bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2022–08–07
twenty papers selected by
Connor Rogerson, University of Cambridge
  1. FOXA1 inhibits hypoxia programs through transcriptional repression of HIF1A.
  2. Multi-omics characterization of mouse hepatoblastoma identifies novel YAP1 target genes.
  3. Histone H3K36me2 and H3K36me3 form a chromatin platform essential for DNMT3A-dependent DNA methylation in mouse oocytes.
  4. SEMplMe: a tool for integrating DNA methylation effects in transcription factor binding affinity predictions.
  5. The continuum of Drosophila embryonic development at single-cell resolution.
  6. Molecular organization of the early stages of nucleosome phase separation visualized by cryo-electron tomography.
  7. Hmga2 protein loss alters nuclear envelope and 3D chromatin structure.
  8. AP-1 transcription factor network explains diverse patterns of cellular plasticity in melanoma cells.
  9. PROBER identifies proteins associated with programmable sequence-specific DNA in living cells.
  10. Prediction of Gene Co-expression from Chromatin Contacts with Graph Attention Network.
  11. The intrinsic and extrinsic effects of TET proteins during gastrulation.
  12. Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity.
  13. Transcription Factors YAP/TAZ and SRF Cooperate To Specify Renal Myofibroblasts in the Developing Mouse Kidney.
  14. METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumourigenesis.
  15. Transient nuclear deformation primes epigenetic state and promotes cell reprogramming.
  16. The transcription factor FoxP3 can fold into two dimerization states with divergent implications for regulatory T cell function and immune homeostasis.
  17. SOX15 transcriptionally increases the function of AOC1 to modulate ferroptosis and progression in prostate cancer.
  18. Transcription factor Sp1 regulates mitotic chromosome assembly and segregation.
  19. A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor development.
  20. FOXL2 and FOXA1 cooperatively assemble on the TP53 promoter in alternative dimer configurations.
  1. Oncogene. 2022 Aug 05.
    FOXA1 inhibits hypoxia programs through transcriptional repression of HIF1A.
    Xiaohai Wang, Lourdes Brea, Xiaodong Lu, Galina Gritsina, Su H Park, Wanqing Xie, Jonathan C Zhao, Jindan Yu.
      Intratumoral hypoxia is associated with castration-resistant prostate cancer (CRPC), a lethal disease. FOXA1 is an epithelial transcription factor that is down-regulated in CRPC. We have previously reported that FOXA1 loss induces epithelial-mesenchymal transition (EMT) and cell motility through elevated TGFβ signaling. However, whether FOXA1 directly regulates hypoxia pathways of CRPC tumors has not been previously studied. Here we report that FOXA1 down-regulation induces hypoxia transcriptional programs, and FOXA1 level is negatively correlated with hypoxia markers in clinical prostate cancer (PCa) samples. Mechanistically, FOXA1 directly binds to an intragenic enhancer of HIF1A to inhibit its expression, and HIF1A, in turn, is critical in mediating FOXA1 loss-induced hypoxia gene expression. Further, we identify CCL2, a chemokine ligand that modulates tumor microenvironment and promotes cancer progression, as a crucial target of the FOXA1-HIF1A axis. We found that FOXA1 loss leads to immunosuppressive macrophage infiltration and increased cell invasion, dependent on HIF1A expression. Critically, therapeutic targeting of HIF1A-CCL2 using pharmacological inhibitors abolishes FOXA1 loss-induced macrophage infiltration and PCa cell invasion. In summary, our study reveals an essential role of FOXA1 in controlling the hypoxic tumor microenvironment and establishes the HIF1A-CCL2 axis as one mechanism of FOXA1 loss-induced CRPC progression.
    DOI:  https://doi.org/10.1038/s41388-022-02423-6
  2. Hepatology. 2022 Aug 06.
    Multi-omics characterization of mouse hepatoblastoma identifies novel YAP1 target genes.
    Tomás C Rodríguez, SuetYan Kwan, Jordan L Smith, Sina Dadafarin, Chern-Horng Wu, Erik J Sontheimer, Wen Xue.
       BACKGROUND & AIMS: Hepatoblastoma (HB) is the most common primary liver malignancy in childhood, and lacks targeted therapeutic options. We previously engineered the first Yes Associated Protein 1 (YAP1S127A )-inducible mouse model of HB, demonstrating tumor regression and re-differentiation after YAP1 withdrawal through genome-wide enhancer modulation. Probing accessibility, transcription, and YAP1 binding at regulatory elements in HB tumors may provide more insight into YAP1-driven tumorigenesis and expose exploitable vulnerabilities in HB.
