Establishment of developmental gene silencing by ordered polycomb complex recruitment in early zebrafish embryos

Vertebrate embryos achieve developmental competency during zygotic genome activation (ZGA) by establishing chromatin states that silence yet poise developmental genes for subsequent lineage-specific activation. Here, we reveal the order of chromatin states in establishing developmental gene poising in preZGA zebrafish embryos. Poising is established at promoters and enhancers that initially contain open/permissive chromatin with 'Placeholder' nucleosomes (bearing H2A.Z, H3K4me1, and H3K27ac), and DNA hypomethylation. Silencing is initiated by the recruitment of Polycomb Repressive Complex 1 (PRC1), and H2Aub1 deposition by catalytic Rnf2 during preZGA and ZGA stages. During postZGA, H2Aub1 enables Aebp2-containing PRC2 recruitment and H3K27me3 deposition. Notably, preventing H2Aub1 (via Rnf2 inhibition) eliminates recruitment of Aebp2-PRC2 and H3K27me3, and elicits transcriptional upregulation of certain developmental genes during ZGA. However, upregulation is independent of H3K27me3 - establishing H2Aub1 as the critical silencing modification at ZGA. Taken together, we reveal the logic and mechanism for establishing poised/silent developmental genes in early vertebrate embryos.

CBX7 is Dualistic in Cancer Progression Based on its Function and Molecular Interactions

Chromobox protein homolog 7 (CBX7) is a member of the Chromobox protein family and participates in the formation of the polycomb repressive complex 1(PRC1). In cells, CBX7 often acts as an epigenetic regulator to regulate gene expression. However, pathologically, abnormal expression of CBX7 can lead to an imbalance of gene expression, which is closely related to the occurrence and progression of cancers. In cancers, CBX7 plays a dual role; On the one hand, it contributes to cancer progression in some cancers by inhibiting oncosuppressor genes. On the other hand, it suppresses cancer progression by interacting with different molecules to regulate the synthesis of cell cycle-related proteins. In addition, CBX7 protein may interact with different RNAs (microRNAs, long noncoding RNAs, circular RNAs) in different cancer environments to participate in a variety of pathways, affecting the development of cancers. Furthermore, CBX7 is involved in cancer-related immune response and DNA repair. In conclusion, CBX7 expression is a key factor in the occurrence and progression of cancers.

SALL1 Modulates CBX4 Stability, Nuclear Bodies, and Regulation of Target Genes

Development is orchestrated through a complex interplay of multiple transcription factors. The comprehension of this interplay will help us to understand developmental processes. Here we analyze the relationship between two key transcription factors: CBX4, a member of the Polycomb Repressive Complex 1 (PRC1), and SALL1, a member of the Spalt-like family with important roles in embryogenesis and limb development. Both proteins localize to nuclear bodies and are modified by the small ubiquitin-like modifier (SUMO). Our results show that CBX4 and SALL1 interact in the nucleoplasm and that increased SALL1 expression reduces ubiquitination of CBX4, enhancing its stability. This is accompanied by an increase in the number and size of CBX4-containing Polycomb bodies, and by a greater repression of CBX4 target genes. Thus, our findings uncover a new way of SALL1-mediated regulation of Polycomb bodies through modulation of CBX4 stability, with consequences in the regulation of its target genes, which could have an impact in cell differentiation and development.

Impaired KDM2B-mediated PRC1 recruitment to chromatin causes neural stem cell senescence and ASD/ID-like behavioral deficits

Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental diseases associated with various genetic mutations. Recent clinical studies report that chromosomal 12q24.31 microdeletions are associated with human ASD/ID. However, the causality and underlying mechanisms linking 12q24.31 microdeletions to ASD/ID pathogenesis remain undetermined. Here we show Kdm2b, one of the genes located in chromosomal 12q24.31, plays a critical role in maintaining neural stem cells (NSCs) in the developing mouse brain. Loss of the CxxC-ZF domain of KDM2B impairs its function in recruiting Polycomb repressive complex 1 (PRC1) to chromatin, resulting in de-repression of genes involved in cell apoptosis, cell cycle arrest, NSC premature senescence, and leading to the loss of NSC populations in the brain. Importantly, the Kdm2b mutation is sufficient to induce ASD/ID-like social and memory deficits in adult mice. Thus, our study reveals a critical role of an epigenetic factor KDM2B in normal brain development, a causality between the Kdm2b mutation and genesis of ASD/ID-like phenotypes in mice, and potential molecular mechanisms linking the function of KDM2B-PRC1 in transcriptional regulation and NSC senescence to the12q24.31 microdeletion-associated ASD/ID.

Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression

Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention.

