bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2024–02–11
23 papers selected by
Connor Rogerson, University of Cambridge
  1. G-quadruplex DNA structure is a positive regulator of MYC transcription.
  2. An Epigenomic fingerprint of human cancers by landscape interrogation of super enhancers at the constituent level.
  3. Heterotypic interactions can drive selective co-condensation of prion-like low-complexity domains of FET proteins and mammalian SWI/SNF complex.
  4. G-quadruplexes promote the motility in MAZ phase-separated condensates to activate CCND1 expression and contribute to hepatocarcinogenesis.
  5. Nucleosome conformation dictates the histone code.
  6. Differential histone acetylation and super-enhancer regulation underlie melanoma cell dedifferentiation.
  7. Cell-free genomics: transcription factor interactions in reconstituted naïve embryonic chromatin.
  8. Simultaneous single-cell analysis of 5mC and 5hmC with SIMPLE-seq.
  9. Integrative high-throughput enhancer surveying and functional verification divulges a YY2-condensed regulatory axis conferring risk for osteoporosis.
  10. Structural basis for RNA polymerase II ubiquitylation and inactivation in transcription-coupled repair.
  11. PRAMEL7 and CUL2 decrease NuRD stability to establish ground-state pluripotency.
  12. IκBζ is a dual-use coactivator of NF-κB and POU transcription factors.
  13. The androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer.
  14. Chromatin binding by HORMAD proteins regulates meiotic recombination initiation.
  15. The nuclear factor ID3 endows macrophages with a potent anti-tumour activity.
  16. Phase separation of YAP-MAML2 differentially regulates the transcriptome.
  17. DNA damage remodels the MITF interactome to increase melanoma genomic instability.
  18. Atypical inflammatory kinase IKBKE phosphorylates and inactivates FoxA1 to promote liver tumorigenesis.
  19. Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes.
  20. Structural insights into histone exchange by human SRCAP complex.
  21. Maternal KLF17 controls zygotic genome activation by acting as a messenger for RNA Pol II recruitment in mouse embryos.
  22. ANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation.
  23. Linker histone H1 drives heterochromatin condensation via phase separation in Arabidopsis.
  1. Proc Natl Acad Sci U S A. 2024 Feb 13. 121(7): e2320240121
    G-quadruplex DNA structure is a positive regulator of MYC transcription.
    Isabel Esain-Garcia, Angie Kirchner, Larry Melidis, Rafael de Cesaris Araujo Tavares, Somdutta Dhir, Angela Simeone, Zutao Yu, Sarah K Madden, Regina Hermann, David Tannahill, Shankar Balasubramanian.
      DNA structure can regulate genome function. Four-stranded DNA G-quadruplex (G4) structures have been implicated in transcriptional regulation; however, previous studies have not directly addressed the role of an individual G4 within its endogenous cellular context. Using CRISPR to genetically abrogate endogenous G4 structure folding, we directly interrogate the G4 found within the upstream regulatory region of the critical human MYC oncogene. G4 loss leads to suppression of MYC transcription from the P1 promoter that is mediated by the deposition of a de novo nucleosome alongside alterations in RNA polymerase recruitment. We also show that replacement of the endogenous MYC G4 with a different G4 structure from the KRAS oncogene restores G4 folding and MYC transcription. Moreover, we demonstrate that the MYC G4 structure itself, rather than its sequence, recruits transcription factors and histone modifiers. Overall, our work establishes that G4 structures are important features of transcriptional regulation that coordinate recruitment of key chromatin proteins and the transcriptional machinery through interactions with DNA secondary structure, rather than primary sequence.
    Keywords:  DNA; G-quadruplex; MYC; epigenetics; transcription
    DOI:  https://doi.org/10.1073/pnas.2320240121
  2. PLoS Comput Biol. 2024 Feb 09. 20(2): e1011873
    An Epigenomic fingerprint of human cancers by landscape interrogation of super enhancers at the constituent level.
    Xiang Liu, Nancy Gillis, Chang Jiang, Anthony McCofie, Timothy I Shaw, Aik-Choon Tan, Bo Zhao, Lixin Wan, Derek R Duckett, Mingxiang Teng.
      Super enhancers (SE), large genomic elements that activate transcription and drive cell identity, have been found with cancer-specific gene regulation in human cancers. Recent studies reported the importance of understanding the cooperation and function of SE internal components, i.e., the constituent enhancers (CE). However, there are no pan-cancer studies to identify cancer-specific SE signatures at the constituent level. Here, by revisiting pan-cancer SE activities with H3K27Ac ChIP-seq datasets, we report fingerprint SE signatures for 28 cancer types in the NCI-60 cell panel. We implement a mixture model to discriminate active CEs from inactive CEs by taking into consideration ChIP-seq variabilities between cancer samples and across CEs. We demonstrate that the model-based estimation of CE states provides improved functional interpretation of SE-associated regulation. We identify cancer-specific CEs by balancing their active prevalence with their capability of encoding cancer type identities. We further demonstrate that cancer-specific CEs have the strongest per-base enhancer activities in independent enhancer sequencing assays, suggesting their importance in understanding critical SE signatures. We summarize fingerprint SEs based on the cancer-specific statuses of their component CEs and build an easy-to-use R package to facilitate the query, exploration, and visualization of fingerprint SEs across cancers.