    APPROACH & RESULTS: Using a multi-omics approach, we integrated high-throughput transcriome and chromatin profiling of our murine HB model to identify dynamic activity at candidate cis-regulatory elements (cCREs). We observed that 1,301 of 305,596 cCREs exhibit "Tumor-modified" (TM) accessibility in HB. We mapped 241 TM enhancers to corresponding genes using accessibility and H3K27Ac profiles. Anti-YAP1 Cleavage under targets and tagmentation (CUT&Tag) in tumors revealed 66 YAP1-bound TM cCRE/gene pairs, 31 of which decrease expression after YAP1 withdrawal. We validated the YAP1-dependent expression of a putative YAP1 target, Jun Dimerization Protein 2 (JDP2), in human HB cell lines using YAP1 and LATS1/2 siRNA knockdown. We also confirmed YAP1-induced activity of the Jdp2 TM enhancer in vitro, and discovered an analogous human enhancer in silico. Finally, we used transcription factor (TF) footprinting to identify putative YAP1 co-factors and characterize HB-specific TF activity, genome-wide.
    CONCLUSIONS: Our chromatin profiling techniques define the regulatory frameworks underlying HB and identify novel, YAP1-regulated gene/enhancer pairs. JDP2 is an extensively validated target with YAP1-dependent expression in human HB cell lines and hepatic malignancies.
    DOI:  https://doi.org/10.1002/hep.32713
  3. Nat Commun. 2022 Aug 03. 13(1): 4440
    Histone H3K36me2 and H3K36me3 form a chromatin platform essential for DNMT3A-dependent DNA methylation in mouse oocytes.
    Seiichi Yano, Takashi Ishiuchi, Shusaku Abe, Satoshi H Namekawa, Gang Huang, Yoshihiro Ogawa, Hiroyuki Sasaki.
      Establishment of the DNA methylation landscape of mammalian oocytes, mediated by the DNMT3A-DNMT3L complex, is crucial for reproduction and development. In mouse oocytes, high levels of DNA methylation occur exclusively in the transcriptionally active regions, with moderate to low levels of methylation in other regions. Histone H3K36me3 mediates the high levels of methylation in the transcribed regions; however, it is unknown which histone mark guides the methylation in the other regions. Here, we show that, in mouse oocytes, H3K36me2 is highly enriched in the X chromosome and is broadly distributed across all autosomes. Upon H3K36me2 depletion, DNA methylation in moderately methylated regions is selectively affected, and a methylation pattern unique to the X chromosome is switched to an autosome-like pattern. Furthermore, we find that simultaneous depletion of H3K36me2 and H3K36me3 results in global hypomethylation, comparable to that of DNMT3A depletion. Therefore, the two histone marks jointly provide the chromatin platform essential for guiding DNMT3A-dependent DNA methylation in mouse oocytes.
    DOI:  https://doi.org/10.1038/s41467-022-32141-2
  4. BMC Bioinformatics. 2022 Aug 04. 23(1): 317
    SEMplMe: a tool for integrating DNA methylation effects in transcription factor binding affinity predictions.
    Sierra S Nishizaki, Alan P Boyle.
       MOTIVATION: Aberrant DNA methylation in transcription factor binding sites has been shown to lead to anomalous gene regulation that is strongly associated with human disease. However, the majority of methylation-sensitive positions within transcription factor binding sites remain unknown. Here we introduce SEMplMe, a computational tool to generate predictions of the effect of methylation on transcription factor binding strength in every position within a transcription factor's motif.
    RESULTS: SEMplMe uses ChIP-seq and whole genome bisulfite sequencing to predict effects of methylation within binding sites. SEMplMe validates known methylation sensitive and insensitive positions within a binding motif, identifies cell type specific transcription factor binding driven by methylation, and outperforms SELEX-based predictions for CTCF. These predictions can be used to identify aberrant sites of DNA methylation contributing to human disease.
    AVAILABILITY AND IMPLEMENTATION: SEMplMe is available from https://github.com/Boyle-Lab/SEMplMe .
    Keywords:  DNA methylation; Gene regulation; Noncoding variation; Open-source; Software; TFBS; Transcription factor
    DOI:  https://doi.org/10.1186/s12859-022-04865-x
  5. Science. 2022 Aug 05. 377(6606): eabn5800
    The continuum of Drosophila embryonic development at single-cell resolution.
