Histone H3K27 methylation modulates the dynamics of FANCD2 on chromatin to facilitate NHEJ and genome stability

Abstract Background & Aims Hepatocellular carcinoma (HCC) is among the malignancies with the highest mortality. The key regulators and their interactive network in HCC pathogenesis remain unclear. Along with genetic mutations, aberrant epigenetic paradigms, including deregulated microRNAs (miRNAs), exert profound impacts on hepatocyte transformation and tumor microenvironment remodeling; however, the underlying mechanisms are largely uncharacterized. Methods We performed RNA sequencing on HCC specimens and bioinformatic analyses to identify tumor-associated miRNAs. The miRNA functional targets and their effects on tumor-infiltrating immune cells were investigated. The upstream events, particularly the epigenetic mechanisms responsible for miRNA deregulation in HCC, were explored. Results The miR-144/miR-451a cluster was downregulated in HCC and predicted a better HCC patient prognosis. These miRNAs promoted macrophage M1 polarization and antitumor activity by targeting hepatocyte growth factor (HGF) and macrophage migration inhibitory factor (MIF). The miR-144/miR-451a cluster and EZH2, the catalytic subunit of polycomb repressive complex (PRC2), formed a feedback circuit in which miR-144 targeted EZH2 and PRC2 epigenetically repressed the miRNA genes via histone H3K27 methylation of the promoter. The miRNA cluster was coordinately silenced by distal enhancer hypermethylation, disrupting chromatin loop formation and enhancer-promoter interactions. Clinical examinations indicated that methylation of this chromatin region is a potential HCC biomarker. Conclusions Our study revealed novel mechanisms underlying miR-144/miR-451a cluster deregulation and the crosstalk between malignant cells and tumor-associated macrophages (TAMs) in HCC, providing new insights into HCC pathogenesis and diagnostic strategies.

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Histone H3K27 methylation–mediated repression of Hairy regulates insect developmental transition by modulating ecdysone biosynthesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2101442118 ◽

2021 ◽

Vol 118 (35) ◽

pp. e2101442118

Author(s):

Yan Yang ◽

Tujing Zhao ◽

Zheng Li ◽

Wenliang Qian ◽

Jian Peng ◽

...

Keyword(s):

Larval Instar ◽

Prothoracic Gland ◽

Insect Development ◽

Down Regulation ◽

Developmental Defects ◽

Polycomb Repressive Complex 2 ◽

H3k27 Methylation ◽

Developmental Transition ◽

Histone H3k27 ◽

Inhibitor Treatment

Insect development is cooperatively orchestrated by the steroid hormone ecdysone and juvenile hormone (JH). The polycomb repressive complex 2 (PRC2)–mediated histone H3K27 trimethylation (H3K27me3) epigenetically silences gene transcription and is essential for a range of biological processes, but the functions of H3K27 methylation in insect hormone action are poorly understood. Here, we demonstrate that H3K27 methylation–mediated repression of Hairy transcription in the larval prothoracic gland (PG) is required for ecdysone biosynthesis in Bombyx and Drosophila. H3K27me3 levels in the PG are dynamically increased during the last larval instar. H3K27me3 reduction induced by the down-regulation of PRC2 activity via inhibitor treatment in Bombyx or PG-specific knockdown of the PRC2 component Su(z)12 in Drosophila diminishes ecdysone biosynthesis and disturbs the larval–pupal transition. Mechanistically, H3K27 methylation targets the JH signal transducer Hairy to repress its transcription in the PG; PG-specific knockdown or overexpression of the Hairy gene disrupts ecdysone biosynthesis and developmental transition; and developmental defects caused by PG-specific Su(z)12 knockdown can be partially rescued by Hairy down-regulation. The application of JH mimic to the PG decreases both H3K27me3 levels and Su(z)12 expression. Altogether, our study reveals that PRC2-mediated H3K27 methylation at Hairy in the PG during the larval period is required for ecdysone biosynthesis and the larval–pupal transition and provides insights into epigenetic regulation of the crosstalk between JH and ecdysone during insect development.

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Antagonistic roles of Polycomb repression and Notch signaling in the maintenance of somatic cell fate in C. elegans.

