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Rao D, Li D, Li L, Xue J, Tu S, Shen EZ. Argonaute CSR-1A promotes H3K9me3 maintenance to protect somatic development in offspring. Nucleic Acids Res 2025; 53:gkaf127. [PMID: 40036504 PMCID: PMC11878544 DOI: 10.1093/nar/gkaf127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 01/14/2025] [Accepted: 02/10/2025] [Indexed: 03/06/2025] Open
Abstract
Parental stress can be encoded into altered epigenetic information to influence their offspring. Concurrently, it is vital for the preservation of a parent's epigenetic information, despite environmental challenges, to ensure accurate inheritance by the next generation. Nevertheless, the complexities of this process and the specific molecular mechanisms involved are not yet fully understood. Here we report that Argonaute CSR-1A potentiates the recovery of histone H3 lysine 9 trimethylation (H3K9me3) in spermatocyte to secure the developmental competence of male offspring. CSR-1A employs its repetitive RG motif to engage with putative histone 3 lysine 9 (H3K9) methyltransferases SET-25 and -32, and helps to restore repressive H3K9me3 chromatin marks following heat-stress, protecting the late development of somatic cells in the progeny. Finally, among the genes regulated by CSR-1A, we identified dim-1, at which decreased H3K9me3 persists in the progeny, and RNAi of dim-1 mitigates the somatic defects associated with csr-1a loss under stress. Thus, CSR-1A coordinates a paternal epigenetic program that shields development from the influences of the paternal environment. We speculate that, driven by both natural environmental stressors and the unique characteristics of spermatogenic chromatin, the emergence of multiple RG motif-featured and spermatogenesis-specific CSR-1A and small RNA serves as a protective strategy to safeguard against variability in the orchestration of inherited developmental programs from the paternal lineage.
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Affiliation(s)
- Di Rao
- Fudan University, Shanghai, China
- Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Dengfeng Li
- Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Lili Li
- Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Junchao Xue
- Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Shikui Tu
- Department of Computer Science and Engineering, Center for Cognitive Machines and Computational Health (CMaCH), Shanghai Jiao Tong University, Shanghai, China
| | - En-Zhi Shen
- Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
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2
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Bulgakov VP. Chromatin modifications and memory in regulation of stress-related polyphenols: finding new ways to control flavonoid biosynthesis. Crit Rev Biotechnol 2024; 44:1478-1494. [PMID: 38697923 DOI: 10.1080/07388551.2024.2336529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 03/10/2024] [Accepted: 03/18/2024] [Indexed: 05/05/2024]
Abstract
The influence of epigenetic factors on plant defense responses and the balance between growth and defense is becoming a central area in plant biology. It is believed that the biosynthesis of secondary metabolites can be regulated by epigenetic factors, but this is not associated with the formation of a "memory" to the previous biosynthetic status. This review shows that some epigenetic effects can result in epigenetic memory, which opens up new areas of research in secondary metabolites, in particular flavonoids. Plant-controlled chromatin modifications can lead to the generation of stress memory, a phenomenon through which information regarding past stress cues is retained, resulting in a modified response to recurring stress. How deeply are the mechanisms of chromatin modification and memory generation involved in the control of flavonoid biosynthesis? This article collects available information from the literature and interactome databases to address this issue. Visualization of the interaction of chromatin-modifying proteins with the flavonoid biosynthetic machinery is presented. Chromatin modifiers and "bookmarks" that may be involved in the regulation of flavonoid biosynthesis through memory have been identified. Through different mechanisms of chromatin modification, plants can harmonize flavonoid metabolism with: stress responses, developmental programs, light-dependent processes, flowering, and longevity programs. The available information points to the possibility of developing chromatin-modifying technologies to control flavonoid biosynthesis.
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Affiliation(s)
- Victor P Bulgakov
- Federal Scientific Center of the East Asia Terrestrial Biodiversity, Far Eastern Branch of the Russian Academy of Sciences, Vladivostok, Russia
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3
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Zhang T, Liu S, Durojaye O, Xiong F, Fang Z, Ullah T, Fu C, Sun B, Jiang H, Xia P, Wang Z, Yao X, Liu X. Dynamic phosphorylation of FOXA1 by Aurora B guides post-mitotic gene reactivation. Cell Rep 2024; 43:114739. [PMID: 39276350 DOI: 10.1016/j.celrep.2024.114739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 06/10/2024] [Accepted: 08/23/2024] [Indexed: 09/17/2024] Open
Abstract
FOXA1 serves as a crucial pioneer transcription factor during developmental processes and plays a pivotal role as a mitotic bookmarking factor to perpetuate gene expression profiles and maintain cellular identity. During mitosis, the majority of FOXA1 dissociates from specific DNA binding sites and redistributes to non-specific binding sites; however, the regulatory mechanisms governing molecular dynamics and activity of FOXA1 remain elusive. Here, we show that mitotic kinase Aurora B specifies the different DNA binding modes of FOXA1 and guides FOXA1 biomolecular condensation in mitosis. Mechanistically, Aurora B kinase phosphorylates FOXA1 at Serine 221 (S221) to liberate the specific, but not the non-specific, DNA binding. Interestingly, the phosphorylation of S221 attenuates the FOXA1 condensation that requires specific DNA binding. Importantly, perturbation of the dynamic phosphorylation impairs accurate gene reactivation and cell proliferation, suggesting that reversible mitotic protein phosphorylation emerges as a fundamental mechanism for the spatiotemporal control of mitotic bookmarking.
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Affiliation(s)
- Ting Zhang
- MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China
| | - Shuaiyu Liu
- MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230027, China
| | - Olanrewaju Durojaye
- MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China
| | - Fangyuan Xiong
- MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230027, China
| | - Zhiyou Fang
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230027, China
| | - Tahir Ullah
- MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China
| | - Chuanhai Fu
- MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230027, China
| | - Bo Sun
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Hao Jiang
- West China Hospital, Sichuan University, Chengdu 610041, China
| | - Peng Xia
- MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Institute of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Zhikai Wang
- MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230027, China.
| | - Xuebiao Yao
- MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230027, China.
| | - Xing Liu
- MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230027, China.
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4
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Tang R, Zhou M, Chen Y, Jiang Z, Fan X, Zhang J, Dong A, Lv L, Mao S, Chen F, Gao G, Min J, Liu K, Yuan K. H3K14ac facilitates the reinstallation of constitutive heterochromatin in Drosophila early embryos by engaging Eggless/SetDB1. Proc Natl Acad Sci U S A 2024; 121:e2321859121. [PMID: 39437264 PMCID: PMC11331121 DOI: 10.1073/pnas.2321859121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 06/24/2024] [Indexed: 10/25/2024] Open
Abstract
Constitutive heterochromatin, a fundamental feature of eukaryotic nucleus essential for transposon silencing and genome stability, is rebuilt on various types of repetitive DNA in the zygotic genome during early embryogenesis. However, the molecular program underlying this process remains poorly understood. Here, we show that histone H3 lysine 14 acetylation (H3K14ac) is engaged in the reinstallation of constitutive heterochromatin in Drosophila early embryos. H3K14ac partially colocalizes with H3 lysine 9 trimethylation (H3K9me3) and its methyltransferase Eggless/SetDB1 around the mid-blastula transition. Concealing H3K14ac by either antibody injection or maternal knockdown of Gcn5 diminishes Eggless/SetDB1 nuclear foci and reduces the deposition of H3K9me3. Structural analysis reveals that Eggless/SetDB1 recognizes H3K14ac via its tandem Tudor domains, and disrupting the binding interface causes defects in Eggless/SetDB1 distribution and derepression of a subset of transposons. Therefore, H3K14ac, a histone modification normally associated with active transcription, is a crucial component of the early embryonic machinery that introduces constitutive heterochromatic features to the newly formed zygotic genome.
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Affiliation(s)
- Ruijun Tang
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Mengqi Zhou
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei, China
| | - Yuwei Chen
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Zhenghui Jiang
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
- Yichun Maternal and Child Health Care Hospital, Yichun, Jiangxi, China
| | - Xunan Fan
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Jingheng Zhang
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Aiping Dong
- Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada
| | - Lu Lv
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Song Mao
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Fang Chen
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Guanjun Gao
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Jinrong Min
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei, China
| | - Ke Liu
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei, China
| | - Kai Yuan
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Furong Laboratory, Hunan, China
- The Biobank of Xiangya Hospital, Central South University, Changsha, Hunan, China
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5
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Bharti H, Han S, Chang HW, Reinberg D. Polycomb repressive complex 2 accessory factors: rheostats for cell fate decision? Curr Opin Genet Dev 2024; 84:102137. [PMID: 38091876 DOI: 10.1016/j.gde.2023.102137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 11/15/2023] [Indexed: 02/12/2024]
Abstract
Epigenetic reprogramming during development is key to cell identity and the activities of the Polycomb repressive complexes are vital for this process. We focus on polycomb repressive complex 2 (PRC2), which catalyzes H3K27me1/2/3 and safeguards cellular integrity by ensuring proper gene repression. Notably, various accessory factors associate with PRC2, strongly influencing cell fate decisions, and their deregulation contributes to various illnesses. Yet, the exact role of these factors during development and carcinogenesis is not fully understood. Here, we present recent progress toward addressing these points and an analysis of the expression levels of PRC2 accessory factors in various tissues and developmental stages to highlight their abundance and roles. Last, we evaluate their contribution to cancer-specific phenotypes, providing insight into novel anticancer therapies.
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Affiliation(s)
- Hina Bharti
- Howard Hughes Medical Institute, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
| | - Sungwook Han
- Howard Hughes Medical Institute, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
| | - Han-Wen Chang
- Howard Hughes Medical Institute, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
| | - Danny Reinberg
- Howard Hughes Medical Institute, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
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6
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Singh A, Chakrabarti S. Diffusion controls local versus dispersed inheritance of histones during replication and shapes epigenomic architecture. PLoS Comput Biol 2023; 19:e1011725. [PMID: 38109423 PMCID: PMC10760866 DOI: 10.1371/journal.pcbi.1011725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 01/02/2024] [Accepted: 12/01/2023] [Indexed: 12/20/2023] Open
Abstract
The dynamics of inheritance of histones and their associated modifications across cell divisions can have major consequences on maintenance of the cellular epigenomic state. Recent experiments contradict the long-held notion that histone inheritance during replication is always local, suggesting that active and repressed regions of the genome exhibit fundamentally different histone dynamics independent of transcription-coupled turnover. Here we develop a stochastic model of histone dynamics at the replication fork and demonstrate that differential diffusivity of histones in active versus repressed chromatin is sufficient to quantitatively explain these recent experiments. Further, we use the model to predict patterns in histone mark similarity between pairs of genomic loci that should be developed as a result of diffusion, but cannot originate from either PRC2 mediated mark spreading or transcriptional processes. Interestingly, using a combination of CHIP-seq, replication timing and Hi-C datasets we demonstrate that all the computationally predicted patterns are consistently observed for both active and repressive histone marks in two different cell lines. While direct evidence for histone diffusion remains controversial, our results suggest that dislodged histones in euchromatin and facultative heterochromatin may exhibit some level of diffusion within "Diffusion-Accessible-Domains" (DADs), leading to redistribution of epigenetic marks within and across chromosomes. Preservation of the epigenomic state across cell divisions therefore might be achieved not by passing on strict positional information of histone marks, but by maintaining the marks in somewhat larger DADs of the genome.