    Diego Calderon, Ronnie Blecher-Gonen, Xingfan Huang, Stefano Secchia, James Kentro, Riza M Daza, Beth Martin, Alessandro Dulja, Christoph Schaub, Cole Trapnell, Erica Larschan, Kate M O'Connor-Giles, Eileen E M Furlong, Jay Shendure.
      Drosophila melanogaster is a powerful, long-standing model for metazoan development and gene regulation. We profiled chromatin accessibility in almost 1 million and gene expression in half a million nuclei from overlapping windows spanning the entirety of embryogenesis. Leveraging developmental asynchronicity within embryo collections, we applied deep neural networks to infer the age of each nucleus, resulting in continuous, multimodal views of molecular and cellular transitions in absolute time. We identify cell lineages; infer their developmental relationships; and link dynamic changes in enhancer usage, transcription factor (TF) expression, and the accessibility of TFs' cognate motifs. With these data, the dynamics of enhancer usage and gene expression can be explored within and across lineages at the scale of minutes, including for precise transitions like zygotic genome activation.
    DOI:  https://doi.org/10.1126/science.abn5800
  6. Mol Cell. 2022 Jul 29. pii: S1097-2765(22)00650-5. [Epub ahead of print]
    Molecular organization of the early stages of nucleosome phase separation visualized by cryo-electron tomography.
    Meng Zhang, César Díaz-Celis, Bibiana Onoa, Cristhian Cañari-Chumpitaz, Katherinne I Requejo, Jianfang Liu, Michael Vien, Eva Nogales, Gang Ren, Carlos Bustamante.
      It has been proposed that the intrinsic property of nucleosome arrays to undergo liquid-liquid phase separation (LLPS) in vitro is responsible for chromatin domain organization in vivo. However, understanding nucleosomal LLPS has been hindered by the challenge to characterize the structure of the resulting heterogeneous condensates. We used cryo-electron tomography and deep-learning-based 3D reconstruction/segmentation to determine the molecular organization of condensates at various stages of LLPS. We show that nucleosomal LLPS involves a two-step process: a spinodal decomposition process yielding irregular condensates, followed by their unfavorable conversion into more compact, spherical nuclei that grow into larger spherical aggregates through accretion of spinodal materials or by fusion with other spherical condensates. Histone H1 catalyzes more than 10-fold the spinodal-to-spherical conversion. We propose that this transition involves exposure of nucleosome hydrophobic surfaces causing modified inter-nucleosome interactions. These results suggest a physical mechanism by which chromatin may transition from interphase to metaphase structures.
    Keywords:  chromatin; condensates; cryo-electron tomography; linker histone H1; liquid-liquid phase separation; nucleation and growth; nucleosome; nucleosome arrays; spinodal decomposition
    DOI:  https://doi.org/10.1016/j.molcel.2022.06.032
  7. BMC Biol. 2022 08 02. 20(1): 171
    Hmga2 protein loss alters nuclear envelope and 3D chromatin structure.
    Giuseppina Divisato, Andrea M Chiariello, Andrea Esposito, Pietro Zoppoli, Federico Zambelli, Maria Antonietta Elia, Graziano Pesole, Danny Incarnato, Fabiana Passaro, Silvia Piscitelli, Salvatore Oliviero, Mario Nicodemi, Silvia Parisi, Tommaso Russo.
       BACKGROUND: The high-mobility group Hmga family of proteins are non-histone chromatin-interacting proteins which have been associated with a number of nuclear functions, including heterochromatin formation, replication, recombination, DNA repair, transcription, and formation of enhanceosomes. Due to its role based on dynamic interaction with chromatin, Hmga2 has a pathogenic role in diverse tumors and has been mainly studied in a cancer context; however, whether Hmga2 has similar physiological functions in normal cells remains less explored. Hmga2 was additionally shown to be required during the exit of embryonic stem cells (ESCs) from the ground state of pluripotency, to allow their transition into epiblast-like cells (EpiLCs), and here, we use that system to gain further understanding of normal Hmga2 function.