10.1101/055137 ◽

2016 ◽

Author(s):

Ringo Pueschel ◽

Francesca Coraggio ◽

Alisha Marti ◽

Peter Meister

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Ectopic Expression ◽

Epigenetic Mark ◽

Cell Plasticity ◽

Cell Therapies ◽

Polycomb Repressive Complex 2 ◽

C Elegans ◽

H3k27 Methylation ◽

Histone H3k27

AbstractReprogramming of somatic cells in intact nematodes allows characterization of cell plasticity determinants, which knowledge is crucial for regenerative cell therapies. By inducing muscle or endoderm transdifferentiation by the ectopic expression of selector transcription factors, we show that cell fate is remarkably robust in fully differentiated larvae. This stability depends on the presence of the Polycomb-associated histone H3K27 methylation, but not H3K9 methylation: in the absence of this epigenetic mark, many cells can be transdifferentiated which correlates with definitive developmental arrest. A candidate RNAi screen unexpectedly uncovered that knock-down of somatic NotchLIN-12 signaling rescues this larval arrest. Similarly in a wild-type context, genetically increasing NotchLIN-12 signaling renders a fraction of the animals sensitive to induced transdifferentiation. This reveals an antagonistic role of the Polycomb repressive complex 2 stabilizing cell fate and Notch signaling enhancing cell plasticity.

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G9a orchestrates PCL3 and KDM7A to promote histone H3K27 methylation

Scientific Reports ◽

10.1038/srep18709 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 18

Author(s):

Mei-Ren Pan ◽

Ming-Chuan Hsu ◽

Li-Tzong Chen ◽

Wen-Chun Hung

Keyword(s):

H3k27 Methylation ◽

Histone H3k27

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Histone demethylase KDM6B regulates human podocyte differentiation in vitro

Biochemical Journal ◽

10.1042/bcj20180968 ◽

2019 ◽

Vol 476 (12) ◽

pp. 1741-1751

Author(s):

Yanyan Guo ◽

Zuying Xiong ◽

Xiaoqiang Guo

Keyword(s):

Histone Methylation ◽

Chromatin Immunoprecipitation ◽

Kidney Development ◽

Histone Demethylase ◽

Differentiation Markers ◽

Chromatin Immunoprecipitation Assay ◽

H3k27 Methylation ◽

Filtration Barrier ◽

Histone H3k27

Abstract Podocytes are terminally differentiated and highly specialized glomerular cells, which have an essential role as a filtration barrier against proteinuria. Histone methylation has been shown to influence cell development, but its role in podocyte differentiation is less understood. In this study, we first examined the expression pattern of histone demethylase KDM6B at different times of cultured human podocytes in vitro. We found that the expression of KDM6B and podocyte differentiation markers WT1 and Nephrin are increased in the podocyte differentiation process. In cultured podocytes, KDM6B knockdown with siRNA impaired podocyte differentiation and led to expression down-regulation of WT1 and Nephrin. The treatment of podocytes with GSK-J4, a specific KDM6B inhibitor, can also obtain similar results. Overexpression of WT1 can rescue differentiated phenotype impaired by disruption of KDM6B. ChIP (chromatin immunoprecipitation) assay further indicated that KDM6B can bind the promoter region of WT1 and reduce the histone H3K27 methylation. Podocytes in glomeruli from nephrotic patients exhibited increased KDM6B contents and reduced H3K27me3 levels. These data suggest a role for KDM6B as a regulator of podocyte differentiation, which is important for the understanding of podocyte function in kidney development and related diseases.