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Affiliation(s)
- Archit Singh
- Simons Centre for the Study of Living Machines, National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
| | - Shaon Chakrabarti
- Simons Centre for the Study of Living Machines, National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
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7
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Wang X, Tang Y, Xu J, Leng H, Shi G, Hu Z, Wu J, Xiu Y, Feng J, Li Q. The N-terminus of Spt16 anchors FACT to MCM2-7 for parental histone recycling. Nucleic Acids Res 2023; 51:11549-11567. [PMID: 37850662 PMCID: PMC10681723 DOI: 10.1093/nar/gkad846] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 09/19/2023] [Accepted: 09/25/2023] [Indexed: 10/19/2023] Open
Abstract
Parental histone recycling is vital for maintaining chromatin-based epigenetic information during replication, yet its underlying mechanisms remain unclear. Here, we uncover an unexpected role of histone chaperone FACT and its N-terminus of the Spt16 subunit during parental histone recycling and transfer in budding yeast. Depletion of Spt16 and mutations at its middle domain that impair histone binding compromise parental histone recycling on both the leading and lagging strands of DNA replication forks. Intriguingly, deletion of the Spt16-N domain impairs parental histone recycling, with a more pronounced defect observed on the lagging strand. Mechanistically, the Spt16-N domain interacts with the replicative helicase MCM2-7 and facilitates the formation of a ternary complex involving FACT, histone H3/H4 and Mcm2 histone binding domain, critical for the recycling and transfer of parental histones to lagging strands. Lack of the Spt16-N domain weakens the FACT-MCM interaction and reduces parental histone recycling. We propose that the Spt16-N domain acts as a protein-protein interaction module, enabling FACT to function as a shuttle chaperone in collaboration with Mcm2 and potentially other replisome components for efficient local parental histone recycling and inheritance.
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Affiliation(s)
- Xuezheng Wang
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Yuantao Tang
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Jiawei Xu
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
| | - He Leng
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Guojun Shi
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Zaifeng Hu
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Jiale Wu
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Yuwen Xiu
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Jianxun Feng
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Qing Li
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
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8
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Paniagua I, Jacobs JJL. Freedom to err: The expanding cellular functions of translesion DNA polymerases. Mol Cell 2023; 83:3608-3621. [PMID: 37625405 DOI: 10.1016/j.molcel.2023.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/02/2023] [Accepted: 07/07/2023] [Indexed: 08/27/2023]
Abstract
Translesion synthesis (TLS) DNA polymerases were originally described as error-prone enzymes involved in the bypass of DNA lesions. However, extensive research over the past few decades has revealed that these enzymes play pivotal roles not only in lesion bypass, but also in a myriad of other cellular processes. Such processes include DNA replication, DNA repair, epigenetics, immune signaling, and even viral infection. This review discusses the wide range of functions exhibited by TLS polymerases, including their underlying biochemical mechanisms and associated mutagenicity. Given their multitasking ability to alleviate replication stress, TLS polymerases represent a cellular dependency and a critical vulnerability of cancer cells. Hence, this review also highlights current and emerging strategies for targeting TLS polymerases in cancer therapy.
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Affiliation(s)
- Inés Paniagua
- Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands
| | - Jacqueline J L Jacobs
- Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
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9
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Djeghloul D, Dimond A, Cheriyamkunnel S, Kramer H, Patel B, Brown K, Montoya A, Whilding C, Wang YF, Futschik ME, Veland N, Montavon T, Jenuwein T, Merkenschlager M, Fisher AG. Loss of H3K9 trimethylation alters chromosome compaction and transcription factor retention during mitosis. Nat Struct Mol Biol 2023; 30:489-501. [PMID: 36941433 PMCID: PMC10113154 DOI: 10.1038/s41594-023-00943-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 02/13/2023] [Indexed: 03/23/2023]
Abstract
Recent studies have shown that repressive chromatin machinery, including DNA methyltransferases and polycomb repressor complexes, binds to chromosomes throughout mitosis and their depletion results in increased chromosome size. In the present study, we show that enzymes that catalyze H3K9 methylation, such as Suv39h1, Suv39h2, G9a and Glp, are also retained on mitotic chromosomes. Surprisingly, however, mutants lacking histone 3 lysine 9 trimethylation (H3K9me3) have unusually small and compact mitotic chromosomes associated with increased histone H3 phospho Ser10 (H3S10ph) and H3K27me3 levels. Chromosome size and centromere compaction in these mutants were rescued by providing exogenous first protein lysine methyltransferase Suv39h1 or inhibiting Ezh2 activity. Quantitative proteomic comparisons of native mitotic chromosomes isolated from wild-type versus Suv39h1/Suv39h2 double-null mouse embryonic stem cells revealed that H3K9me3 was essential for the efficient retention of bookmarking factors such as Esrrb. These results highlight an unexpected role for repressive heterochromatin domains in preserving transcription factor binding through mitosis and underscore the importance of H3K9me3 for sustaining chromosome architecture and epigenetic memory during cell division.
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Affiliation(s)
- Dounia Djeghloul
- Epigenetic Memory Group, MRC London Institute of Medical Sciences, Imperial College London, London, UK.
| | - Andrew Dimond
- Epigenetic Memory Group, MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Sherry Cheriyamkunnel
- Epigenetic Memory Group, MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Holger Kramer
- Biological Mass Spectrometry and Proteomics Facility, MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Bhavik Patel
- Flow Cytometry Facility, MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Karen Brown
- Epigenetic Memory Group, MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Alex Montoya
- Biological Mass Spectrometry and Proteomics Facility, MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Chad Whilding
- Microscopy Facility, MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Yi-Fang Wang
- Bioinformatics, MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Matthias E Futschik
- Bioinformatics, MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Nicolas Veland
- Epigenetic Memory Group, MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Thomas Montavon
- Max-Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Thomas Jenuwein
- Max-Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Matthias Merkenschlager
- Lymphocyte Development Group, MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Amanda G Fisher
- Epigenetic Memory Group, MRC London Institute of Medical Sciences, Imperial College London, London, UK.
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10
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Abstract
BACKGROUND Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies. AIMS Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential. METHODS English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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11
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Ribas-Aulinas F, Ribo S, Casas E, Mourin-Fernandez M, Ramon-Krauel M, Diaz R, Lerin C, Kalko SG, Vavouri T, Jimenez-Chillaron JC. Intergenerational Inheritance of Hepatic Steatosis in a Mouse Model of Childhood Obesity: Potential Involvement of Germ-Line microRNAs. Nutrients 2023; 15:nu15051241. [PMID: 36904241 PMCID: PMC10005268 DOI: 10.3390/nu15051241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/23/2023] [Accepted: 02/27/2023] [Indexed: 03/05/2023] Open
Abstract
Childhood obesity increases the risk of developing metabolic syndrome later in life. Moreover, metabolic dysfunction may be inherited into the following generation through non-genomic mechanisms, with epigenetics as a plausible candidate. The pathways involved in the development of metabolic dysfunction across generations in the context of childhood obesity remain largely unexplored. We have developed a mouse model of early adiposity by reducing litter size at birth (small litter group, SL: 4 pups/dam; control group, C: 8 pups/dam). Mice raised in small litters (SL) developed obesity, insulin resistance and hepatic steatosis with aging. Strikingly, the offspring of SL males (SL-F1) also developed hepatic steatosis. Paternal transmission of an environmentally induced phenotype strongly suggests epigenetic inheritance. We analyzed the hepatic transcriptome in C-F1 and SL-F1 mice to identify pathways involved in the development of hepatic steatosis. We found that the circadian rhythm and lipid metabolic process were the ontologies with highest significance in the liver of SL-F1 mice. We explored whether DNA methylation and small non-coding RNAs might be involved in mediating intergenerational effects. Sperm DNA methylation was largely altered in SL mice. However, these changes did not correlate with the hepatic transcriptome. Next, we analyzed small non-coding RNA content in the testes of mice from the parental generation. Two miRNAs (miR-457 and miR-201) appeared differentially expressed in the testes of SL-F0 mice. They are known to be expressed in mature spermatozoa, but not in oocytes nor early embryos, and they may regulate the transcription of lipogenic genes, but not clock genes, in hepatocytes. Hence, they are strong candidates to mediate the inheritance of adult hepatic steatosis in our murine model. In conclusion, litter size reduction leads to intergenerational effects through non-genomic mechanisms. In our model, DNA methylation does not seem to play a role on the circadian rhythm nor lipid genes. However, at least two paternal miRNAs might influence the expression of a few lipid-related genes in the first-generation offspring, F1.
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Affiliation(s)
| | - Sílvia Ribo
- Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues, 08950 Barcelona, Spain
| | - Eduard Casas
- Josep Carreras Leukemia Research Institute (IJC), 08916 Badalona, Spain
| | | | - Marta Ramon-Krauel
- Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues, 08950 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ruben Diaz
- Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues, 08950 Barcelona, Spain
| | - Carles Lerin
- Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues, 08950 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Susana G. Kalko
- Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain
| | - Tanya Vavouri
- Josep Carreras Leukemia Research Institute (IJC), 08916 Badalona, Spain
| | - Josep C. Jimenez-Chillaron
- Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues, 08950 Barcelona, Spain
- School of Medicine, University of Barcelona, L’Hospitalet, 08907 Barcelona, Spain
- Correspondence: or ; Tel.: +34-934024267
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12
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Nguyen NH, Vu NT, Cheong JJ. Transcriptional Stress Memory and Transgenerational Inheritance of Drought Tolerance in Plants. Int J Mol Sci 2022; 23:12918. [PMID: 36361708 PMCID: PMC9654142 DOI: 10.3390/ijms232112918] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/19/2022] [Accepted: 10/25/2022] [Indexed: 12/03/2023] Open
Abstract
Plants respond to drought stress by producing abscisic acid, a chemical messenger that regulates gene expression and thereby expedites various physiological and cellular processes including the stomatal operation to mitigate stress and promote tolerance. To trigger or suppress gene transcription under drought stress conditions, the surrounding chromatin architecture must be converted between a repressive and active state by epigenetic remodeling, which is achieved by the dynamic interplay among DNA methylation, histone modifications, loop formation, and non-coding RNA generation. Plants can memorize chromatin status under drought conditions to enable them to deal with recurrent stress. Furthermore, drought tolerance acquired during plant growth can be transmitted to the next generation. The epigenetically modified chromatin architectures of memory genes under stressful conditions can be transmitted to newly developed cells by mitotic cell division, and to germline cells of offspring by overcoming the restraints on meiosis. In mammalian cells, the acquired memory state is completely erased and reset during meiosis. The mechanism by which plant cells overcome this resetting during meiosis to transmit memory is unclear. In this article, we review recent findings on the mechanism underlying transcriptional stress memory and the transgenerational inheritance of drought tolerance in plants.