    RESULTS: We demonstrated that Hmga2 KO pluripotent stem cells fail to develop into EpiLCs. By using this experimental system, we studied the chromatin changes that take place upon the induction of EpiLCs and we observed that the loss of Hmga2 affects the histone mark H3K27me3, whose levels are higher in Hmga2 KO cells. Accordingly, a sustained expression of polycomb repressive complex 2 (PRC2), responsible for H3K27me3 deposition, was observed in KO cells. However, gene expression differences between differentiating wt vs Hmga2 KO cells did not show any significant enrichments of PRC2 targets. Similarly, endogenous Hmga2 association to chromatin in epiblast stem cells did not show any clear relationships with gene expression modification observed in Hmga2 KO. Hmga2 ChIP-seq confirmed that this protein preferentially binds to the chromatin regions associated with nuclear lamina. Starting from this observation, we demonstrated that nuclear lamina underwent severe alterations when Hmga2 KO or KD cells were induced to exit from the naïve state and this phenomenon is accompanied by a mislocalization of the heterochromatin mark H3K9me3 within the nucleus. As nuclear lamina (NL) is involved in the organization of 3D chromatin structure, we explored the possible effects of Hmga2 loss on this phenomenon. The analysis of Hi-C data in wt and Hmga2 KO cells allowed us to observe that inter-TAD (topologically associated domains) interactions in Hmga2 KO cells are different from those observed in wt cells. These differences clearly show a peculiar compartmentalization of inter-TAD interactions in chromatin regions associated or not to nuclear lamina.
    CONCLUSIONS: Overall, our results indicate that Hmga2 interacts with heterochromatic lamin-associated domains, and highlight a role for Hmga2 in the crosstalk between chromatin and nuclear lamina, affecting the establishment of inter-TAD interactions.
    Keywords:  High mobility group proteins; Histone modifications; Lamin; Nuclear envelope; Pluripotent stem cells; Topologically associated domains
    DOI:  https://doi.org/10.1186/s12915-022-01375-3
  8. Cell Rep. 2022 Aug 02. pii: S2211-1247(22)00956-1. [Epub ahead of print]40(5): 111147
    AP-1 transcription factor network explains diverse patterns of cellular plasticity in melanoma cells.
    Natacha Comandante-Lou, Douglas G Baumann, Mohammad Fallahi-Sichani.
      Cellular plasticity associated with fluctuations in transcriptional programs allows individual cells in a tumor to adopt heterogeneous differentiation states and switch phenotype during their adaptive responses to therapies. Despite increasing knowledge of such transcriptional programs, the molecular basis of cellular plasticity remains poorly understood. Here, we combine multiplexed transcriptional and protein measurements at population and single-cell levels with multivariate statistical modeling to show that the state of AP-1 transcription factor network plays a unifying role in explaining diverse patterns of plasticity in melanoma. We find that a regulated balance among AP-1 factors cJUN, JUND, FRA2, FRA1, and cFOS determines the intrinsic diversity of differentiation states and adaptive responses to MAPK inhibitors in melanoma cells. Perturbing this balance through genetic depletion of specific AP-1 proteins, or by MAPK inhibitors, shifts cellular heterogeneity in a predictable fashion. Thus, AP-1 may serve as a critical node for manipulating cellular plasticity with potential therapeutic implications.
    Keywords:  AP-1 transcription factors; BRAF-mutant melanoma; CP: Cancer; CP: Molecular biology; MAPK signaling pathway; adaptive drug resistance; cellular plasticity; computational modeling; differentiation state heterogeneity; single-cell analysis; statistical learning; targeted therapies
    DOI:  https://doi.org/10.1016/j.celrep.2022.111147
  9. Nat Methods. 2022 Aug;19(8): 959-968
    PROBER identifies proteins associated with programmable sequence-specific DNA in living cells.
    Smarajit Mondal, Muthukumar Ramanathan, Weili Miao, Robin M Meyers, Deepti Rao, Vanessa Lopez-Pajares, Zurab Siprashvili, David L Reynolds, Douglas F Porter, Ian Ferguson, Poornima Neela, Yang Zhao, Lindsey M Meservey, Margaret Guo, Yen-Yu Yang, Lin Li, Yinsheng Wang, Paul A Khavari.
      DNA-protein interactions mediate physiologic gene regulation and may be altered by DNA variants linked to polygenic disease. To enhance the speed and signal-to-noise ratio (SNR) in the identification and quantification of proteins associated with specific DNA sequences in living cells, we developed proximal biotinylation by episomal recruitment (PROBER). PROBER uses high-copy episomes to amplify SNR, and proximity proteomics (BioID) to identify the transcription factors and additional gene regulators associated with short DNA sequences of interest. PROBER quantified both constitutive and inducible association of transcription factors and corresponding chromatin regulators to target DNA sequences and binding quantitative trait loci due to single-nucleotide variants. PROBER identified alterations in regulator associations due to cancer hotspot mutations in the hTERT promoter, indicating that these mutations increase promoter association with specific gene activators. PROBER provides an approach to rapidly identify proteins associated with specific DNA sequences and their variants in living cells.