    DOI:  https://doi.org/10.1371/journal.pcbi.1011873
  3. Nat Commun. 2024 Feb 07. 15(1): 1168
    Heterotypic interactions can drive selective co-condensation of prion-like low-complexity domains of FET proteins and mammalian SWI/SNF complex.
    Richoo B Davis, Anushka Supakar, Aishwarya Kanchi Ranganath, Mahdi Muhammad Moosa, Priya R Banerjee.
      Prion-like domains (PLDs) are low-complexity protein sequences enriched within nucleic acid-binding proteins including those involved in transcription and RNA processing. PLDs of FUS and EWSR1 play key roles in recruiting chromatin remodeler mammalian SWI/SNF (mSWI/SNF) complex to oncogenic FET fusion protein condensates. Here, we show that disordered low-complexity domains of multiple SWI/SNF subunits are prion-like with a strong propensity to undergo intracellular phase separation. These PLDs engage in sequence-specific heterotypic interactions with the PLD of FUS in the dilute phase at sub-saturation conditions, leading to the formation of PLD co-condensates. In the dense phase, homotypic and heterotypic PLD interactions are highly cooperative, resulting in the co-mixing of individual PLD phases and forming spatially homogeneous condensates. Heterotypic PLD-mediated positive cooperativity in protein-protein interaction networks is likely to play key roles in the co-phase separation of mSWI/SNF complex with transcription factors containing homologous low-complexity domains.
    DOI:  https://doi.org/10.1038/s41467-024-44945-5
  4. Nat Commun. 2024 Feb 05. 15(1): 1045
    G-quadruplexes promote the motility in MAZ phase-separated condensates to activate CCND1 expression and contribute to hepatocarcinogenesis.
    Wenmeng Wang, Dangdang Li, Qingqing Xu, Jiahui Cheng, Zhiwei Yu, Guangyue Li, Shiyao Qiao, Jiasong Pan, Hao Wang, Jinming Shi, Tongsen Zheng, Guangchao Sui.
      G-quadruplexes (G4s) can recruit transcription factors to activate gene expression, but detailed mechanisms remain enigmatic. Here, we demonstrate that G4s in the CCND1 promoter propel the motility in MAZ phase-separated condensates and subsequently activate CCND1 transcription. Zinc finger (ZF) 2 of MAZ is a responsible for G4 binding, while ZF3-5, but not a highly disordered region, is critical for MAZ condensation. MAZ nuclear puncta overlaps with signals of G4s and various coactivators including BRD4, MED1, CDK9 and active RNA polymerase II, as well as gene activation histone markers. MAZ mutants lacking either G4 binding or phase separation ability did not form nuclear puncta, and showed deficiencies in promoting hepatocellular carcinoma cell proliferation and xenograft tumor formation. Overall, we unveiled that G4s recruit MAZ to the CCND1 promoter and facilitate the motility in MAZ condensates that compartmentalize coactivators to activate CCND1 expression and subsequently exacerbate hepatocarcinogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-45353-5
  5. Elife. 2024 Feb 06. pii: e78866. [Epub ahead of print]13
    Nucleosome conformation dictates the histone code.
    Matthew R Marunde, Harrison A Fuchs, Jonathan M Burg, Irina K Popova, Anup Vaidya, Nathan W Hall, Ellen N Weinzapfel, Matthew J Meiners, Rachel Watson, Zachary B Gillespie, Hailey F Taylor, Laylo Mukhsinova, Ugochi C Onuoha, Sarah A Howard, Katherine Novitzky, Eileen T McAnarney, Krzysztof Krajewski, Martis W Cowles, Marcus A Cheek, Zu-Wen Sun, Bryan J Venters, Michael-C Keogh, Catherine A Musselman.
      Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized 'codes' that are read by specialized regions (reader domains) in chromatin associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP : histone PTM] specificities, and thus decipher the histone code and guide epigenetic therapies. However, this has largely been done using the reductive approach of isolated reader domains and histone peptides, which cannot account for any higher order factors. Here we show that the [BPTF PHD finger and bromodomain : histone PTM] interaction is dependent on nucleosome context. The tandem reader selectively associates with nucleosomal H3K4me3 and H3K14ac or H3K18ac, a combinatorial engagement that despite being in cis is not predicted by peptides. This in vitro specificity of the BPTF tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. We propose that regulatable histone tail accessibility and its impact on the binding potential of reader domains necessitates we refine the 'histone code' concept and interrogate it at the nucleosome level.