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Affiliation(s)
- Nguyen Hoai Nguyen
- Faculty of Biotechnology, Ho Chi Minh City Open University, Ho Chi Minh City 700000, Vietnam
| | - Nam Tuan Vu
- Center for Food and Bioconvergence, Seoul National University, Seoul 08826, Korea
| | - Jong-Joo Cheong
- Center for Food and Bioconvergence, Seoul National University, Seoul 08826, Korea
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13
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Li X, Wang M, Liu S, Chen X, Qiao Y, Yang X, Yao J, Wu S. Paternal transgenerational nutritional epigenetic effect: A new insight into nutritional manipulation to reduce the use of antibiotics in animal feeding. ANIMAL NUTRITION 2022; 11:142-151. [PMID: 36204282 PMCID: PMC9527621 DOI: 10.1016/j.aninu.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 07/10/2022] [Accepted: 07/14/2022] [Indexed: 11/15/2022]
Abstract
The use of antibiotics in animal feeding has been banned in many countries because of increasing concerns about the development of bacterial resistance to antibiotics and potential issues on food safety. Searching for antibiotic substitutes is essential. Applying transgenerational epigenetic technology to animal production could be an alternative. Some environmental changes can be transferred to memory-like responses in the offspring through epigenetic mechanisms without changing the DNA sequence. In this paper, we reviewed those nutrients and non-nutritional additives that have transgenerational epigenetic effects, including some amino acids, vitamins, and polysaccharides. The paternal transgenerational nutritional epigenetic regulation was particularly focused on mechanism of the substantial contribution of male stud animals to the animal industries. We illustrated the effects of paternal transgenerational epigenetics on the metabolism and immunity in farming animals and proposed strategies to modulate male breeding livestock or poultry.
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Affiliation(s)
- Xinyi Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
- Department of Medicine, Karolinska Institutet, Solna, Stockholm 17165, Sweden
| | - Mengya Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Shimin Liu
- Institute of Agriculture, University of Western Australia, Crawley, WA 6009, Australia
| | - Xiaodong Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yu Qiao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
- Department of Animal Engineering, Yangling Vocational and Technical College, Yangling, Shaanxi 712100, China
| | - Xiaojun Yang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Junhu Yao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
- Corresponding authors.
| | - Shengru Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
- Corresponding authors.
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14
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Sump B, Brickner DG, D'Urso A, Kim SH, Brickner JH. Mitotically heritable, RNA polymerase II-independent H3K4 dimethylation stimulates INO1 transcriptional memory. eLife 2022; 11:e77646. [PMID: 35579426 PMCID: PMC9129879 DOI: 10.7554/elife.77646] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 05/15/2022] [Indexed: 11/13/2022] Open
Abstract
For some inducible genes, the rate and molecular mechanism of transcriptional activation depend on the prior experiences of the cell. This phenomenon, called epigenetic transcriptional memory, accelerates reactivation, and requires both changes in chromatin structure and recruitment of poised RNA polymerase II (RNAPII) to the promoter. Memory of inositol starvation in budding yeast involves a positive feedback loop between transcription factor-dependent interaction with the nuclear pore complex and histone H3 lysine 4 dimethylation (H3K4me2). While H3K4me2 is essential for recruitment of RNAPII and faster reactivation, RNAPII is not required for H3K4me2. Unlike RNAPII-dependent H3K4me2 associated with transcription, RNAPII-independent H3K4me2 requires Nup100, SET3C, the Leo1 subunit of the Paf1 complex and, upon degradation of an essential transcription factor, is inherited through multiple cell cycles. The writer of this mark (COMPASS) physically interacts with the potential reader (SET3C), suggesting a molecular mechanism for the spreading and re-incorporation of H3K4me2 following DNA replication.
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Affiliation(s)
- Bethany Sump
- Department of Molecular Biosciences, Northwestern UniversityEvanstonUnited States
| | - Donna G Brickner
- Department of Molecular Biosciences, Northwestern UniversityEvanstonUnited States
| | - Agustina D'Urso
- Department of Molecular Biosciences, Northwestern UniversityEvanstonUnited States
| | - Seo Hyun Kim
- Department of Molecular Biosciences, Northwestern UniversityEvanstonUnited States
| | - Jason H Brickner
- Department of Molecular Biosciences, Northwestern UniversityEvanstonUnited States
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15
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Mitotic drive in asymmetric epigenetic inheritance. Biochem Soc Trans 2022; 50:675-688. [PMID: 35437581 PMCID: PMC9162470 DOI: 10.1042/bst20200267] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 01/14/2023]
Abstract
Asymmetric cell division (ACD) produces two daughter cells with distinct cell fates. This division mode is widely used during development and by adult stem cells during tissue homeostasis and regeneration, which can be regulated by both extrinsic cues such as signaling molecules and intrinsic factors such as epigenetic information. While the DNA replication process ensures that the sequences of sister chromatids are identical, how epigenetic information is re-distributed during ACD has remained largely unclear in multicellular organisms. Studies of Drosophila male germline stem cells (GSCs) have revealed that sister chromatids incorporate pre-existing and newly synthesized histones differentially and segregate asymmetrically during ACD. To understand the underlying molecular mechanisms of this phenomenon, two key questions must be answered: first, how and when asymmetric histone information is established; and second, how epigenetically distinct sister chromatids are distinguished and segregated. Here, we discuss recent advances which help our understanding of this interesting and important cell division mode.
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16
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Yamazaki S, Ikeda S, Minami N. Comparative analysis of histone H3K27me3 modifications between blastocysts and somatic tissues in cattle. Anim Sci J 2022; 93:e13684. [PMID: 35083819 DOI: 10.1111/asj.13684] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/28/2021] [Accepted: 01/06/2022] [Indexed: 01/28/2023]
Abstract
Epigenetic modifications established in the early developmental stages can have long-term consequences throughout life. This concept encompasses the possibility of controlling livestock health and diseases by epigenetic regulation during early development. To explore the candidates of epigenetic modifications in early embryos that might exert long-lasting effects in adulthood, we aimed to obtain genome-wide histone H3 lysine 27 trimethylation (H3K27me3) profiles of bovine blastocysts and compare these data with those from adult somatic tissues in order to extract common and typical features between them. Bovine blastocysts were produced in vitro and subjected to chromatin immunoprecipitation-sequencing analysis of H3K27me3. Comparative analysis of the blastocyst-derived H3K27me3 profile performed using publicly available data from adult muscle, fat, and liver tissues revealed that (1) blastocyst-specific modifications against somatic tissues were enriched in immune function-related genes, (2) somatic modifications "sieved" by blastocyst modifications were enriched in biological processes in tissue-specific trends, (3) the modifications common in blastocyst and each somatic tissue were largely overlapped and enriched in developmentally important genes, including homeobox and imprinted genes. The results of this study produced a genome-wide H3K27me3 profile of bovine blastocysts and revealed its common and typical features in relation to the profiles of adult somatic tissues.
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Affiliation(s)
- Satomi Yamazaki
- Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Shuntaro Ikeda
- Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Naojiro Minami
- Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
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17
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Yao Y, Wen Q, Zhang T, Yu C, Chan KM, Gan H. Advances in Approaches to Study Chromatin-Mediated Epigenetic Memory. ACS Synth Biol 2022; 11:16-25. [PMID: 34965084 DOI: 10.1021/acssynbio.1c00394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Chromatin structure contains critical epigenetic information in various forms, such as histone post-translational modifications (PTMs). The deposition of certain histone PTMs can remodel the chromatin structure, resulting in gene expression alteration. The epigenetic information carried by histone PTMs could be inherited by daughter cells to maintain the gene expression status. Recently, studies revealed that several conserved replisome proteins regulate the recycling of parental histones carrying epigenetic information in Saccharomyces cerevisiae. Hence, the proper recycling and deposition of parental histones onto newly synthesized DNA strands is presumed to be essential for epigenetic inheritance. Here, we first reviewed the fundamental mechanisms of epigenetic modification establishment and maintenance discovered within fungal models. Next, we discussed the functions of parental histone chaperones and the potential impacts of the parental histone recycling process on heterochromatin-mediated transcriptional silencing inheritance. Subsequently, we summarized novel synthetic biology approaches developed to analyze individual epigenetic components during epigenetic inheritance in fungal and mammalian systems. These newly emerged research paradigms enable us to dissect epigenetic systems in a bottom-up manner. Furthermore, we highlighted the approaches developed in this emerging field and discussed the potential applications of these engineered regulators to building synthetic epigenetic systems.
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Affiliation(s)
- Yuan Yao
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Qing Wen
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Tianjun Zhang
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- Department of Molecular and Biomedical Science, School of Biological Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
| | - Chuanhe Yu
- The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, United States
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR 999077, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen 518172, China
| | - Haiyun Gan
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
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18
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Hime GR, Stonehouse SLA, Pang TY. Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man. World J Psychiatry 2021; 11:711-735. [PMID: 34733638 PMCID: PMC8546770 DOI: 10.5498/wjp.v11.i10.711] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/19/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Mental illness remains the greatest chronic health burden globally with few in-roads having been made despite significant advances in genomic knowledge in recent decades. The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations, and that has to be supported by a continuous growth in knowledge. The majority of neuropsychiatric symptoms reflect complex gene-environment interactions, with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms. It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stress-related behavioural phenotypes in both paternal and maternal lineages, providing further supporting evidence for heritability in humans. However, unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions. While rodents will remain the dominant model system for preclinical studies (especially for addressing complex behavioural phenotypes), there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models. Here, we will discuss the utility and advantages of two alternative model organisms-Caenorhabditis elegans and Drosophila melanogaster-and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry.
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Affiliation(s)
- Gary R Hime
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, VIC, Australia
| | - Sophie LA Stonehouse
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville 3052, VIC, Australia
| | - Terence Y Pang
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, VIC, Australia
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville 3052, VIC, Australia
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19
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Rashidi M, Tavalaee M, Abbasi H, Nomikos M, Nasr-Esfahani MH. Increased de novo DNA Methylation Enzymes in Sperm of Individuals with Varicocele. CELL JOURNAL 2021; 23:389-396. [PMID: 34455713 PMCID: PMC8405077 DOI: 10.22074/cellj.2021.7265] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 03/07/2020] [Indexed: 12/14/2022]
Abstract
Objective Chronic genital heat-stress associated with varicocele leads to DNA hypo-methylation of spermatozoa. The objective of this study was comparing level of DNA methyl-transferases (DNMTs) in sperm of men suffering varicocele with fertile individuals. Materials and Methods In this case-control study, semen samples were obtained from 35 infertile men with varicocele (grade II or III) and 26 fertile men. Sperm parameters were assessed according to World Health Organization (WHO) protocol. DNMTs enzymes level were assessed by flow cytometer and fluorescence microscope. mRNAs expression of these DNMTs were also assessed by real-time reverse transcription polymerase chain reaction (RT-PCR). Results DNMT1 and DNMT3A proteins were mainly localized in equatorial and mid-piece regions of sperm head, respectively, while DNMT3B protein appeared to be localized mainly in equatorial and anterior regions of sperm head. In contrast to DNMT1, expression and percentage of DNMT3A and DNMT3B at RNA and protein levels were significantly higher in the varicocele group compared to the fertile group (P<0.05). In addition, significant correlations were found between sperm concentration and motility as well as DNMT1 and DNMT3B proteins levels in the infertile individuals with varicocele (P<0.05). Additionally, significant correlations were observed between abnormal sperm morphology with DNMTs proteins in the infertile individuals with varicocele. Conclusion Unlike DNMT1, which is involved in maintenance of DNA methylation at both RNA and protein levels, expression of de novo methylation enzymes (DNMT3A and DNMT3B) at both levels were increased in the varicocele group compared to the fertile group. Based on literature, this increase might be due to the dual roles played by DNMT3A and DNMT3B, as methyl-transferases in normal condition as well as dehydroxymethylases in stress condition, like varicocele. Although, this hypothesis needs further validation.