    DOI:  https://doi.org/10.1038/s41592-022-01552-w
  10. Bioinformatics. 2022 Aug 05. pii: btac535. [Epub ahead of print]
    Prediction of Gene Co-expression from Chromatin Contacts with Graph Attention Network.
    Ke Zhang, Chenxi Wang, Liping Sun, Jie Zheng.
       MOTIVATION: The technology of high-throughput chromatin conformation capture (Hi-C) allows genome-wide measurement of chromatin interactions. Several studies have shown statistically significant relationships between gene-gene spatial contacts and their co-expression. It is desirable to uncover epigenetic mechanisms of transcriptional regulation behind such relationships using computational modeling. Existing methods for predicting gene co-expression from Hi-C data use manual feature engineering or unsupervised learning, which either limits the prediction accuracy or lacks interpretability.
    RESULTS: To address these issues, we propose HiCoEx, a novel end-to-end framework for explainable prediction of gene co-expression from Hi-C data based on graph neural network. We apply graph attention mechanism to a gene contact network inferred from Hi-C data to distinguish the importance among different neighboring genes of each gene, and learn the gene representation to predict co-expression in a supervised and task-specific manner. Then, from the trained model, we extract the learned gene embeddings as a model interpretation to distill biological insights. Experimental results show that HiCoEx can learn gene representation from 3D genomics signals automatically to improve prediction accuracy, and make the black box model explainable by capturing some biologically meaningful patterns, e.g., in a gene contact network, the common neighbors of two central genes might contribute to the co-expression of the two central genes through sharing enhancers.
    AVAILABILITY: The source code is freely available at https://github.com/JieZheng-ShanghaiTech/HiCoEx.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btac535
  11. Cell. 2022 Jul 30. pii: S0092-8674(22)00842-X. [Epub ahead of print]
    The intrinsic and extrinsic effects of TET proteins during gastrulation.
    Saifeng Cheng, Markus Mittnenzweig, Yoav Mayshar, Aviezer Lifshitz, Marko Dunjić, Yoach Rais, Raz Ben-Yair, Stephanie Gehrs, Elad Chomsky, Zohar Mukamel, Hernan Rubinstein, Katharina Schlereth, Netta Reines, Ayelet-Hashahar Orenbuch, Amos Tanay, Yonatan Stelzer.
      Mice deficient for all ten-eleven translocation (TET) genes exhibit early gastrulation lethality. However, separating cause and effect in such embryonic failure is challenging. To isolate cell-autonomous effects of TET loss, we used temporal single-cell atlases from embryos with partial or complete mutant contributions. Strikingly, when developing within a wild-type embryo, Tet-mutant cells retain near-complete differentiation potential, whereas embryos solely comprising mutant cells are defective in epiblast to ectoderm transition with degenerated mesoderm potential. We map de-repressions of early epiblast factors (e.g., Dppa4 and Gdf3) and failure to activate multiple signaling from nascent mesoderm (Lefty, FGF, and Notch) as likely cell-intrinsic drivers of TET loss phenotypes. We further suggest loss of enhancer demethylation as the underlying mechanism. Collectively, our work demonstrates an unbiased approach for defining intrinsic and extrinsic embryonic gene function based on temporal differentiation atlases and disentangles the intracellular effects of the demethylation machinery from its broader tissue-level ramifications.
    Keywords:  DNA demethylation; cell fate decisions; developmental biology; epigenetics; genome editing; mouse gastrulation; single-cell genomics; stem cells
    DOI:  https://doi.org/10.1016/j.cell.2022.06.049
  12. Proc Natl Acad Sci U S A. 2022 Aug 09. 119(32): e2116956119
    Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity.
    Owen H Funk, Yaman Qalieh, Daniel Z Doyle, Mandy M Lam, Kenneth Y Kwan.