Transition from Seeds to Seedlings: Hormonal and Epigenetic Aspects

Transition from seed to seedling is one of the critical developmental steps, dramatically affecting plant growth and viability. Before plants enter the vegetative phase of their ontogenesis, massive rearrangements of signaling pathways and switching of gene expression programs are required. This results in suppression of the genes controlling seed maturation and activation of those involved in regulation of vegetative growth. At the level of hormonal regulation, these events are controlled by the balance of abscisic acid and gibberellins, although ethylene, auxins, brassinosteroids, cytokinins, and jasmonates are also involved. The key players include the members of the LAFL network—the transcription factors LEAFY COTYLEDON1 and 2 (LEC 1 and 2), ABSCISIC ACID INSENSITIVE3 (ABI3), and FUSCA3 (FUS3), as well as DELAY OF GERMINATION1 (DOG1). They are the negative regulators of seed germination and need to be suppressed before seedling development can be initiated. This repressive signal is mediated by chromatin remodeling complexes—POLYCOMB REPRESSIVE COMPLEX 1 and 2 (PRC1 and PRC2), as well as PICKLE (PKL) and PICKLE-RELATED2 (PKR2) proteins. Finally, epigenetic methylation of cytosine residues in DNA, histone post-translational modifications, and post-transcriptional downregulation of seed maturation genes with miRNA are discussed. Here, we summarize recent updates in the study of hormonal and epigenetic switches involved in regulation of the transition from seed germination to the post-germination stage.

H2A ubiquitination is essential for Polycomb Repressive Complex 1-mediated gene regulation in Marchantia polymorpha

Background Polycomb repressive complex 1 (PRC1) and PRC2 are chromatin regulators maintaining transcriptional repression. The deposition of H3 lysine 27 tri-methylation (H3K27me3) by PRC2 is known to be required for transcriptional repression, whereas the contribution of H2A ubiquitination (H2Aub) in the Polycomb repressive system remains unclear in plants. Results We directly test the requirement of H2Aub for gene regulation in Marchantia polymorpha by generating point mutations in H2A that prevent ubiquitination by PRC1. These mutants show reduced H3K27me3 levels on the same target sites as mutants defective in PRC1 subunits MpBMI1 and the homolog MpBMI1L, revealing that PRC1-catalyzed H2Aub is essential for Polycomb system function. Furthermore, by comparing transcriptome data between mutants in MpH2A and MpBMI1/1L, we demonstrate that H2Aub contributes to the PRC1-mediated transcriptional level of genes and transposable elements. Conclusion Together, our data demonstrates that H2Aub plays a direct role in H3K27me3 deposition and is required for PRC1-mediated transcriptional changes in both genes and transposable elements in Marchantia.

VAL1 as an assembly platform co-ordinating co-transcriptional repression and chromatin regulation at Arabidopsis FLC

Polycomb (PcG) silencing is crucial for development across eukaryotes, but how PcG targets are regulated is still incompletely understood. The slow timescale of cold-induced PcG silencing at Arabidopsis thaliana FLOWERING LOCUS C (FLC) makes it an excellent system to dissect this mechanism. Binding of the DNA binding protein VAL1 to an FLC intronic RY motif within the PcG nucleation region is an early step in the silencing process. VAL1 interacts with APOPTOSIS AND SPLICING ASSOCIATED PROTEIN (ASAP) complex and POLYCOMB REPRESSIVE COMPLEX 1 (PRC1). Here, we show that ASAP and PRC1 function as co-repressors that quantitatively regulate FLC transcription. Upon the shift to cold PRC1-mediated H2Aub accumulates only at the nucleation region, is transiently maintained after transfer back to warm, but unlike the PRC2-delivered H3K27me3 does not spread across the locus. H2K27me3 thus provides long-term epigenetic silencing, whereas H2Aub is a transient repression signal. Overall, our work highlights how a DNA sequence-specific binding protein can act as an assembly platform co-ordinating the co-transcriptional repression and chromatin regulation necessary for Polycomb silencing.

VAL genes regulate vegetative phase change via miR156-dependent and independent mechanisms

How organisms control when to transition between different stages of development is a key question in biology. In plants, epigenetic silencing by Polycomb repressive complex 1 (PRC1) and PRC2 plays a crucial role in promoting developmental transitions, including from juvenile-to-adult phases of vegetative growth. PRC1/2 are known to repress the master regulator of vegetative phase change, miR156, leading to the transition to adult growth, but how this process is regulated temporally is unknown. Here we investigate whether transcription factors in the VIVIPAROUS/ABI3-LIKE (VAL) gene family provide the temporal signal for the epigenetic repression of miR156. Exploiting a novel val1 allele, we found that VAL1 and VAL2 redundantly regulate vegetative phase change by controlling the overall level, rather than temporal dynamics, of miR156 expression. Furthermore, we discovered that VAL1 and VAL2 also act independently of miR156 to control this important developmental transition. In combination, our results highlight the complexity of temporal regulation in plants.