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Affiliation(s)
- Moloud Rashidi
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.,Department of Biology, Faculty of Science, NourDanesh Institute of Higher Education, Isfahan, Iran
| | - Marziyeh Tavalaee
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | | | - Michail Nomikos
- College of Medicine, Member of QU Health, Qatar University, Doha, Qatar
| | - Mohammad Hossein Nasr-Esfahani
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran. .,Isfahan Fertility and Infertility Center, Isfahan, Iran
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20
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Abstract
Environmental hypoxia exposure causes fertility problems in human and animals. Compelling evidence suggests that chronic hypoxia impairs spermatogenesis and reduces sperm motility. However, it is unclear whether paternal hypoxic exposure affects fertilization and early embryo development. In the present study, we exposed male mice to high altitude (3200 m above sea level) for 7 or 60 days to evaluate the effects of hypoxia on sperm quality, zygotic DNA methylation and blastocyst formation. Compared with age-matched controls, hypoxia-treated males exhibited reduced fertility after mating with normoxic females as a result of defects in sperm motility and function. Results of in vitro fertilization (IVF) experiments revealed that 60 days' exposure significantly reduced cleavage and blastocyst rates by 30% and 70%, respectively. Immunohistochemical staining of pronuclear formation indicated that the pronuclear formation process was disturbed and expression of imprinted genes was reduced in early embryos after paternal hypoxia. Overall, the findings of this study suggested that exposing male mice to hypoxia impaired sperm function and affected key events during early embryo development in mammals.
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21
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Ishibashi M, Ikeda S, Minami N. Comparative analysis of histone H3K4me3 modifications between blastocysts and somatic tissues in cattle. Sci Rep 2021; 11:8253. [PMID: 33859293 PMCID: PMC8050253 DOI: 10.1038/s41598-021-87683-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 02/26/2021] [Indexed: 01/28/2023] Open
Abstract
Epigenetic changes induced in the early developmental stages by the surrounding environment can have not only short-term but also long-term consequences throughout life. This concept constitutes the “Developmental Origins of Health and Disease” (DOHaD) hypothesis and encompasses the possibility of controlling livestock health and diseases by epigenetic regulation during early development. As a preliminary step for examining changes of epigenetic modifications in early embryos and their long-lasting effects in fully differentiated somatic tissues, we aimed to obtain high-throughput genome-wide histone H3 lysine 4 trimethylation (H3K4me3) profiles of bovine blastocysts and to compare these data with those from adult somatic tissues in order to extract common and typical features between these tissues in terms of H3K4me3 modifications. Bovine blastocysts were produced in vitro and subjected to chromatin immunoprecipitation-sequencing analysis of H3K4me3. Comparative analysis of the blastocyst-derived H3K4me3 profile with publicly available data from adult liver and muscle tissues revealed that the blastocyst profile could be used as a “sieve” to extract somatic tissue-specific modifications in genes closely related to tissue-specific functions. Furthermore, principal component analysis of the level of common modifications between blastocysts and somatic tissues in meat production-related and imprinted genes well characterized inter- and intra-tissue differences. The results of this study produced a referential genome-wide H3K4me3 profile of bovine blastocysts within the limits of their in vitro source and revealed its common and typical features in relation to the profiles of adult tissues.
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Affiliation(s)
- Mao Ishibashi
- Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
| | - Shuntaro Ikeda
- Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan.
| | - Naojiro Minami
- Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
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22
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Shan CM, Bao K, Diedrich J, Chen X, Lu C, Yates JR, Jia S. The INO80 Complex Regulates Epigenetic Inheritance of Heterochromatin. Cell Rep 2020; 33:108561. [PMID: 33378674 PMCID: PMC7896557 DOI: 10.1016/j.celrep.2020.108561] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/31/2020] [Accepted: 12/03/2020] [Indexed: 12/21/2022] Open
Abstract
One key aspect of epigenetic inheritance is that chromatin structures can be stably inherited through generations after the removal of the signals that establish such structures. In fission yeast, the RNA interference (RNAi) pathway is critical for the targeting of histone methyltransferase Clr4 to pericentric repeats to establish heterochromatin. However, pericentric heterochromatin cannot be properly inherited in the absence of RNAi, suggesting the existence of mechanisms that counteract chromatin structure inheritance. Here, we show that mutations of components of the INO80 chromatin-remodeling complex allow pericentric heterochromatin inheritance in RNAi mutants. The ability of INO80 to counter heterochromatin inheritance is attributed to one subunit, Iec5, which promotes histone turnover at heterochromatin but has little effects on nucleosome positioning at heterochromatin, gene expression, or the DNA damage response. These analyses demonstrate the importance of the INO80 chromatin-remodeling complex in controlling heterochromatin inheritance and maintaining the proper heterochromatin landscape of the genome.
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Affiliation(s)
- Chun-Min Shan
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Kehan Bao
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Jolene Diedrich
- Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Xiao Chen
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Chao Lu
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - John R Yates
- Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Songtao Jia
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
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23
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Dong E, Pandey SC. Prenatal stress induced chromatin remodeling and risk of psychopathology in adulthood. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 156:185-215. [PMID: 33461663 PMCID: PMC7864549 DOI: 10.1016/bs.irn.2020.08.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
New insights into the pathophysiology of psychiatric disorders suggest the existence of a complex interplay between genetics and environment. This notion is supported by evidence suggesting that exposure to stress during pregnancy exerts profound effects on the neurodevelopment and behavior of the offspring and predisposes them to psychiatric disorders later in life. Accumulated evidence suggests that vulnerability to psychiatric disorders may result from permanent negative effects of long-term changes in synaptic plasticity due to altered epigenetic mechanisms (histone modifications and DNA methylation) that lead to condensed chromatin architecture, thereby decreasing the expression of candidate genes during early brain development. In this chapter, we have summarized the literature of clinical studies on psychiatric disorders induced by maternal stress during pregnancy. We also discussed the epigenetic alterations of gene regulations induced by prenatal stress. Because the clinical manifestations of psychiatric disorders are complex, it is obvious that the biological progression of these diseases cannot be studied only in postmortem brains of patients and the use of animal models is required. Therefore, in this chapter, we have introduced a well-established mouse model of prenatal stress (PRS) generated in restrained pregnant dams. The behavioral phenotypes of the offspring (PRS mice) born to the stressed dam and underlying epigenetic changes in key molecules related to synaptic activity were described and highlighted. PRS mice may serve as a useful model for investigating the pathogenesis of psychiatric disorders and may be a useful tool for screening for the potential compounds that may normalize aberrant epigenetic mechanisms induced by prenatal stress.
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Affiliation(s)
- Erbo Dong
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States.
| | - Subhash C Pandey
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States; Jesse Brown VA Medical Center, Chicago, IL, United States
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Yuan Y, Yuan H, Yang G, Yun H, Zhao M, Liu Z, Zhao L, Geng Y, Liu L, Wang J, Zhang H, Wang Y, Zhang XD. IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA. Clin Epigenetics 2020; 12:135. [PMID: 32894195 PMCID: PMC7487718 DOI: 10.1186/s13148-020-00928-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
Background Hepatitis B virus covalently closed circular DNA (HBV cccDNA) is assembled by histones and non-histones into a chromatin-like cccDNA minichromosome in the nucleus. The cellular histone acetyltransferase GCN5, displaying succinyltransferase activity, is recruited onto cccDNA to modulate HBV transcription in cells. Clinically, IFN-α is able to repress cccDNA. However, the underlying mechanism of IFN-α in the depression of cccDNA mediated by GCN5 is poorly understood. Here, we explored the effect of IFN-α on GCN5-mediated succinylation in the epigenetic regulation of HBV cccDNA minichromosome. Results Succinylation modification of the cccDNA minichromosome has been observed in HBV-infected human liver-chimeric mice and HBV-expressing cell lines. Moreover, histone H3K79 succinylation by GCN5 was identified in the system. Interestingly, the mutant of histone H3K79 efficiently blocked the replication of HBV, and interference with GCN5 resulted in decreased levels of HBV DNA, HBsAg, and HBeAg in the supernatant from de novo HBV-infected HepaRG cells. Consistently, the levels of histone H3K79 succinylation were significantly elevated in the livers of HBV-infected human liver-chimeric mice. The knockdown or overexpression of GCN5 or the mutant of GCN5 could affect the binding of GCN5 to cccDNA or H3K79 succinylation, leading to a change in cccDNA transcription activity. In addition, Southern blot analysis validated that siGCN5 decreased the levels of cccDNA in the cells, suggesting that GCN5-mediated succinylation of histone H3K79 contributes to the epigenetic regulation of cccDNA minichromosome. Strikingly, IFN-α effectively depressed histone H3K79 succinylation in HBV cccDNA minichromosome in de novo HepG2-NTCP and HBV-infected HepaRG cells. Conclusions IFN-α epigenetically regulates the HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA. Our findings provide new insights into the mechanism by which IFN-α modulate the epigenetic regulation of HBV cccDNA minichromosome.
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Affiliation(s)
- Ying Yuan
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Hongfeng Yuan
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Guang Yang
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Haolin Yun
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Man Zhao
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Zixian Liu
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Lina Zhao
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Yu Geng
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Lei Liu
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Jiapei Wang
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Huihui Zhang
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Yufei Wang
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China
| | - Xiao-Dong Zhang
- Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China.
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25
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Jeronimo C, Poitras C, Robert F. Histone Recycling by FACT and Spt6 during Transcription Prevents the Scrambling of Histone Modifications. Cell Rep 2020; 28:1206-1218.e8. [PMID: 31365865 DOI: 10.1016/j.celrep.2019.06.097] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 05/28/2019] [Accepted: 06/27/2019] [Indexed: 12/27/2022] Open
Abstract
Genomic DNA is framed by additional layers of information, referred to as the epigenome. Epigenomic marks such as DNA methylation, histone modifications, and histone variants are concentrated on specific genomic sites, where they can both instruct and reflect gene expression. How this information is maintained, notably in the face of transcription, is not completely understood. Specifically, the extent to which modified histones themselves are retained through RNA polymerase II passage is unclear. Here, we show that several histone modifications are mislocalized when the transcription-coupled histone chaperones FACT or Spt6 are disrupted in Saccharomyces cerevisiae. In the absence of functional FACT or Spt6, transcription generates nucleosome loss, which is partially compensated for by the increased activity of non-transcription-coupled histone chaperones. The random incorporation of transcription-evicted modified histones scrambles epigenomic information. Our work highlights the importance of local recycling of modified histones by FACT and Spt6 during transcription in the maintenance of the epigenomic landscape.