    Keywords:  chromosomes; gene expression; human; molecular biophysics; structural biology
    DOI:  https://doi.org/10.7554/eLife.78866
  6. JCI Insight. 2024 Feb 06. pii: e166611. [Epub ahead of print]
    Differential histone acetylation and super-enhancer regulation underlie melanoma cell dedifferentiation.
    Karen Mendelson, Tiphaine C Martin, Christie B Nguyen, Min Hsu, Jia Xu, Claudia Cv Lang, Reinhard Dummer, Yvonne Saenger, Jane L Messina, Vernon K Sondak, Garrett Desman, Dan Hasson, Emily Bernstein, Ramon E Parsons, Julide Tok Celebi.
      Dedifferentiation or phenotype switching refers to the transition from a proliferative to an invasive cellular state. We previously identified a 122-gene epigenetic gene signature that classifies primary melanomas as low- versus high-risk (denoted as Epgn1 or Epgn3). We found that the transcriptomes of the Epgn1 low-risk and Epgn3 high-risk cells are similar to the proliferative and invasive cellular states, respectively. These signatures were further validated in melanoma tumor samples. Examination of the chromatin landscape revealed differential H3K27 acetylation in the Epgn1 low-risk versus Epgn3 high-risk cell lines that corroborated with a differential super-enhancer and enhancer landscape. Melanocytic lineage genes (MITF, its targets and regulators) were associated with super-enhancers in the Epgn1 low-risk state whereas invasiveness genes were linked with Epgn3 high-risk status. We identified ITGA3 gene as marked by a super-enhancer element in the Epgn3 invasive cells. Silencing of ITGA3 enhanced invasiveness in both in vitro and in vivo systems suggesting it as a negative regulator of invasion. In conclusion, we define chromatin landscape changes associated with Epgn1/3 and phenotype switching during early steps of melanoma progression that regulate transcriptional reprogramming. This super-enhancer and enhancer-driven epigenetic regulatory mechanism resulting in major changes in the transcriptome could be important in future therapeutic targeting efforts.
    Keywords:  Dermatology; Melanoma
    DOI:  https://doi.org/10.1172/jci.insight.166611
  7. Biochem Soc Trans. 2024 Feb 08. pii: BST20230878. [Epub ahead of print]
    Cell-free genomics: transcription factor interactions in reconstituted naïve embryonic chromatin.
    Peter B Becker.
      Extracts from Drosophila preblastoderm embryos (DREX) form the basis of a powerful in vitro chromatin reconstitution system that assembles entire genomes into complex chromatin with physiological nucleosome spacing and polymer condensation. As the zygotic genome has not yet been activated in preblastoderm embryos, the reconstitution extract lacks endogenous transcription factors (TFs) and the RNA polymerase machinery. At the same time, it contains high levels of ATP-dependent nucleosome sliding enzymes that render the reconstituted chromatin dynamic. The naïve chromatin can be used to determine the intrinsic DNA binding properties of exogenous, usually recombinant TFs (or DNA binding proteins in general) in a complex chromatin context. Recent applications of the system include the description of cooperation and competition of Drosophila pioneer TFs for composite binding sites, and the characterization of nucleosome interactions of mammalian pioneer TFs in the heterologous system.
    Keywords:   Drosophila preblastoderm embryo; chromatin immunoprecipitation; nucleosome binding; nucleosome remodelling; pioneer transcription factor
    DOI:  https://doi.org/10.1042/BST20230878
  8. Nat Biotechnol. 2024 Feb 09.
    Simultaneous single-cell analysis of 5mC and 5hmC with SIMPLE-seq.
    Dongsheng Bai, Xiaoting Zhang, Huifen Xiang, Zijian Guo, Chenxu Zhu, Chengqi Yi.
      Dynamic 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications to DNA regulate gene expression in a cell-type-specific manner and are associated with various biological processes, but the two modalities have not yet been measured simultaneously from the same genome at the single-cell level. Here we present SIMPLE-seq, a scalable, base resolution method for joint analysis of 5mC and 5hmC from thousands of single cells. Based on orthogonal labeling and recording of 'C-to-T' mutational signals from 5mC and 5hmC sites, SIMPLE-seq detects these two modifications from the same molecules in single cells and enables unbiased DNA methylation dynamics analysis of heterogeneous biological samples. We applied this method to mouse embryonic stem cells, human peripheral blood mononuclear cells and mouse brain to give joint epigenome maps at single-cell and single-molecule resolution. Integrated analysis of these two cytosine modifications reveals distinct epigenetic patterns associated with divergent regulatory programs in different cell types as well as cell states.