      Histone variants, which can be expressed outside of S-phase and deposited DNA synthesis-independently, provide long-term histone replacement in postmitotic cells, including neurons. Beyond replenishment, histone variants also play active roles in gene regulation by modulating chromatin states or enabling nucleosome turnover. Here, we uncover crucial roles for the histone H3 variant H3.3 in neuronal development. We find that newborn cortical excitatory neurons, which have only just completed replication-coupled deposition of canonical H3.1 and H3.2, substantially accumulate H3.3 immediately postmitosis. Codeletion of H3.3-encoding genes H3f3a and H3f3b from newly postmitotic neurons abrogates H3.3 accumulation, markedly alters the histone posttranslational modification landscape, and causes widespread disruptions to the establishment of the neuronal transcriptome. These changes coincide with developmental phenotypes in neuronal identities and axon projections. Thus, preexisting, replication-dependent histones are insufficient for establishing neuronal chromatin and transcriptome; de novo H3.3 is required. Stage-dependent deletion of H3f3a and H3f3b from 1) cycling neural progenitor cells, 2) neurons immediately postmitosis, or 3) several days later, reveals the first postmitotic days to be a critical window for de novo H3.3. After H3.3 accumulation within this developmental window, codeletion of H3f3a and H3f3b does not lead to immediate H3.3 loss, but causes progressive H3.3 depletion over several months without widespread transcriptional disruptions or cellular phenotypes. Our study thus uncovers key developmental roles for de novo H3.3 in establishing neuronal chromatin, transcriptome, identity, and connectivity immediately postmitosis that are distinct from its role in maintaining total histone H3 levels over the neuronal lifespan.
    Keywords:  cerebral cortex; chromatin; development; histone modification; neuronal identity
    DOI:  https://doi.org/10.1073/pnas.2116956119
  13. J Am Soc Nephrol. 2022 Aug 02. pii: ASN.2021121559. [Epub ahead of print]
    Transcription Factors YAP/TAZ and SRF Cooperate To Specify Renal Myofibroblasts in the Developing Mouse Kidney.
    Keri A Drake, Christopher Chaney, Mohita Patel, Amrita Das, Julia Bittencourt, Martin Cohn, Thomas J Carroll.
       BACKGROUND: The embryonic renal stroma consists of multiple molecularly distinct cell subpopulations, the functional significance of which is largely unknown. Previous work has demonstrated that the transcription factors YAP and TAZ play roles in the development and morphogenesis of the nephrons, collecting ducts, and nephron progenitor cells.
    METHODS: In embryonic mouse kidneys, we identified a subpopulation of stromal cells with enriched activity in YAP and TAZ. To evaluate the function of these cell types, we genetically ablated both Yap and Taz from the stromal progenitor population and examined how gene activity and development of YAP/TAZ mutant kidneys are affected over a developmental time course.
    RESULTS: We found that YAP and TAZ are active in a subset of renal interstitium and that stromal-specific coablation of YAP/TAZ disrupts cortical fibroblast, pericyte, and myofibroblast development, with secondary effects on peritubular capillary differentiation. We also demonstrated that the transcription factor SRF cooperates with YAP/TAZ to drive expression of at least a subset of renal myofibroblast target genes and to specify myofibroblasts, but not cortical fibroblasts or pericytes.
    CONCLUSIONS: These findings reveal a critical role for YAP/TAZ in specific embryonic stromal cells and suggest that interaction with cofactors, such as SRF, influence the expression of cell type-specific target genes, thus driving stromal heterogeneity. Further, this work reveals functional roles for renal stroma heterogeneity in creating unique microenvironments that influence the differentiation and maintenance of the renal parenchyma.
    Keywords:  Hippo/Warts; fibroblast heterogeneity; kidney development; myofibroblasts; pericyte; stromal microenvironment
    DOI:  https://doi.org/10.1681/ASN.2021121559
  14. Nat Cell Biol. 2022 Aug 04.
    METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumourigenesis.
    Xueju Wei, Yue Huo, Jingnan Pi, Yufeng Gao, Shuan Rao, Manman He, Qinglv Wei, Peng Song, Yiying Chen, Dongxu Lu, Wei Song, Junbo Liang, Lingjie Xu, Haixia Wang, Guolin Hong, Yuehong Guo, Yanmin Si, Jiayue Xu, Xiaoshuang Wang, Yanni Ma, Shuyang Yu, Dongling Zou, Jing Jin, Fang Wang, Jia Yu.
      METTL3 encodes the predominant catalytic enzyme to promote m6A methylation in nucleus. Recently, accumulating evidence has shown the expression of METTL3 in cytoplasm, but its function is not fully understood. Here we demonstrated an m6A-independent mechanism for METTL3 to promote tumour progression. In gastric cancer, METTL3 could not only facilitate cancer progression via m6A modification, but also bind to numerous non-m6A-modified mRNAs, suggesting an unexpected role of METTL3. Mechanistically, cytoplasm-anchored METTL3 interacted with PABPC1 to stabilize its association with cap-binding complex eIF4F, which preferentially promoted the translation of epigenetic factors without m6A modification. Clinical investigation showed that cytoplasmic distributed METTL3 was highly correlated with gastric cancer progression, and this finding could be expanded to prostate cancer. Therefore, the cytoplasmic METTL3 enhances the translation of epigenetic mRNAs, thus serving as an oncogenic driver in cancer progression, and METTL3 subcellular distribution can assist diagnosis and predict prognosis for patients with cancer.