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Affiliation(s)
- Célia Jeronimo
- Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada
| | - Christian Poitras
- Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada
| | - François Robert
- Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada; Département de Médecine, Faculté de Médecine, Université de Montréal, 2900 Boul. Édouard-Montpetit, Montréal, QC, Canada.
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26
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Djeghloul D, Patel B, Kramer H, Dimond A, Whilding C, Brown K, Kohler AC, Feytout A, Veland N, Elliott J, Bharat TAM, Tarafder AK, Löwe J, Ng BL, Guo Y, Guy J, Huseyin MK, Klose RJ, Merkenschlager M, Fisher AG. Identifying proteins bound to native mitotic ESC chromosomes reveals chromatin repressors are important for compaction. Nat Commun 2020; 11:4118. [PMID: 32807789 PMCID: PMC7431861 DOI: 10.1038/s41467-020-17823-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 07/15/2020] [Indexed: 12/14/2022] Open
Abstract
Epigenetic information is transmitted from mother to daughter cells through mitosis. Here, to identify factors that might play a role in conveying epigenetic memory through cell division, we report on the isolation of unfixed, native chromosomes from metaphase-arrested cells using flow cytometry and perform LC-MS/MS to identify chromosome-bound proteins. A quantitative proteomic comparison between metaphase-arrested cell lysates and chromosome-sorted samples reveals a cohort of proteins that were significantly enriched on mitotic ESC chromosomes. These include pluripotency-associated transcription factors, repressive chromatin-modifiers such as PRC2 and DNA methyl-transferases, and proteins governing chromosome architecture. Deletion of PRC2, Dnmt1/3a/3b or Mecp2 in ESCs leads to an increase in the size of individual mitotic chromosomes, consistent with de-condensation. Similar results were obtained by the experimental cleavage of cohesin. Thus, we identify chromosome-bound factors in pluripotent stem cells during mitosis and reveal that PRC2, DNA methylation and Mecp2 are required to maintain chromosome compaction.
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Affiliation(s)
- Dounia Djeghloul
- Lymphocyte Development Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - Bhavik Patel
- Flow Cytometry Facility, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - Holger Kramer
- Biological Mass Spectrometry and Proteomics Facility, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - Andrew Dimond
- Lymphocyte Development Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - Chad Whilding
- Microscopy Facility, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - Karen Brown
- Lymphocyte Development Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - Anne-Céline Kohler
- Lymphocyte Development Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - Amelie Feytout
- Lymphocyte Development Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - Nicolas Veland
- Lymphocyte Development Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - James Elliott
- Flow Cytometry Facility, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - Tanmay A M Bharat
- Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, Oxford, UK
| | - Abul K Tarafder
- Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, Oxford, UK
| | - Jan Löwe
- MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK
| | - Bee L Ng
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
| | - Ya Guo
- Lymphocyte Development Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - Jacky Guy
- The Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BH, UK
| | - Miles K Huseyin
- Department of Biochemistry, University of Oxford, OX1 3QU, Oxford, UK
| | - Robert J Klose
- Department of Biochemistry, University of Oxford, OX1 3QU, Oxford, UK
| | - Matthias Merkenschlager
- Lymphocyte Development Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
| | - Amanda G Fisher
- Lymphocyte Development Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.
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27
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Samata M, Alexiadis A, Richard G, Georgiev P, Nuebler J, Kulkarni T, Renschler G, Basilicata MF, Zenk FL, Shvedunova M, Semplicio G, Mirny L, Iovino N, Akhtar A. Intergenerationally Maintained Histone H4 Lysine 16 Acetylation Is Instructive for Future Gene Activation. Cell 2020; 182:127-144.e23. [DOI: 10.1016/j.cell.2020.05.026] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 02/22/2020] [Accepted: 05/14/2020] [Indexed: 10/24/2022]
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28
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Escobar TM, Oksuz O, Saldaña-Meyer R, Descostes N, Bonasio R, Reinberg D. Active and Repressed Chromatin Domains Exhibit Distinct Nucleosome Segregation during DNA Replication. Cell 2020; 179:953-963.e11. [PMID: 31675501 DOI: 10.1016/j.cell.2019.10.009] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 05/06/2019] [Accepted: 10/08/2019] [Indexed: 11/25/2022]
Abstract
Chromatin domains and their associated structures must be faithfully inherited through cellular division to maintain cellular identity. However, accessing the localized strategies preserving chromatin domain inheritance, specifically the transfer of parental, pre-existing nucleosomes with their associated post-translational modifications (PTMs) during DNA replication, is challenging in living cells. We devised an inducible, proximity-dependent labeling system to irreversibly mark replication-dependent H3.1 and H3.2 histone-containing nucleosomes at desired loci in mouse embryonic stem cells so that their fate after DNA replication could be followed. Strikingly, repressed chromatin domains are preserved through local re-deposition of parental nucleosomes. In contrast, nucleosomes decorating active chromatin domains do not exhibit such preservation. Notably, altering cell fate leads to an adjustment of the positional inheritance of parental nucleosomes that reflects the corresponding changes in chromatin structure. These findings point to important mechanisms that contribute to parental nucleosome segregation to preserve cellular identity.
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Affiliation(s)
- Thelma M Escobar
- Howard Hughes Medical Institute, New York University Langone Medical Center, New York, NY 10016, USA; New York University Langone Medical Center, New York, NY 10016, USA
| | - Ozgur Oksuz
- Howard Hughes Medical Institute, New York University Langone Medical Center, New York, NY 10016, USA; New York University Langone Medical Center, New York, NY 10016, USA
| | - Ricardo Saldaña-Meyer
- Howard Hughes Medical Institute, New York University Langone Medical Center, New York, NY 10016, USA; New York University Langone Medical Center, New York, NY 10016, USA
| | - Nicolas Descostes
- Howard Hughes Medical Institute, New York University Langone Medical Center, New York, NY 10016, USA; New York University Langone Medical Center, New York, NY 10016, USA
| | - Roberto Bonasio
- Howard Hughes Medical Institute, New York University Langone Medical Center, New York, NY 10016, USA; New York University Langone Medical Center, New York, NY 10016, USA
| | - Danny Reinberg
- Howard Hughes Medical Institute, New York University Langone Medical Center, New York, NY 10016, USA; New York University Langone Medical Center, New York, NY 10016, USA.
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29
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Llorà-Batlle O, Tintó-Font E, Cortés A. Transcriptional variation in malaria parasites: why and how. Brief Funct Genomics 2020; 18:329-341. [PMID: 31114839 DOI: 10.1093/bfgp/elz009] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 02/04/2019] [Accepted: 04/10/2019] [Indexed: 12/24/2022] Open
Abstract
Transcriptional differences enable the generation of alternative phenotypes from the same genome. In malaria parasites, transcriptional plasticity plays a major role in the process of adaptation to fluctuations in the environment. Multiple studies with culture-adapted parasites and field isolates are starting to unravel the different transcriptional alternatives available to Plasmodium falciparum and the underlying molecular mechanisms. Here we discuss how epigenetic variation, directed transcriptional responses and also genetic changes that affect transcript levels can all contribute to transcriptional variation and, ultimately, parasite survival. Some transcriptional changes are driven by stochastic events. These changes can occur spontaneously, resulting in heterogeneity within parasite populations that provides the grounds for adaptation by dynamic natural selection. However, transcriptional changes can also occur in response to external cues. A better understanding of the mechanisms that the parasite has evolved to alter its transcriptome may ultimately contribute to the design of strategies to combat malaria to which the parasite cannot adapt.
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Affiliation(s)
- Oriol Llorà-Batlle
- ISGlobal, Hospital Clínic - Universitat de Barcelona, 08036 Barcelona, Catalonia, Spain
| | - Elisabet Tintó-Font
- ISGlobal, Hospital Clínic - Universitat de Barcelona, 08036 Barcelona, Catalonia, Spain
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30
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Jadhav U, Manieri E, Nalapareddy K, Madha S, Chakrabarti S, Wucherpfennig K, Barefoot M, Shivdasani RA. Replicational Dilution of H3K27me3 in Mammalian Cells and the Role of Poised Promoters. Mol Cell 2020; 78:141-151.e5. [PMID: 32027840 PMCID: PMC7376365 DOI: 10.1016/j.molcel.2020.01.017] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 12/02/2019] [Accepted: 01/13/2020] [Indexed: 12/22/2022]
Abstract
Polycomb repressive complex 2 (PRC2) places H3K27me3 at developmental genes and is causally implicated in keeping bivalent genes silent. It is unclear if that silence requires minimum H3K27me3 levels and how the mark transmits faithfully across mammalian somatic cell generations. Mouse intestinal cells lacking EZH2 methyltransferase reduce H3K27me3 proportionately at all PRC2 target sites, but ∼40% uniform residual levels keep target genes inactive. These genes, derepressed in PRC2-null villus cells, remain silent in intestinal stem cells (ISCs). Quantitative chromatin immunoprecipitation and computational modeling indicate that because unmodified histones dilute H3K27me3 by 50% each time DNA replicates, PRC2-deficient ISCs initially retain sufficient H3K27me3 to avoid gene derepression. EZH2 mutant human lymphoma cells also require multiple divisions before H3K27me3 dilution relieves gene silencing. In both cell types, promoters with high basal H3K4me2/3 activate in spite of some residual H3K27me3, compared to less-poised promoters. These findings have implications for PRC2 inhibition in cancer therapy.
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Affiliation(s)
- Unmesh Jadhav
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Elisa Manieri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Kodandaramireddy Nalapareddy
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Shariq Madha
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Shaon Chakrabarti
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Kai Wucherpfennig
- Department of Cancer Immunology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | | | - Ramesh A Shivdasani
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
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31
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Fröhlich J, Grundhoff A. Epigenetic control in Kaposi sarcoma-associated herpesvirus infection and associated disease. Semin Immunopathol 2020; 42:143-157. [PMID: 32219477 PMCID: PMC7174275 DOI: 10.1007/s00281-020-00787-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 01/20/2020] [Indexed: 12/15/2022]
Abstract
Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several malignancies of endothelial and B-cell origin. The fact that latently infected tumor cells in these malignancies do not express classical viral oncogenes suggests that pathogenesis of KSHV-associated disease results from multistep processes that, in addition to constitutive viral gene expression, may require accumulation of cellular alterations. Heritable changes of the epigenome have emerged as an important co-factor that contributes to the pathogenesis of many non-viral cancers. Since KSHV encodes a number of factors that directly or indirectly manipulate host cell chromatin, it is an intriguing possibility that epigenetic reprogramming also contributes to the pathogenesis of KSHV-associated tumors. The fact that heritable histone modifications have also been shown to regulate viral gene expression programs in KSHV-infected tumor cells underlines the importance of epigenetic control during latency and tumorigenesis. We here review what is presently known about the role of epigenetic regulation of viral and host chromatin in KSHV infection and discuss how viral manipulation of these processes may contribute to the development of KSHV-associated disease.