    DOI:  https://doi.org/10.1038/s41587-024-02148-9
  9. Cell Genom. 2024 Jan 31. pii: S2666-979X(24)00028-4. [Epub ahead of print] 100501
    Integrative high-throughput enhancer surveying and functional verification divulges a YY2-condensed regulatory axis conferring risk for osteoporosis.
    Xiao-Feng Chen, Yuan-Yuan Duan, Ying-Ying Jia, Qian-Hua Dong, Wei Shi, Yan Zhang, Shan-Shan Dong, Meng Li, Zhongbo Liu, Fei Chen, Xiao-Ting Huang, Ruo-Han Hao, Dong-Li Zhu, Rui-Hua Jing, Yan Guo, Tie-Lin Yang.
      The precise roles of chromatin organization at osteoporosis risk loci remain largely elusive. Here, we combined chromatin interaction conformation (Hi-C) profiling and self-transcribing active regulatory region sequencing (STARR-seq) to qualify enhancer activities of prioritized osteoporosis-associated single-nucleotide polymorphisms (SNPs). We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) that linked to hundreds of candidate target genes through chromatin interactions across 146 loci. Functional characterizations revealed active epigenetic enrichment for baaSNPs and prevailing osteoporosis-relevant regulatory roles for their chromatin interaction genes. Further motif enrichment and network mapping prioritized several putative, key transcription factors (TFs) controlling osteoporosis binding to baaSNPs. Specifically, we selected one top-ranked TF and deciphered that an intronic baaSNP (rs11202530) could allele-preferentially bind to YY2 to augment PAPSS2 expression through chromatin interactions and promote osteoblast differentiation. Our results underline the roles of TF-mediated enhancer-promoter contacts for osteoporosis, which may help to better understand the intricate molecular regulatory mechanisms underlying osteoporosis risk loci.
    Keywords:  Hi-C; PAPSS2; STARR-seq; YY2; chromatin interaction; enhancer; genetic regulatory network; osteoblast differentiation; osteoporosis; transcription factor
    DOI:  https://doi.org/10.1016/j.xgen.2024.100501
  10. Nat Struct Mol Biol. 2024 Feb 05.
    Structural basis for RNA polymerase II ubiquitylation and inactivation in transcription-coupled repair.
    Goran Kokic, George Yakoub, Diana van den Heuvel, Annelotte P Wondergem, Paula J van der Meer, Yana van der Weegen, Aleksandar Chernev, Isaac Fianu, Thornton J Fokkens, Sonja Lorenz, Henning Urlaub, Patrick Cramer, Martijn S Luijsterburg.
      During transcription-coupled DNA repair (TCR), RNA polymerase II (Pol II) transitions from a transcriptionally active state to an arrested state that allows for removal of DNA lesions. This transition requires site-specific ubiquitylation of Pol II by the CRL4CSA ubiquitin ligase, a process that is facilitated by ELOF1 in an unknown way. Using cryogenic electron microscopy, biochemical assays and cell biology approaches, we found that ELOF1 serves as an adaptor to stably position UVSSA and CRL4CSA on arrested Pol II, leading to ligase neddylation and activation of Pol II ubiquitylation. In the presence of ELOF1, a transcription factor IIS (TFIIS)-like element in UVSSA gets ordered and extends through the Pol II pore, thus preventing reactivation of Pol II by TFIIS. Our results provide the structural basis for Pol II ubiquitylation and inactivation in TCR.
    DOI:  https://doi.org/10.1038/s41594-023-01207-0
  11. EMBO Rep. 2024 Feb 08.
    PRAMEL7 and CUL2 decrease NuRD stability to establish ground-state pluripotency.
    Meneka Rupasinghe, Cristiana Bersaglieri, Deena M Leslie Pedrioli, Patrick Ga Pedrioli, Martina Panatta, Michael O Hottiger, Paolo Cinelli, Raffaella Santoro.
      Pluripotency is established in E4.5 preimplantation epiblast. Embryonic stem cells (ESCs) represent the immortalization of pluripotency, however, their gene expression signature only partially resembles that of developmental ground-state. Induced PRAMEL7 expression, a protein highly expressed in the ICM but lowly expressed in ESCs, reprograms developmentally advanced ESC+serum into ground-state pluripotency by inducing a gene expression signature close to developmental ground-state. However, how PRAMEL7 reprograms gene expression remains elusive. Here we show that PRAMEL7 associates with Cullin2 (CUL2) and this interaction is required to establish ground-state gene expression. PRAMEL7 recruits CUL2 to chromatin and targets regulators of repressive chromatin, including the NuRD complex, for proteasomal degradation. PRAMEL7 antagonizes NuRD-mediated repression of genes implicated in pluripotency by decreasing NuRD stability and promoter association in a CUL2-dependent manner. Our data link proteasome degradation pathways to ground-state gene expression, offering insights to generate in vitro models to reproduce the in vivo ground-state pluripotency.