    DOI:  https://doi.org/10.1038/s41556-022-00968-y
  15. Nat Mater. 2022 Aug 04.
    Transient nuclear deformation primes epigenetic state and promotes cell reprogramming.
    Yang Song, Jennifer Soto, Binru Chen, Tyler Hoffman, Weikang Zhao, Ninghao Zhu, Qin Peng, Longwei Liu, Chau Ly, Pak Kin Wong, Yingxiao Wang, Amy C Rowat, Siavash K Kurdistani, Song Li.
      Cell reprogramming has wide applications in tissue regeneration, disease modelling and personalized medicine. In addition to biochemical cues, mechanical forces also contribute to the modulation of the epigenetic state and a variety of cell functions through distinct mechanisms that are not fully understood. Here we show that millisecond deformation of the cell nucleus caused by confinement into microfluidic channels results in wrinkling and transient disassembly of the nuclear lamina, local detachment of lamina-associated domains in chromatin and a decrease of histone methylation (histone H3 lysine 9 trimethylation) and DNA methylation. These global changes in chromatin at the early stage of cell reprogramming boost the conversion of fibroblasts into neurons and can be partially reproduced by inhibition of histone H3 lysine 9 and DNA methylation. This mechanopriming approach also triggers macrophage reprogramming into neurons and fibroblast conversion into induced pluripotent stem cells, being thus a promising mechanically based epigenetic state modulation method for cell engineering.
    DOI:  https://doi.org/10.1038/s41563-022-01312-3
  16. Immunity. 2022 Aug 03. pii: S1074-7613(22)00335-1. [Epub ahead of print]
    The transcription factor FoxP3 can fold into two dimerization states with divergent implications for regulatory T cell function and immune homeostasis.
    Fangwei Leng, Wenxiang Zhang, Ricardo N Ramirez, Juliette Leon, Yi Zhong, Lifei Hou, Koichi Yuki, Joris van der Veeken, Alexander Y Rudensky, Christophe Benoist, Sun Hur.
      FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrated that unlike other known forkhead TFs, FoxP3 formed a head-to-head dimer using a unique linker (Runx1-binding region [RBR]) preceding the forkhead domain. Head-to-head dimerization conferred distinct DNA-binding specificity and created a docking site for the cofactor Runx1. RBR was also important for proper folding of the forkhead domain, as truncation of RBR induced domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impaired FoxP3 function, as demonstrated with the disease-causing mutation R337Q, whereas a swap-suppressive mutation largely rescued R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states: head-to-head dimerization representing functional specialization of an ancient DBD and swap dimerization associated with impaired functions.
    Keywords:  Foxp3; IPEX; Runx1; Treg; forkhead; homodimer; transcription factor
    DOI:  https://doi.org/10.1016/j.immuni.2022.07.002
  17. Cell Death Dis. 2022 Aug 03. 13(8): 673
    SOX15 transcriptionally increases the function of AOC1 to modulate ferroptosis and progression in prostate cancer.
    Yinghui Ding, Yuankang Feng, Zhenlin Huang, Yu Zhang, Xiang Li, Ruoyang Liu, Hao Li, Tao Wang, Yafei Ding, Zhankui Jia, Jinjian Yang.
      Amine oxidase copper-containing 1 (AOC1) is considered an oncogene in many types of tumors. Nevertheless, there have been no investigations of AOC1 and its regulatory mechanism in prostate cancer. Here, we reveal a novel action of AOC1 and a tumor suppressor mechanism in prostate cancer. AOC1 is downregulated in prostate cancer. Abatement of AOC1 in prostate cancer tissue is positively correlated with the tumor size, lymph node metastasis, and Gleason score for prostate cancer. Conversely, high expression of AOC1 is significantly associated with reduced proliferation and migration in prostate cancer both in vitro and in vivo. We show that the anticancer effect of AOC1 is mediated by its action on spermidine which leads to the activation of reactive oxygen species and ferroptosis. AOC1 expression in prostate cancer is positively regulated by the transcription factor SOX15. Therefore, SOX15 can transcriptionally promote AOC1 expression and strengthen this effect. Targeting AOC1 and SOX15 may be promising for the treatment of prostate cancer.
    DOI:  https://doi.org/10.1038/s41419-022-05108-w
  18. Chromosoma. 2022 Aug 02.
    Transcription factor Sp1 regulates mitotic chromosome assembly and segregation.