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Affiliation(s)
- Jacqueline Fröhlich
- Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Adam Grundhoff
- Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
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32
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Zhao W, Wang Y, Liang FS. Chemical and Light Inducible Epigenome Editing. Int J Mol Sci 2020; 21:ijms21030998. [PMID: 32028669 PMCID: PMC7037166 DOI: 10.3390/ijms21030998] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 01/30/2020] [Accepted: 01/30/2020] [Indexed: 12/22/2022] Open
Abstract
The epigenome defines the unique gene expression patterns and resulting cellular behaviors in different cell types. Epigenome dysregulation has been directly linked to various human diseases. Epigenome editing enabling genome locus-specific targeting of epigenome modifiers to directly alter specific local epigenome modifications offers a revolutionary tool for mechanistic studies in epigenome regulation as well as the development of novel epigenome therapies. Inducible and reversible epigenome editing provides unique temporal control critical for understanding the dynamics and kinetics of epigenome regulation. This review summarizes the progress in the development of spatiotemporal-specific tools using small molecules or light as inducers to achieve the conditional control of epigenome editing and their applications in epigenetic research.
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Humphries B, Wang Z, Yang C. MicroRNA Regulation of Epigenetic Modifiers in Breast Cancer. Cancers (Basel) 2019; 11:E897. [PMID: 31252590 PMCID: PMC6678197 DOI: 10.3390/cancers11070897] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 06/16/2019] [Accepted: 06/24/2019] [Indexed: 12/20/2022] Open
Abstract
Epigenetics refers to the heritable changes in gene expression without a change in the DNA sequence itself. Two of these major changes include aberrant DNA methylation as well as changes to histone modification patterns. Alterations to the epigenome can drive expression of oncogenes and suppression of tumor suppressors, resulting in tumorigenesis and cancer progression. In addition to modifications of the epigenome, microRNA (miRNA) dysregulation is also a hallmark for cancer initiation and metastasis. Advances in our understanding of cancer biology demonstrate that alterations in the epigenome are not only a major cause of miRNA dysregulation in cancer, but that miRNAs themselves also indirectly drive these DNA and histone modifications. More explicitly, recent work has shown that miRNAs can regulate chromatin structure and gene expression by directly targeting key enzymes involved in these processes. This review aims to summarize these research findings specifically in the context of breast cancer. This review also discusses miRNAs as epigenetic biomarkers and as therapeutics, and presents a comprehensive summary of currently validated epigenetic targets in breast cancer.
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Affiliation(s)
- Brock Humphries
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI 48109; USA.
| | - Zhishan Wang
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Chengfeng Yang
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
- Center for Research on Environment Disease, College of Medicine, University of Kentucky, Lexington, KY 40536; USA.
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34
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Capella M, Braun S. Neutral epigenetic inheritance: being prepared for future generations. Nat Struct Mol Biol 2019; 26:391-392. [DOI: 10.1038/s41594-019-0239-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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35
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Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs. Proc Natl Acad Sci U S A 2019; 116:10547-10556. [PMID: 31061112 PMCID: PMC6534971 DOI: 10.1073/pnas.1820810116] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Obesity is a major public health issue worldwide. Easy accessibility of junk food is considered a major contributor to the current obesity epidemic. Thus, the impact of maternal overnutrition in determining disease susceptibility in offspring has received wide attention. It has also been shown that the effects of maternal overnutrition are not limited to the immediate offspring but can also be transmitted to successive generations. Among different epigenetic marks, sperm small noncoding RNAs (sncRNAs) have recently been reported as a direct mediator of acquired traits to the progeny following postnatal trauma or paternal diet. Here, we investigate whether sperm sncRNAs contributes to the transmission of metabolic and hedonic phenotypes across generations following maternal overnutrition. There is a growing body of evidence linking maternal overnutrition to obesity and psychopathology that can be conserved across multiple generations. Recently, we demonstrated in a maternal high-fat diet (HFD; MHFD) mouse model that MHFD induced enhanced hedonic behaviors and obesogenic phenotypes that were conserved across three generations via the paternal lineage, which was independent of sperm methylome changes. Here, we show that sperm tRNA-derived small RNAs (tsRNAs) partly contribute to the transmission of such phenotypes. We observe increased expression of sperm tsRNAs in the F1 male offspring born to HFD-exposed dams. Microinjection of sperm tsRNAs from the F1-HFD male into normal zygotes reproduces obesogenic phenotypes and addictive-like behaviors, such as increased preference of palatable foods and enhanced sensitivity to drugs of abuse in the resultant offspring. The expression of several of the differentially expressed sperm tsRNAs predicted targets such as CHRNA2 and GRIN3A, which have been implicated in addiction pathology, are altered in the mesolimbic reward brain regions of the F1-HFD father and the resultant HFD-tsRNA offspring. Together, our findings demonstrate that sperm tsRNA is a potential vector that contributes to the transmission of MHFD-induced addictive-like behaviors and obesogenic phenotypes across generations, thereby emphasizing its role in diverse pathological outcomes.
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Vagner M, Zambonino-Infante JL, Mazurais D. Fish facing global change: are early stages the lifeline? MARINE ENVIRONMENTAL RESEARCH 2019; 147:159-178. [PMID: 31027942 DOI: 10.1016/j.marenvres.2019.04.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 04/09/2019] [Accepted: 04/09/2019] [Indexed: 06/09/2023]
Abstract
The role of phenotypic plasticity in the acclimation and adaptive potential of an organism to global change is not currently accounted for in prediction models. The high plasticity of marine fishes is mainly attributed to their early stages, during which morphological, structural and behavioural functions are particularly sensitive to environmental constraints. This developmental plasticity can determine later physiological performances and fitness, and may further affect population dynamics and ecosystem functioning. This review asks the essential question of what role early stages play in the ability of fish to later cope with the effects of global change, considering three key environmental factors (temperature, hypoxia and acidification). After having identified the carry-over effects of early exposure reported in the literature, we propose areas that we believe warrant the most urgent attention for further research to better understand the role of developmental plasticity in the responses of marine organisms to global change.
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Affiliation(s)
- Marie Vagner
- CNRS, UMR 7266 LIENSs, Institut du littoral et de l'environnement, 2 rue Olympe de Gouges, 17000, La Rochelle, France.
| | | | - David Mazurais
- Ifremer, UMR 6539 LEMAR, ZI pointe du diable, 29280, Plouzané, France
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Lev I, Bril R, Liu Y, Ceré LI, Rechavi O. Inter-generational consequences for growing Caenorhabditis elegans in liquid. Philos Trans R Soc Lond B Biol Sci 2019; 374:20180125. [PMID: 30966881 PMCID: PMC6460074 DOI: 10.1098/rstb.2018.0125] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2018] [Indexed: 12/12/2022] Open
Abstract
In recent years, studies in Caenorhabditis elegans nematodes have shown that different stresses can generate multigenerational changes. Here, we show that worms that grow in liquid media, and also their plate-grown progeny, are different from worms whose ancestors were grown on plates. It has been suggested that C. elegans might encounter liquid environments in nature, although actual observations in the wild are few and far between. By contrast, in the laboratory, growing worms in liquid is commonplace, and often used as an alternative to growing worms on agar plates, to control the composition of the worms' diet, to starve (and synchronize) worms or to grow large populations for biochemical assays. We found that plate-grown descendants of M9 liquid medium-grown worms were longer than control worms, and the heritable effects were already apparent very early in development. We tested for the involvement of different known epigenetic inheritance mechanisms, but could not find a single mutant in which these inter-generational effects are cancelled. While we found that growing in liquid always leads to inter-generational changes in the worms' size, trans-generational effects were found to be variable, and in some cases, the effects were gone after one to two generations. These results demonstrate that standard cultivation conditions in early life can dramatically change the worms' physiology in adulthood, and can also affect the next generations. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.
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Affiliation(s)
- Itamar Lev
- Department of Neurobiology, Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel
| | - Roberta Bril
- Department of Neurobiology, Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel
| | - Yunan Liu
- Department of Neurobiology, Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel
| | - Lucila Inés Ceré
- Department of Neurobiology, Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel
| | - Oded Rechavi
- Department of Neurobiology, Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel
- Allen Discovery Center at Tufts University, Medford, MA 02155, USA
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Kang S, Chovatiya G, Tumbar T. Epigenetic control in skin development, homeostasis and injury repair. Exp Dermatol 2019; 28:453-463. [PMID: 30624812 PMCID: PMC6488370 DOI: 10.1111/exd.13872] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/11/2018] [Accepted: 01/05/2019] [Indexed: 12/14/2022]
Abstract
Cell-type- and cell-state-specific patterns of covalent modifications on DNA and histone tails form global epigenetic profiles that enable spatiotemporal regulation of gene expression. These epigenetic profiles arise from coordinated activities of transcription factors and epigenetic modifiers, which result in cell-type-specific outputs in response to dynamic environmental conditions and signalling pathways. Recent mouse genetic and functional studies have highlighted the physiological significance of global DNA and histone epigenetic modifications in skin. Importantly, specific epigenetic profiles are emerging for adult skin stem cells that are associated with their cell fate plasticity and proper activity in tissue regeneration. We can now begin to draw a more comprehensive picture of how epigenetic modifiers orchestrate their cell-intrinsic role with microenvironmental cues for proper skin development, homeostasis and wound repair. The field is ripe to begin to implement these findings from the laboratory into skin therapies.
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Affiliation(s)
- Sangjo Kang
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York
| | - Gopal Chovatiya
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York
| | - Tudorita Tumbar
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York
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Shukla A, Bunkar N, Kumar R, Bhargava A, Tiwari R, Chaudhury K, Goryacheva IY, Mishra PK. Air pollution associated epigenetic modifications: Transgenerational inheritance and underlying molecular mechanisms. THE SCIENCE OF THE TOTAL ENVIRONMENT 2019; 656:760-777. [PMID: 30530146 DOI: 10.1016/j.scitotenv.2018.11.381] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/23/2018] [Accepted: 11/25/2018] [Indexed: 05/28/2023]
Abstract
Air pollution is one of the leading causes of deaths in Southeast Asian countries including India. Exposure to air pollutants affects vital cellular mechanisms and is intimately linked with the etiology of a number of chronic diseases. Earlier work from our laboratory has shown that airborne particulate matter disturbs the mitochondrial machinery and causes significant damage to the epigenome. Mitochondrial reactive oxygen species possess the ability to trigger redox-sensitive signaling mechanisms and induce irreversible epigenomic changes. The electrophilic nature of reactive metabolites can directly result in deprotonation of cytosine at C-5 position or interfere with the DNA methyltransferases activity to cause alterations in DNA methylation. In addition, it also perturbs level of cellular metabolites critically involved in different epigenetic processes like acetylation and methylation of histone code and DNA hypo or hypermethylation. Interestingly, these modifications may persist through downstream generations and result in the transgenerational epigenomic inheritance. This phenomenon of subsequent transfer of epigenetic modifications is mainly associated with the germ cells and relies on the germline stability of the epigenetic states. Overall, the recent literature supports, and arguably strengthens, the contention that air pollution might contribute to transmission of epimutations from gametes to zygotes by involving mitochondrial DNA, parental allele imprinting, histone withholding and non-coding RNAs. However, larger prospective studies using innovative, integrated epigenome-wide metabolomic strategy are highly warranted to assess the air pollution induced transgenerational epigenetic inheritance and associated human health effects.