    Keywords:  Cullin 2; Ground-state Pluripotency; NuRD; PRAMEL7; UHRF1
    DOI:  https://doi.org/10.1038/s44319-024-00083-z
  12. Mol Cell. 2024 Jan 24. pii: S1097-2765(24)00008-X. [Epub ahead of print]
    IκBζ is a dual-use coactivator of NF-κB and POU transcription factors.
    Aktan Alpsoy, Xiaoli S Wu, Sujay Pal, Olaf Klingbeil, Pramod Kumar, Osama El Demerdash, Benan Nalbant, Christopher R Vakoc.
      OCA-B, OCA-T1, and OCA-T2 belong to a family of coactivators that bind to POU transcription factors (TFs) to regulate gene expression in immune cells. Here, we identify IκBζ (encoded by the NFKBIZ gene) as an additional coactivator of POU TFs. Although originally discovered as an inducible regulator of NF-κB, we show here that IκBζ shares a microhomology with OCA proteins and uses this segment to bind to POU TFs and octamer-motif-containing DNA. Our functional experiments suggest that IκBζ requires its interaction with POU TFs to coactivate immune-related genes. This finding is reinforced by epigenomic analysis of MYD88L265P-mutant lymphoma cells, which revealed colocalization of IκBζ with the POU TF OCT2 and NF-κB:p50 at hundreds of DNA elements harboring octamer and κB motifs. These results suggest that IκBζ is a transcriptional coactivator that can amplify and integrate the output of NF-κB and POU TFs at inducible genes in immune cells.
    Keywords:  IκBζ; NF-κB; NFKBIZ; OCA-B; OCT1; OCT2; POU2F1; POU2F2; p50
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.007
  13. Genome Biol. 2024 Feb 05. 25(1): 44
    The androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer.
    Leila Hosseinzadeh, Zoya Kikhtyak, Geraldine Laven-Law, Stephen M Pederson, Caroline G Puiu, Clive S D'Santos, Elgene Lim, Jason S Carroll, Wayne D Tilley, Amy R Dwyer, Theresa E Hickey.
       BACKGROUND: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employ an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease.
    RESULTS: The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer.
    CONCLUSIONS: AR and GATA3 interact to transcriptionally regulate luminal epithelial cell differentiation in breast cancer regardless of ER status. This interaction facilitates the tumor suppressor function of AR and mechanistically explains why AR expression is associated with less proliferative, more differentiated breast tumors and better overall survival in breast cancer.
    Keywords:  Androgen receptor; Breast; GATA3; Luminal lineage
    DOI:  https://doi.org/10.1186/s13059-023-03161-y
  14. EMBO J. 2024 Feb 08.
    Chromatin binding by HORMAD proteins regulates meiotic recombination initiation.
    Carolyn R Milano, Sarah N Ur, Yajie Gu, Jessie Zhang, Rachal Allison, George Brown, Matthew J Neale, Eelco C Tromer, Kevin D Corbett, Andreas Hochwagen.
      The meiotic chromosome axis coordinates chromosome organization and interhomolog recombination in meiotic prophase and is essential for fertility. In S. cerevisiae, the HORMAD protein Hop1 mediates the enrichment of axis proteins at nucleosome-rich islands through a central chromatin-binding region (CBR). Here, we use cryoelectron microscopy to show that the Hop1 CBR directly recognizes bent nucleosomal DNA through a composite interface in its PHD and winged helix-turn-helix domains. Targeted disruption of the Hop1 CBR-nucleosome interface causes a localized reduction of axis protein binding and meiotic DNA double-strand breaks (DSBs) in axis islands and leads to defects in chromosome synapsis. Synthetic effects with mutants of the Hop1 regulator Pch2 suggest that nucleosome binding delays a conformational switch in Hop1 from a DSB-promoting, Pch2-inaccessible state to a DSB-inactive, Pch2-accessible state to regulate the extent of meiotic DSB formation. Phylogenetic analyses of meiotic HORMADs reveal an ancient origin of the CBR, suggesting that the mechanisms we uncover are broadly conserved.
    Keywords:  Budding Yeast; Chromatin; Chromosome Segregation; HORMA; Meiosis
    DOI:  https://doi.org/10.1038/s44318-024-00034-3
  15. Nature. 2024 Feb 07.
    The nuclear factor ID3 endows macrophages with a potent anti-tumour activity.
    Zihou Deng, Pierre-Louis Loyher, Tomi Lazarov, Li Li, Zeyang Shen, Bhavneet Bhinder, Hairu Yang, Yi Zhong, Araitz Alberdi, Joan Massague, Joseph C Sun, Robert Benezra, Christopher K Glass, Olivier Elemento, Christine A Iacobuzio-Donahue, Frederic Geissmann.