    Samuel Flashner, Michelle Swift, Aislinn Sowash, Alexander N Fahmy, Jane Azizkhan-Clifford.
      Aneuploidy is a pervasive feature of cancer cells that results from chromosome missegregation. Several transcription factors have been associated with aneuploidy; however, no studies to date have demonstrated that mammalian transcription factors directly regulate chromosome segregation during mitosis. Here, we demonstrate that the ubiquitously expressed transcription factor specificity protein 1 (Sp1), which we have previously linked to aneuploidy, has a mitosis-specific role regulating chromosome segregation. We find that Sp1 localizes to mitotic centromeres and auxin-induced rapid Sp1 degradation at mitotic onset results in chromosome segregation errors and aberrant mitotic progression. Furthermore, rapid Sp1 degradation results in anomalous mitotic chromosome assembly characterized by loss of condensin complex I localization to mitotic chromosomes and chromosome condensation defects. Consistent with these defects, Sp1 degradation results in reduced chromosome passenger complex activity and histone H3 serine 10 phosphorylation during mitosis, which is essential for condensin complex I recruitment and chromosome condensation. Together, these data provide the first evidence of a mammalian transcription factor acting specifically during mitosis to regulate chromosome segregation.
    Keywords:  Chromosome passenger complex; Chromosome segregation; Condensin complex I; Mitosis; Sp1; Transcription factor
    DOI:  https://doi.org/10.1007/s00412-022-00778-z
  19. Sci Adv. 2022 Aug 05. 8(31): eabn3986
    A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor development.
    Valerio Benedetti, Federica Banfi, Mattia Zaghi, Raquel Moll-Diaz, Luca Massimino, Laura Argelich, Edoardo Bellini, Simone Bido, Sharon Muggeo, Gabriele Ordazzo, Giuseppina Mastrototaro, Matteo Moneta, Alessandro Sessa, Vania Broccoli.
      Current therapies remain unsatisfactory in preventing the recurrence of glioblastoma multiforme (GBM), which leads to poor patient survival. By rational engineering of the transcription factor SOX2, a key promoter of GBM malignancy, together with the Kruppel-associated box and DNA methyltransferase3A/L catalytic domains, we generated a synthetic repressor named SOX2 epigenetic silencer (SES), which induces the transcriptional silencing of its original targets. By doing so, SES kills both glioma cell lines and patient-derived cancer stem cells in vitro and in vivo. SES expression, through local viral delivery in mouse xenografts, induces strong regression of human tumors and survival rescue. Conversely, SES is not harmful to neurons and glia, also thanks to a minimal promoter that restricts its expression in mitotically active cells, rarely present in the brain parenchyma. Collectively, SES produces a significant silencing of a large fraction of the SOX2 transcriptional network, achieving high levels of efficacy in repressing aggressive brain tumors.
    DOI:  https://doi.org/10.1126/sciadv.abn3986
  20. Nucleic Acids Res. 2022 Aug 03. pii: gkac673. [Epub ahead of print]
    FOXL2 and FOXA1 cooperatively assemble on the TP53 promoter in alternative dimer configurations.
    Yuri Choi, Yongyang Luo, Seunghwa Lee, Hanyong Jin, Hye-Jin Yoon, Yoonsoo Hahn, Jeehyeon Bae, Hyung Ho Lee.
      Although both the p53 and forkhead box (FOX) family proteins are key transcription factors associated with cancer progression, their direct relationship is unknown. Here, we found that FOX family proteins bind to the non-canonical homotypic cluster of the p53 promoter region (TP53). Analysis of crystal structures of FOX proteins (FOXL2 and FOXA1) bound to the p53 homotypic cluster indicated that they interact with a 2:1 stoichiometry accommodated by FOX-induced DNA allostery. In particular, FOX proteins exhibited distinct dimerization patterns in recognition of the same p53-DNA; dimer formation of FOXA1 involved protein-protein interaction, but FOXL2 did not. Biochemical and biological functional analyses confirmed the cooperative binding of FOX proteins to the TP53 promoter for the transcriptional activation of TP53. In addition, up-regulation of TP53 was necessary for FOX proteins to exhibit anti-proliferative activity in cancer cells. These analyses reveal the presence of a discrete characteristic within FOX family proteins in which FOX proteins regulate the transcription activity of the p53 tumor suppressor via cooperative binding to the TP53 promoter in alternative dimer configurations.
    DOI:  https://doi.org/10.1093/nar/gkac673
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