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Affiliation(s)
- Anushi Shukla
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bhopal, India
| | - Neha Bunkar
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bhopal, India
| | - Rajat Kumar
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bhopal, India
| | - Arpit Bhargava
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bhopal, India
| | - Rajnarayan Tiwari
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bhopal, India
| | - Koel Chaudhury
- School of Medical Science & Technology, Indian Institute of Technology, Kharagpur, India
| | - Irina Y Goryacheva
- Department of General and Inorganic Chemistry, Saratov State University, Saratov, Russia
| | - Pradyumna K Mishra
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bhopal, India.
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Khateb M, Azriel A, Levi BZ. The Third Intron of IRF8 Is a Cell-Type-Specific Chromatin Priming Element during Mouse Embryonal Stem Cell Differentiation. J Mol Biol 2019; 431:210-222. [PMID: 30502383 DOI: 10.1016/j.jmb.2018.11.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/07/2018] [Accepted: 11/20/2018] [Indexed: 01/09/2023]
Abstract
Interferon regulatory factor 8 (IRF8) is a nuclear transcription factor that plays a key role in the hierarchical differentiation of hematopoietic stem cells toward monocyte/dendritic cell lineages. Therefore, its expression is mainly limited to bone marrow-derived cells. The molecular mechanisms governing this cell-type-restricted expression have been described. However, the molecular mechanisms that are responsible for its silencing in non-hematopoietic cells are elusive. Recently, we demonstrated a role for IRF8 third intron in restricting its expression in non-hematopoietic cells. Furthermore, we showed that this intron alone is sufficient to promote repressed chromatin a cell-type-specific manner. Here we demonstrate the effect of the IRF8 third intron on chromatin conformation during murine embryonal stem cell differentiation. Using genome editing, we provide data showing that the third intron plays a key role in priming the chromatin state of the IRF8 locus during cell differentiation. It mediates dual regulatory effects in a cell-type-specific mode. It acts as a repressor element governing chromatin state of the IRF8 locus during embryonal stem cell differentiation to cardiomyocytes that are expression-restrictive cells. Conversely, it functions as an activator element that is essential for open chromatin structure during the differentiation of these cells to dendritic cells that are expression-permissive cells. Together, these results point to the role of IRF8 third intron as a cell-type-specific chromatin priming element during embryonal stem cell differentiation. These data add another layer to our understanding of the molecular mechanisms governing misexpression of a cell-type-specific gene such as IRF8.
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Affiliation(s)
- Mamduh Khateb
- Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Aviva Azriel
- Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Ben-Zion Levi
- Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel.
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Ruiz JL, Yerbanga RS, Lefèvre T, Ouedraogo JB, Corces VG, Gómez-Díaz E. Chromatin changes in Anopheles gambiae induced by Plasmodium falciparum infection. Epigenetics Chromatin 2019; 12:5. [PMID: 30616642 PMCID: PMC6322293 DOI: 10.1186/s13072-018-0250-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 12/19/2018] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Infection by the human malaria parasite leads to important changes in mosquito phenotypic traits related to vector competence. However, we still lack a clear understanding of the underlying mechanisms and, in particular, of the epigenetic basis for these changes. We have examined genome-wide distribution maps of H3K27ac, H3K9ac, H3K9me3 and H3K4me3 by ChIP-seq and the transcriptome by RNA-seq, of midguts from Anopheles gambiae mosquitoes blood-fed uninfected and infected with natural isolates of the human malaria parasite Plasmodium falciparum in Burkina Faso. RESULTS We report 15,916 regions containing differential histone modification enrichment between infected and uninfected, of which 8339 locate at promoters and/or intersect with genes. The functional annotation of these regions allowed us to identify infection-responsive genes showing differential enrichment in various histone modifications, such as CLIP proteases, antimicrobial peptides-encoding genes, and genes related to melanization responses and the complement system. Further, the motif analysis of regions differentially enriched in various histone modifications predicts binding sites that might be involved in the cis-regulation of these regions, such as Deaf1, Pangolin and Dorsal transcription factors (TFs). Some of these TFs are known to regulate immunity gene expression in Drosophila and are involved in the Notch and JAK/STAT signaling pathways. CONCLUSIONS The analysis of malaria infection-induced chromatin changes in mosquitoes is important not only to identify regulatory elements and genes underlying mosquito responses to P. falciparum infection, but also for possible applications to the genetic manipulation of mosquitoes and to other mosquito-borne systems.
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Affiliation(s)
- José L. Ruiz
- Estación Biológica de Doñana (EBD), Consejo Superior de Investigaciones Científicas, 41092 Seville, Spain
- Instituto de Parasitología y Biomedicina López-Neyra (IPBLN), Consejo Superior de Investigaciones Científicas, 18016 Granada, Spain
| | - Rakiswendé S. Yerbanga
- Institut de Recherche en Sciences de la Santé (IRSS), 01 BP 171, Bobo Dioulasso, Burkina Faso
| | - Thierry Lefèvre
- Institut de Recherche en Sciences de la Santé (IRSS), 01 BP 171, Bobo Dioulasso, Burkina Faso
- MIVEGEC, IRD, CNRS, University of Montpellier, Montpellier, France
| | - Jean B. Ouedraogo
- Institut de Recherche en Sciences de la Santé (IRSS), 01 BP 171, Bobo Dioulasso, Burkina Faso
| | - Victor G. Corces
- Department of Biology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322 USA
| | - Elena Gómez-Díaz
- Estación Biológica de Doñana (EBD), Consejo Superior de Investigaciones Científicas, 41092 Seville, Spain
- Instituto de Parasitología y Biomedicina López-Neyra (IPBLN), Consejo Superior de Investigaciones Científicas, 18016 Granada, Spain
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Kishimoto S, Uno M, Nishida E. Molecular mechanisms regulating lifespan and environmental stress responses. Inflamm Regen 2018; 38:22. [PMID: 30555601 PMCID: PMC6287349 DOI: 10.1186/s41232-018-0080-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 07/25/2018] [Indexed: 12/22/2022] Open
Abstract
Throughout life, organisms are subjected to a variety of environmental perturbations, including temperature, nutrient conditions, and chemical agents. Exposure to external signals induces diverse changes in the physiological conditions of organisms. Genetically identical individuals exhibit highly phenotypic variations, which suggest that environmental variations among individuals can affect their phenotypes in a cumulative and inhomogeneous manner. The organismal phenotypes mediated by environmental conditions involve development, metabolic pathways, fertility, pathological processes, and even lifespan. It is clear that genetic factors influence the lifespan of organisms. Likewise, it is now increasingly recognized that environmental factors also have a large impact on the regulation of aging. Multiple studies have reported on the contribution of epigenetic signatures to the long-lasting phenotypic effects induced by environmental signals. Nevertheless, the mechanism of how environmental stimuli induce epigenetic changes at specific loci, which ultimately elicit phenotypic variations, is still largely unknown. Intriguingly, in some cases, the altered phenotypes associated with epigenetic changes could be stably passed on to the next generations. In this review, we discuss the environmental regulation of organismal viability, that is, longevity and stress resistance, and the relationship between this regulation and epigenetic factors, focusing on studies in the nematode C. elegans.
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Affiliation(s)
- Saya Kishimoto
- RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe, 650-0047 Japan.,2Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, 606-8502 Japan
| | - Masaharu Uno
- RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe, 650-0047 Japan.,2Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, 606-8502 Japan
| | - Eisuke Nishida
- RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe, 650-0047 Japan.,2Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, 606-8502 Japan
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Abstract
Inheritance of genomic DNA underlies the vast majority of biological inheritance, yet it has been clear for decades that additional epigenetic information can be passed on to future generations. Here, we review major model systems for transgenerational epigenetic inheritance via the germline in multicellular organisms. In addition to surveying examples of epivariation that may arise stochastically or in response to unknown stimuli, we also discuss the induction of heritable epigenetic changes by genetic or environmental perturbations. Mechanistically, we discuss the increasingly well-understood molecular pathways responsible for epigenetic inheritance, with a focus on the unusual features of the germline epigenome.
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Affiliation(s)
- Ana Bošković
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
| | - Oliver J. Rando
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
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Baptissart M, Sèdes L, Holota H, Thirouard L, Martinot E, de Haze A, Rouaisnel B, Caira F, Beaudoin C, Volle DH. Multigenerational impacts of bile exposure are mediated by TGR5 signaling pathways. Sci Rep 2018; 8:16875. [PMID: 30443025 PMCID: PMC6237852 DOI: 10.1038/s41598-018-34863-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 08/16/2018] [Indexed: 01/26/2023] Open
Abstract
Besides their well-known roles in digestion and fat solubilization, bile acids (BAs) have been described as signaling molecules activating the nuclear receptor Farnesoid-X-receptor (FXRα) or the G-protein-coupled bile acid receptor-1 (GPBAR-1 or TGR5). In previous reports, we showed that BAs decrease male fertility due to abnormalities of the germ cell lineage dependent on Tgr5 signaling pathways. In the presentstudy, we tested whether BA exposure could impact germ cell DNA integrity leading to potential implications for progeny. For that purpose, adult F0 male mice were fed a diet supplemented with cholic acid (CA) or the corresponding control diet during 3.5 months prior mating. F1 progeny from CA exposed founders showed higher perinatal lethality, impaired BA homeostasis and reduced postnatal growth, as well as altered glucose metabolism in later life. The majority of these phenotypic traits were maintained up to the F2 generation. In F0 sperm cells, differential DNA methylation associated with CA exposure may contribute to the initial programming of developmental and metabolic defects observed in F1 and F2 offspring. Tgr5 knock-out mice combined with in vitro strategies defined the critical role of paternal Tgr5 dependent pathways in the multigenerational impacts of ancestral CA exposure.
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Affiliation(s)
- Marine Baptissart
- INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63000, Clermont-Ferrand, France
| | - Lauriane Sèdes
- INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63000, Clermont-Ferrand, France
| | - Hélène Holota
- INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63000, Clermont-Ferrand, France
| | - Laura Thirouard
- INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63000, Clermont-Ferrand, France
| | - Emmanuelle Martinot
- INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63000, Clermont-Ferrand, France
| | - Angélique de Haze
- INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63000, Clermont-Ferrand, France
| | - Betty Rouaisnel
- INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63000, Clermont-Ferrand, France
| | - Françoise Caira
- INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63000, Clermont-Ferrand, France
| | - Claude Beaudoin
- INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63000, Clermont-Ferrand, France
| | - David H Volle
- INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63000, Clermont-Ferrand, France.