      Macrophage activation is controlled by a balance between activating and inhibitory receptors1-7, which protect normal tissues from excessive damage during infection8,9 but promote tumour growth and metastasis in cancer7,10. Here we report that the Kupffer cell lineage-determining factor ID3 controls this balance and selectively endows Kupffer cells with the ability to phagocytose live tumour cells and orchestrate the recruitment, proliferation and activation of natural killer and CD8 T lymphoid effector cells in the liver to restrict the growth of a variety of tumours. ID3 shifts the macrophage inhibitory/activating receptor balance to promote the phagocytic and lymphoid response, at least in part by buffering the binding of the transcription factors ELK1 and E2A at the SIRPA locus. Furthermore, loss- and gain-of-function experiments demonstrate that ID3 is sufficient to confer this potent anti-tumour activity to mouse bone-marrow-derived macrophages and human induced pluripotent stem-cell-derived macrophages. Expression of ID3 is therefore necessary and sufficient to endow macrophages with the ability to form an efficient anti-tumour niche, which could be harnessed for cell therapy in cancer.
    DOI:  https://doi.org/10.1038/s41586-023-06950-4
  16. Proc Natl Acad Sci U S A. 2024 Feb 13. 121(7): e2310430121
    Phase separation of YAP-MAML2 differentially regulates the transcriptome.
    Chan-I Chung, Junjiao Yang, Xiaoyu Yang, Hongjiang Liu, Zhimin Ma, Frank Szulzewsky, Eric C Holland, Yin Shen, Xiaokun Shu.
      Phase separation (PS) drives the formation of biomolecular condensates that are emerging biological structures involved in diverse cellular processes. Recent studies have unveiled PS-induced formation of several transcriptional factor (TF) condensates that are transcriptionally active, but how strongly PS promotes gene activation remains unclear. Here, we show that the oncogenic TF fusion Yes-associated protein 1-Mastermind like transcriptional coactivator 2 (YAP-MAML2) undergoes PS and forms liquid-like condensates that bear the hallmarks of transcriptional activity. Furthermore, we examined the contribution of PS to YAP-MAML2-mediated gene expression by developing a chemogenetic tool that dissolves TF condensates, allowing us to compare phase-separated and non-phase-separated conditions at identical YAP-MAML2 protein levels. We found that a small fraction of YAP-MAML2-regulated genes is further affected by PS, which include the canonical YAP target genes CTGF and CYR61, and other oncogenes. On the other hand, majority of YAP-MAML2-regulated genes are not affected by PS, highlighting that transcription can be activated effectively by diffuse complexes of TFs with the transcriptional machinery. Our work opens new directions in understanding the role of PS in selective modulation of gene expression, suggesting differential roles of PS in biological processes.
    DOI:  https://doi.org/10.1073/pnas.2310430121
  17. Genes Dev. 2024 Feb 05.
    DNA damage remodels the MITF interactome to increase melanoma genomic instability.
    Romuald Binet, Jean-Philippe Lambert, Marketa Tomkova, Samuel Tischfield, Arianna Baggiolini, Sarah Picaud, Sovan Sarkar, Pakavarin Louphrasitthiphol, Diogo Dias, Suzanne Carreira, Timothy C Humphrey, Panagis Fillipakopoulos, Richard White, Colin R Goding.
      Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA damage response (DDR) programs. However, some cells (for example, in skin) are normally exposed to high levels of DNA-damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown. Using melanoma as a model, we show here that the microphthalmia-associated transcription factor MITF, a lineage addition oncogene that coordinates many aspects of melanocyte and melanoma biology, plays a nontranscriptional role in shaping the DDR. On exposure to DNA-damaging agents, MITF is phosphorylated at S325, and its interactome is dramatically remodeled; most transcription cofactors dissociate, and instead MITF interacts with the MRE11-RAD50-NBS1 (MRN) complex. Consequently, cells with high MITF levels accumulate stalled replication forks and display defects in homologous recombination-mediated repair associated with impaired MRN recruitment to DNA damage. In agreement with this, high MITF levels are associated with increased single-nucleotide and copy number variant burdens in melanoma. Significantly, the SUMOylation-defective MITF-E318K melanoma predisposition mutation recapitulates the effects of DNA-PKcs-phosphorylated MITF. Our data suggest that a nontranscriptional function of a lineage-restricted transcription factor contributes to a tissue-specialized modulation of the DDR that can impact cancer initiation.
    Keywords:  DNA damage repair; DNA replication; E318K; MITF; NBS1; SUMOylation; homologous recombination; melanoma; replication stress
    DOI:  https://doi.org/10.1101/gad.350740.123
  18. Sci Adv. 2024 Feb 09. 10(6): eadk2285
    Atypical inflammatory kinase IKBKE phosphorylates and inactivates FoxA1 to promote liver tumorigenesis.
