes nonalcoholic fatty liver disease by mediating mTORC1-dependent inhibition of hepatic fatty acid oxidation.
    Shun Fujinuma, Hirokazu Nakatsumi, Hideyuki Shimizu, Shigeaki Sugiyama, Akihito Harada, Takeshi Goya, Masatake Tanaka, Motoyuki Kohjima, Masatomo Takahashi, Yoshihiro Izumi, Mikako Yagi, Dongchon Kang, Mari Kaneko, Mayo Shigeta, Takeshi Bamba, Yasuyuki Ohkawa, Keiichi I Nakayama.
      Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disorder caused by overnutrition and can lead to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). The transcription factor Forkhead box K1 (FOXK1) is implicated in regulation of lipid metabolism downstream of mechanistic target of rapamycin complex 1 (mTORC1), but its role in NAFLD-NASH pathogenesis is understudied. Here, we show that FOXK1 mediates nutrient-dependent suppression of lipid catabolism in the liver. Hepatocyte-specific deletion of Foxk1 in mice fed a NASH-inducing diet ameliorates not only hepatic steatosis but also associated inflammation, fibrosis, and tumorigenesis, resulting in improved survival. Genome-wide transcriptomic and chromatin immunoprecipitation analyses identify several lipid metabolism-related genes, including Ppara, as direct targets of FOXK1 in the liver. Our results suggest that FOXK1 plays a key role in the regulation of hepatic lipid metabolism and that its inhibition is a promising therapeutic strategy for NAFLD-NASH, as well as for HCC.
    Keywords:  CP: Metabolism; FOXK1; Forkhead box K1; HCC; NAFLD; NASH; conditional knockout mouse; hepatocellular carcinoma; lipid metabolism; mTORC1; mechanistic target of rapamycin complex 1; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis
    DOI:  https://doi.org/10.1016/j.celrep.2023.112530
  20. Nat Commun. 2023 May 22. 14(1): 2922
    Base editing-mediated one-step inactivation of the Dnmt gene family reveals critical roles of DNA methylation during mouse gastrulation.
    Qing Li, Jiansen Lu, Xidi Yin, Yunjian Chang, Chao Wang, Meng Yan, Li Feng, Yanbo Cheng, Yun Gao, Beiying Xu, Yao Zhang, Yingyi Wang, Guizhong Cui, Luang Xu, Yidi Sun, Rong Zeng, Yixue Li, Naihe Jing, Guo-Liang Xu, Ligang Wu, Fuchou Tang, Jinsong Li.
      During embryo development, DNA methylation is established by DNMT3A/3B and subsequently maintained by DNMT1. While much research has been done in this field, the functional significance of DNA methylation in embryogenesis remains unknown. Here, we establish a system of simultaneous inactivation of multiple endogenous genes in zygotes through screening for base editors that can efficiently introduce a stop codon. Embryos with mutations in Dnmts and/or Tets can be generated in one step with IMGZ. Dnmt-null embryos display gastrulation failure at E7.5. Interestingly, although DNA methylation is absent, gastrulation-related pathways are down-regulated in Dnmt-null embryos. Moreover, DNMT1, DNMT3A, and DNMT3B are critical for gastrulation, and their functions are independent of TET proteins. Hypermethylation can be sustained by either DNMT1 or DNMT3A/3B at some promoters, which are related to the suppression of miRNAs. The introduction of a single mutant allele of six miRNAs and paternal IG-DMR partially restores primitive streak elongation in Dnmt-null embryos. Thus, our results unveil an epigenetic correlation between promoter methylation and suppression of miRNA expression for gastrulation and demonstrate that IMGZ can accelerate deciphering the functions of multiple genes in vivo.
    DOI:  https://doi.org/10.1038/s41467-023-38528-z
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