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Cutuli D, Berretta E, Laricchiuta D, Caporali P, Gelfo F, Petrosini L. Pre-reproductive Parental Enriching Experiences Influence Progeny's Developmental Trajectories. Front Behav Neurosci 2018; 12:254. [PMID: 30483072 PMCID: PMC6240645 DOI: 10.3389/fnbeh.2018.00254] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 10/10/2018] [Indexed: 01/09/2023] Open
Abstract
While the positive effects of environmental enrichment (EE) applied after weaning, in adulthood, during aging, or even in the presence of brain damage have been widely described, the transgenerational effects of pre-reproductive EE have been less examined. And yet, this issue is remarkable given that parental environmental experience may imprint offspring’s phenotype over generations through many epigenetic processes. Interactions between individual and environment take place lifelong even before conception. In fact, the environment pre-reproductively experienced by the mother and/or the father exerts a substantial impact on neural development and motor and cognitive performances of the offspring, even if not directly exposed to social, cognitive, physical and/or motor enrichment. Furthermore, pre-reproductive parental enrichment exerts a transgenerational impact on coping response to stress as well as on the social behavior of the offspring. Among the effects of pre-reproductive parental EE, a potentiation of the maternal care and a decrease in global methylation levels in the frontal cortex and hippocampus of the progeny have been described. Finally, pre-reproductive EE modifies different pathways of neuromodulation in the brain of the offspring (involving brain-derived neurotrophic factor, oxytocin and glucocorticoid receptors). The present review highlights the importance of pre-reproductive parental enrichment in altering the performances not only of animals directly experiencing it, but also of their progeny, thus opening the way to new hypotheses on the inheritance mechanisms of behavioral traits.
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Affiliation(s)
- Debora Cutuli
- Department of Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.,Fondazione Santa Lucia, Rome, Italy
| | - Erica Berretta
- Department of Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.,Fondazione Santa Lucia, Rome, Italy
| | - Daniela Laricchiuta
- Department of Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.,Fondazione Santa Lucia, Rome, Italy
| | - Paola Caporali
- Department of Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.,Fondazione Santa Lucia, Rome, Italy
| | - Francesca Gelfo
- Fondazione Santa Lucia, Rome, Italy.,Department of Human Sciences, Guglielmo Marconi University, Rome, Italy
| | - Laura Petrosini
- Department of Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.,Fondazione Santa Lucia, Rome, Italy
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Saltzman AL, Soo MW, Aram R, Lee JT. Multiple Histone Methyl-Lysine Readers Ensure Robust Development and Germline Immortality in Caenorhabditis elegans. Genetics 2018; 210:907-923. [PMID: 30185429 PMCID: PMC6218232 DOI: 10.1534/genetics.118.301518] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 08/23/2018] [Indexed: 11/18/2022] Open
Abstract
Chromatin modifications, including methylation of histone H3 at lysine 27 (H3K27me) by the Polycomb group proteins, play a broadly conserved role in the maintenance of cell fate. Diverse chromatin organization modifier (chromo) domain proteins act as "readers" of histone methylation states. However, understanding the functional relationships among chromo domains and their roles in the inheritance of gene expression patterns remains challenging. Here, we identify two chromo-domain proteins, CEC-1 and CEC-6, as potential readers of H3K27me in Caenorhabditis elegans, where they have divergent expression patterns and contribute to distinct phenotypes. Both cec-1 and cec-6 genetically interact with another chromo-domain gene, cec-3, a reader of H3K9 methylation. Combined loss of cec-1 and cec-3 leads to developmental defects in the adult that result in decreased fitness. Furthermore, loss of cec-6 and cec-3 surprisingly leads to a progressive loss of fertility across generations, a "mortal germline" phenotype. Our results provide evidence of functional compensation between H3K27me and H3K9me heterochromatin pathways, and show that histone methylation readers contribute to both somatic development and transgenerational fitness.
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Affiliation(s)
- Arneet L Saltzman
- Department of Molecular Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts 02114
- Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115
| | - Mark W Soo
- Department of Molecular Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts 02114
| | - Reta Aram
- Department of Cell and Systems Biology, University of Toronto, Ontario M5S 3G5, Canada
| | - Jeannie T Lee
- Department of Molecular Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts 02114
- Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115
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KDM3A histone demethylase functions as an essential factor for activation of JAK2-STAT3 signaling pathway. Proc Natl Acad Sci U S A 2018; 115:11766-11771. [PMID: 30377265 DOI: 10.1073/pnas.1805662115] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Janus tyrosine kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway is essential for modulating cellular development, differentiation, and homeostasis. Thus, dysregulation of JAK2-STAT3 signaling pathway is frequently associated with human malignancies. Here, we provide evidence that lysine-specific demethylase 3A (KDM3A) functions as an essential epigenetic enzyme for the activation of JAK2-STAT3 signaling pathway. KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2-KDM3A signaling cascade induced by IL-6 leads to alteration of histone H3K9 methylation as a predominant epigenetic event, thereby providing the functional and mechanistic link between activation of JAK2-STAT3 signaling pathway and its epigenetic control. Together, our findings demonstrate that inhibition of KDM3A phosphorylation could be a potent therapeutic strategy to control oncogenic effect of JAK2-STAT3 signaling pathway.
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Reverón-Gómez N, González-Aguilera C, Stewart-Morgan KR, Petryk N, Flury V, Graziano S, Johansen JV, Jakobsen JS, Alabert C, Groth A. Accurate Recycling of Parental Histones Reproduces the Histone Modification Landscape during DNA Replication. Mol Cell 2018; 72:239-249.e5. [PMID: 30146316 PMCID: PMC6202308 DOI: 10.1016/j.molcel.2018.08.010] [Citation(s) in RCA: 166] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/25/2018] [Accepted: 08/07/2018] [Indexed: 12/22/2022]
Abstract
Chromatin organization is disrupted genome-wide during DNA replication. On newly synthesized DNA, nucleosomes are assembled from new naive histones and old modified histones. It remains unknown whether the landscape of histone post-translational modifications (PTMs) is faithfully copied during DNA replication or the epigenome is perturbed. Here we develop chromatin occupancy after replication (ChOR-seq) to determine histone PTM occupancy immediately after DNA replication and across the cell cycle. We show that H3K4me3, H3K36me3, H3K79me3, and H3K27me3 positional information is reproduced with high accuracy on newly synthesized DNA through histone recycling. Quantitative ChOR-seq reveals that de novo methylation to restore H3K4me3 and H3K27me3 levels occurs across the cell cycle with mark- and locus-specific kinetics. Collectively, this demonstrates that accurate parental histone recycling preserves positional information and allows PTM transmission to daughter cells while modification of new histones gives rise to complex epigenome fluctuations across the cell cycle that could underlie cell-to-cell heterogeneity.
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Affiliation(s)
- Nazaret Reverón-Gómez
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; The Novo Nordisk Center for Protein Research (CPR), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Cristina González-Aguilera
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Kathleen R Stewart-Morgan
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; The Novo Nordisk Center for Protein Research (CPR), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Nataliya Petryk
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; The Novo Nordisk Center for Protein Research (CPR), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Valentin Flury
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; The Novo Nordisk Center for Protein Research (CPR), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Simona Graziano
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; The Novo Nordisk Center for Protein Research (CPR), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Jens Vilstrup Johansen
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Janus Schou Jakobsen
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Constance Alabert
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Anja Groth
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; The Novo Nordisk Center for Protein Research (CPR), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
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49
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Yu C, Gan H, Serra-Cardona A, Zhang L, Gan S, Sharma S, Johansson E, Chabes A, Xu RM, Zhang Z. A mechanism for preventing asymmetric histone segregation onto replicating DNA strands. Science 2018; 361:1386-1389. [PMID: 30115745 PMCID: PMC6597248 DOI: 10.1126/science.aat8849] [Citation(s) in RCA: 182] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 07/30/2018] [Indexed: 12/11/2022]
Abstract
How parental histone (H3-H4)2 tetramers, the primary carriers of epigenetic modifications, are transferred onto leading and lagging strands of DNA replication forks for epigenetic inheritance remains elusive. Here we show that parental (H3-H4)2 tetramers are assembled into nucleosomes onto both leading and lagging strands, with a slight preference for lagging strands. The lagging-strand preference increases markedly in budding yeast cells lacking Dpb3 and Dpb4, two subunits of the leading strand DNA polymerase, Pol ε, owing to the impairment of parental (H3-H4)2 transfer to leading strands. Dpb3-Dpb4 binds H3-H4 in vitro and participates in the inheritance of heterochromatin. These results indicate that different proteins facilitate the transfer of parental (H3-H4)2 onto leading versus lagging strands and that Dbp3-Dpb4 plays an important role in this poorly understood process.
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Affiliation(s)
- Chuanhe Yu
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Haiyun Gan
- Institute for Cancer Genetics, Department of Pediatrics and Genetics and Development, Columbia University, New York, NY 10032, USA
| | - Albert Serra-Cardona
- Institute for Cancer Genetics, Department of Pediatrics and Genetics and Development, Columbia University, New York, NY 10032, USA
| | - Lin Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Songlin Gan
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Sushma Sharma
- Department of Medical Biochemistry and Biophysics, Umeå University, SE 90187 Umeå, Sweden
| | - Erik Johansson
- Department of Medical Biochemistry and Biophysics, Umeå University, SE 90187 Umeå, Sweden
| | - Andrei Chabes
- Department of Medical Biochemistry and Biophysics, Umeå University, SE 90187 Umeå, Sweden
| | - Rui-Ming Xu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhiguo Zhang
- Institute for Cancer Genetics, Department of Pediatrics and Genetics and Development, Columbia University, New York, NY 10032, USA.
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50
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Yoshida K, Muratani M, Araki H, Miura F, Suzuki T, Dohmae N, Katou Y, Shirahige K, Ito T, Ishii S. Mapping of histone-binding sites in histone replacement-completed spermatozoa. Nat Commun 2018; 9:3885. [PMID: 30250204 PMCID: PMC6155156 DOI: 10.1038/s41467-018-06243-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 08/14/2018] [Indexed: 12/11/2022] Open
Abstract
The majority of histones are replaced by protamines during spermatogenesis, but small amounts are retained in mammalian spermatozoa. Since nucleosomes in spermatozoa influence epigenetic inheritance, it is important to know how histones are distributed in the sperm genome. Conflicting data, which may result from different conditions used for micrococcal nuclease (MNase) digestion, have been reported: retention of nucleosomes at either gene promoter regions or within distal gene-poor regions. Here, we find that the swim-up sperm used in many studies contain about 10% population of sperm which have not yet completed the histone-to-protamine replacement. We develop a method to purify histone replacement-completed sperm (HRCS) and to completely solubilize histones from cross-linked HRCS without MNase digestion. Our results indicate that histones are retained at specific promoter regions in HRCS. This method allows the study of epigenetic status in mature sperm. While a majority of histones are replaced by protamines during spermatogenesis, a small amount is retained in mammalian spermatozoa. Here the authors develop a method to purify histones from replacement-completed sperm (HRCS), completely solubilize histones from cross-linked HRCS without MNase digestion, and map histone-binding sites in these cells.
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Affiliation(s)
- Keisuke Yoshida
- Cluster for Pioneering Research, CREST Research Project of JST (Japan Science and Technology Agency), RIKEN Tsukuba Institute, Tsukuba, Ibaraki, 305-0074, Japan.
| | - Masafumi Muratani
- Department of Genome Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan
| | - Hiromitsu Araki
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan
| | - Fumihito Miura
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan
| | - Takehiro Suzuki
- Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan
| | - Naoshi Dohmae
- Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan
| | - Yuki Katou
- Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan
| | - Katsuhiko Shirahige
- Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan
| | - Takashi Ito
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan
| | - Shunsuke Ishii
- Cluster for Pioneering Research, CREST Research Project of JST (Japan Science and Technology Agency), RIKEN Tsukuba Institute, Tsukuba, Ibaraki, 305-0074, Japan. .,Department of Functional Genomics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
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