    Bing Gao, Xueji Wu, Lang Bu, Qiwei Jiang, Lei Wang, Haining Liu, Xiaomei Zhang, Yuanzhong Wu, Xiaoxing Li, Jingting Li, Ying Liang, Lixia Xu, Wei Xie, Jianping Guo.
      Physiologically, FoxA1 plays a key role in liver differentiation and development, and pathologically exhibits an oncogenic role in prostate and breast cancers. However, its role and upstream regulation in liver tumorigenesis remain unclear. Here, we demonstrate that FoxA1 acts as a tumor suppressor in liver cancer. Using a CRISPR-based kinome screening approach, noncanonical inflammatory kinase IKBKE has been identified to inhibit FoxA1 transcriptional activity. Notably, IKBKE directly binds to and phosphorylates FoxA1 to reduce its complex formation and DNA interaction, leading to elevated hepatocellular malignancies. Nonphosphorylated mimic Foxa1 knock-in mice markedly delay liver tumorigenesis in hydrodynamic transfection murine models, while phospho-mimic Foxa1 knock-in phenocopy Foxa1 knockout mice to exhibit developmental defects and liver inflammation. Notably, Ikbke knockout delays diethylnitrosamine (DEN)-induced mouse liver tumor development. Together, our findings not only reveal FoxA1 as a bona fide substrate and negative nuclear effector of IKBKE in hepatocellular carcinioma (HCC) but also provide a promising strategy to target IKBEK for HCC therapy.
    DOI:  https://doi.org/10.1126/sciadv.adk2285
  19. Nat Commun. 2024 Feb 05. 15(1): 897
    Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes.
    Carlos Company, Matthias Jürgen Schmitt, Yuliia Dramaretska, Michela Serresi, Sonia Kertalli, Ben Jiang, Jiang-An Yin, Adriano Aguzzi, Iros Barozzi, Gaetano Gargiulo.
      Descriptive data are rapidly expanding in biomedical research. Instead, functional validation methods with sufficient complexity remain underdeveloped. Transcriptional reporters allow experimental characterization and manipulation of developmental and disease cell states, but their design lacks flexibility. Here, we report logical design of synthetic cis-regulatory DNA (LSD), a computational framework leveraging phenotypic biomarkers and trans-regulatory networks as input to design reporters marking the activity of selected cellular states and pathways. LSD uses bulk or single-cell biomarkers and a reference genome or custom cis-regulatory DNA datasets with user-defined boundary regions. By benchmarking validated reporters, we integrate LSD with a computational ranking of phenotypic specificity of putative cis-regulatory DNA. Experimentally, LSD-designed reporters targeting a wide range of cell states are functional without minimal promoters. Applied to broadly expressed genes from human and mouse tissues, LSD generates functional housekeeper-like sLCRs compatible with size constraints of AAV vectors for gene therapy applications. A mesenchymal glioblastoma reporter designed by LSD outperforms previously validated ones and canonical cell surface markers. In genome-scale CRISPRa screens, LSD facilitates the discovery of known and novel bona fide cell-state drivers. Thus, LSD captures core principles of cis-regulation and is broadly applicable to studying complex cell states and mechanisms of transcriptional regulation.
    DOI:  https://doi.org/10.1038/s41467-024-45069-6
  20. Cell Discov. 2024 Feb 08. 10(1): 15
    Structural insights into histone exchange by human SRCAP complex.
    Jiali Yu, Fengrui Sui, Feng Gu, Wanjun Li, Zishuo Yu, Qianmin Wang, Shuang He, Li Wang, Yanhui Xu.
      Histone variant H2A.Z is found at promoters and regulates transcription. The ATP-dependent chromatin remodeler SRCAP complex (SRCAP-C) promotes the replacement of canonical histone H2A-H2B dimer with H2A.Z-H2B dimer. Here, we determined structures of human SRCAP-C bound to H2A-containing nucleosome at near-atomic resolution. The SRCAP subunit integrates a 6-subunit actin-related protein (ARP) module and an ATPase-containing motor module. The ATPase-associated ARP module encircles half of the nucleosome along the DNA and may restrain net DNA translocation, a unique feature of SRCAP-C. The motor module adopts distinct nucleosome binding modes in the apo (nucleotide-free), ADP-bound, and ADP-BeFx-bound states, suggesting that ATPase-driven movement destabilizes H2A-H2B by unwrapping the entry DNA and pulls H2A-H2B out of nucleosome through the ZNHIT1 subunit. Structure-guided chromatin immunoprecipitation sequencing analysis confirmed the requirement of H2A-contacting ZNHIT1 in maintaining H2A.Z occupancy on the genome. Our study provides structural insights into the mechanism of H2A-H2A.Z exchange mediated by SRCAP-C.