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Polycomb Repression without Bristles: Facultative Heterochromatin and Genome Stability in Fungi

Genes ◽

10.3390/genes11060638 ◽

2020 ◽

Vol 11 (6) ◽

pp. 638 ◽

Cited By ~ 1

Author(s):

John B. Ridenour ◽

Mareike Möller ◽

Michael Freitag

Keyword(s):

Transcriptional Repression ◽

Genome Stability ◽

Genome Instability ◽

Future Research ◽

Genome Maintenance ◽

Facultative Heterochromatin ◽

H3k27 Methylation ◽

Polycomb Repression ◽

Fungal Genomes ◽

And Function

Genome integrity is essential to maintain cellular function and viability. Consequently, genome instability is frequently associated with dysfunction in cells and associated with plant, animal, and human diseases. One consequence of relaxed genome maintenance that may be less appreciated is an increased potential for rapid adaptation to changing environments in all organisms. Here, we discuss evidence for the control and function of facultative heterochromatin, which is delineated by methylation of histone H3 lysine 27 (H3K27me) in many fungi. Aside from its relatively well understood role in transcriptional repression, accumulating evidence suggests that H3K27 methylation has an important role in controlling the balance between maintenance and generation of novelty in fungal genomes. We present a working model for a minimal repressive network mediated by H3K27 methylation in fungi and outline challenges for future research.

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Histone H3K27 methylation perturbs transcriptional robustness and underpins dispensability of highly conserved genes in fungi

10.1101/2021.05.21.445187 ◽

2021 ◽

Author(s):

Sabina Moser Tralamazza ◽

Leen Nachira Abraham ◽

Benedito Correa ◽

Daniel Croll

Keyword(s):

Gene Expression ◽

Gc Content ◽

Housekeeping Gene ◽

Closely Related Species ◽

Histone Marks ◽

H3k27 Methylation ◽

Conserved Genes ◽

Repressive Histone Mark ◽

Histone H3k27 ◽

Evolutionary Fate

Epigenetic modifications are key regulators of gene expression and underpin genome integrity. Yet, how epigenetic changes affect the evolution and transcriptional robustness of genes remains largely unknown. Here, we show how the repressive histone mark H3K27me3 influences the trajectory of highly conserved genes in fungi. We first performed transcriptomic profiling on closely related species of the plant pathogen Fusarium graminearum species complex. We determined transcriptional responsiveness of genes across environmental conditions to determine expression robustness. To infer evolutionary conservation of coding sequences, we used a comparative genomics framework of 23 species across the Fusarium genus. We integrated histone methylation data from three Fusarium species across the phylogenetic breadth of the genus. Gene expression variation is negatively correlated with gene conservation confirming that highly conserved genes show higher expression robustness. Furthermore, we show that highly conserved genes marked by H3K27me3 deviate from the typical housekeeping gene archetype. Compared to the genomic background, H3K27me3 marked genes encode smaller proteins, exhibit lower GC content, weaker codon usage bias, higher levels of hydrophobicity and are enriched for functions related to regulation and membrane transport. The evolutionary age of conserved genes with H3K27me3 histone marks falls typically within the origins of the Fusarium genus. We show that highly conserved genes marked by H3K27me3 are more likely to be dispensable for survival. Lastly, we show that conserved genes exposed to repressive H3K27me3 marks across distantly related fungi predict transcriptional perturbation at the microevolutionary scale in Fusarium fungi. In conclusion, we establish how repressive histone marks determine the evolutionary fate of highly conserved genes across evolutionary timescales.

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Ezh2 as an epigenetic checkpoint regulator during monocyte differentiation: a potential target to improve cardiac repair after myocardial infarction

10.1101/2021.02.17.428828 ◽

2021 ◽

Author(s):

Rondeaux Julie ◽

Groussard Déborah ◽

Renet Sylvanie ◽

Tardif Virginie ◽

Dumesnil Anaïs ◽

...

Keyword(s):

Myocardial Infarction ◽

Macrophage Polarization ◽

Human Monocyte ◽

Cardiac Repair ◽

Monocyte Differentiation ◽

H3k27 Methylation ◽

Genes Expression ◽

Histone H3k27 ◽

Epigenetic Modulation

AbstractEpigenetic regulation of histone H3K27 methylation has recently emerged as a key step during M2-like macrophage polarization, essential for cardiac repair after Myocardial Infarction (MI). We demonstrate for the first-time that EZH2, responsible for H3K27 methylation, has an ectopic cytoplasmic localization during monocyte differentiation in M2 macrophages. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, enhances bivalent genes, expression to promote human monocyte repair functions. GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction after MI in vivo. In conclusion, our study reveals that epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling after MI.

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