    DOI:  https://doi.org/10.1038/s41421-023-00640-1
  21. Dev Cell. 2024 Jan 31. pii: S1534-5807(24)00032-7. [Epub ahead of print]
    Maternal KLF17 controls zygotic genome activation by acting as a messenger for RNA Pol II recruitment in mouse embryos.
    Yue Hu, Yuxiang Wang, Yuanlin He, Maosheng Ye, Jie Yuan, Chao Ren, Xia Wang, Siqi Wang, Yueshuai Guo, Qiqi Cao, Shuai Zhou, Bing Wang, Anlan He, Jiongsong Hu, Xuejiang Guo, Wenjie Shu, Ran Huo.
      Initiation of timely and sufficient zygotic genome activation (ZGA) is crucial for the beginning of life, yet our knowledge of transcription factors (TFs) contributing to ZGA remains limited. Here, we screened the proteome of early mouse embryos after cycloheximide (CHX) treatment and identified maternally derived KLF17 as a potential TF for ZGA genes. Using a conditional knockout (cKO) mouse model, we further investigated the role of maternal KLF17 and found that it promotes embryonic development and full fertility. Mechanistically, KLF17 preferentially binds to promoters and recruits RNA polymerase II (RNA Pol II) in early 2-cell embryos, facilitating the expression of major ZGA genes. Maternal Klf17 knockout resulted in a downregulation of 9% of ZGA genes and aberrant RNA Pol II pre-configuration, which could be partially rescued by introducing exogenous KLF17. Overall, our study provides a strategy for screening essential ZGA factors and identifies KLF17 as a crucial TF in this process.
    Keywords:  KLF17; RNA Pol II pre-configuration; early embryonic development; maternal transcription factor; zygotic genome activation
    DOI:  https://doi.org/10.1016/j.devcel.2024.01.013
  22. Nat Commun. 2024 Feb 03. 15(1): 1038
    ANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation.
    Luigi Mazzeo, Soumitra Ghosh, Emery Di Cicco, Jovan Isma, Daniele Tavernari, Anastasia Samarkina, Paola Ostano, Markus K Youssef, Christian Simon, G Paolo Dotto.
      There are significant commonalities among several pathologies involving fibroblasts, ranging from auto-immune diseases to fibrosis and cancer. Early steps in cancer development and progression are closely linked to fibroblast senescence and transformation into tumor-promoting cancer-associated fibroblasts (CAFs), suppressed by the androgen receptor (AR). Here, we identify ANKRD1 as a mesenchymal-specific transcriptional coregulator under direct AR negative control in human dermal fibroblasts (HDFs) and a key driver of CAF conversion, independent of cellular senescence. ANKRD1 expression in CAFs is associated with poor survival in HNSCC, lung, and cervical SCC patients, and controls a specific gene expression program of myofibroblast CAFs (my-CAFs). ANKRD1 binds to the regulatory region of my-CAF effector genes in concert with AP-1 transcription factors, and promotes c-JUN and FOS association. Targeting ANKRD1 disrupts AP-1 complex formation, reverses CAF activation, and blocks the pro-tumorigenic properties of CAFs in an orthotopic skin cancer model. ANKRD1 thus represents a target for fibroblast-directed therapy in cancer and potentially beyond.
    DOI:  https://doi.org/10.1038/s41467-024-45308-w
  23. Plant Cell. 2024 Feb 03. pii: koae034. [Epub ahead of print]
    Linker histone H1 drives heterochromatin condensation via phase separation in Arabidopsis.
    Shengbo He, Yiming Yu, Liang Wang, Jingyi Zhang, Zhengyong Bai, Guohong Li, Pilong Li, Xiaoqi Feng.
      In the eukaryotic nucleus, heterochromatin forms highly condensed, visible foci known as heterochromatin foci (HF). These HF are enriched with linker histone H1, a key player in heterochromatin condensation and silencing. However, it is unknown how H1 aggregates HF and condenses heterochromatin. In this study, we established that H1 facilitates heterochromatin condensation by enhancing inter- and intra-chromosomal interactions between and within heterochromatic regions of the Arabidopsis (Arabidopsis thaliana) genome. We demonstrated that H1 drives HF formation via phase separation, which requires its C-terminal intrinsically disordered region (C-IDR). A truncated H1 lacking the C-IDR fails to form foci or recover HF in the h1 mutant background, whereas C-IDR with a short stretch of the globular domain (18 out of 71 amino acids) is sufficient to rescue both defects. In addition, C-IDR is essential for H1's roles in regulating nucleosome repeat length and DNA methylation in Arabidopsis, indicating that phase separation capability is required for chromatin functions of H1. Our data suggest that bacterial H1-like proteins, which have been shown to condense DNA, are intrinsically disordered and capable of mediating phase separation. Therefore, we propose that phase separation mediated by H1 or H1-like proteins may represent an ancient mechanism for condensing chromatin and DNA.
    DOI:  https://doi.org/10.1093/plcell/koae034
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