CTCF-dependent chromatin architecture and SUZ12/PRC2 complex recruitment are required for peripheral myelination and repair
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA574954 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10202911.fastq.gz | Fastqsanger.gz | |||
| SRR10202912.fastq.gz | Fastqsanger.gz | |||
| SRR10202913.fastq.gz | Fastqsanger.gz | |||
| SRR10202914.fastq.gz | Fastqsanger.gz | |||
| SRR10202915_1.fastq.gz | Fastqsanger.gz |
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Project description:Chromatin organization is critical for cell growth, differentiation, and disease development, however, its functions in peripheral myelination and myelin repair remain elusive. Here we observed a global diminution of chromatin accessibility during Schwann cell differentiation and demonstrated that the chromatin organizer CCCTC-binding factor (CTCF) is critical for Schwann cell myelination and myelin regeneration after nerve injury. Inhibition of Ctcf or its deletion blocked Schwann cell differentiation at the pre-myelinating stage, whereas overexpression of CTCF promoted the myelination program. CTCF establishes the chromatin interaction loop between promoters and regulatory elements to promote expression of key pro-myelinogenic factors such as EGR2. In addition, CTCF interacts with SUZ12, a component of polycomb-repressive-complex 2, to repress expression of immature Schwann cell-associated regulators including HES1, RSPO2, and CALCA. Together, our findings reveal the dual role of CTCF-dependent chromatin organization in promoting myelinogenic programs and recruiting chromatin-repressive complexes to block differentiation inhibitors to control peripheral myelination and myelin repair.
2020-06-22 | GSE138117 | GEO
Project description:Polycomb repressive complex 2 (PRC2) maintains repression of genes specific for other cell differentiation stages through methylation of histone H3 lysine 27 (H3K27me3) and is regulated by nascent RNA. In endometrial stromal sarcoma, the PRC2 subunit SUZ12 is often fused with the transcription factor JAZF1. How JAZF1-SUZ12 affects PRC2 function and cell differentiation are unknown. Here, we show that JAZF1-SUZ12 disrupts PRC2 recruitment, gene expression and cell differentiation. The loss of the SUZ12 N-terminus in the fusion protein disrupted interaction with JARID2, EPOP and PALI1 and prevented recruitment of PRC2 from RNA to chromatin. JAZF1-SUZ12 occupied PRC2 target genes in undifferentiated cells but relocated to JAZF1 target genes during cell differentiation, altering patterns of H3K27me3 and gene expression and disrupting cell differentiation. We then performed RNA-seq in primary human cells expreesing all proteins, showing that JAZF1-SUZ12 was promoting a specific set of genes upregulated in decidualisation, while blocking immune related genes. These results reveal the defects in PRC2 function and cell differentiation caused by the JAZF1-SUZ12 fusion protein, which may underlie its role in oncogenesis.
2022-04-25 | GSE169658 | GEO
Project description:JAZF1-SUZ12 dysregulates PRC2 recruitment and gene expression during cell differentiation
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Project description:The Polycomb repressive complex 2 (PRC2) catalyzes H3K27 methylation and is required for maintaining transcriptional patterns and cellular identity, but the specification and maintenance of genomic PRC2 binding and H3K27 methylation patterns remain incompletely understood. Epigenetic mechanisms have been proposed, wherein pre-existing H3K27 methylation directs recruitment and regulates the catalytic activity of PRC2 to support its own maintenance. Here we investigate if such mechanisms are required for specifying H3K27 methylation patterns in mouse embryonic stem cells. Through genetic knockouts of subunits, we find that PRC2 is responsible for all levels of H3K27 methylation, and that methylation patterns can be accurately established de novo, when a subunit is reintroduced in the absence of pre-existing H3K27 methylation and PRC2 chromatin binding. Furthermore, we find that the core-subunit SUZ12 directs genomic binding of PRC2, which is essential for establishing correct methylation patterns.
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Project description:Chromatin organization is critical for cell growth, differentiation, and disease development, however, its functions in peripheral myelination and myelin repair remain elusive. In this report, we demonstrate that the CCCTC-binding factor (CTCF), a crucial chromatin organizer, is essential for Schwann cell myelination and myelin regeneration after nerve injury. Inhibition of CTCF or its deletion blocks Schwann cell differentiation at the pro-myelinating stage, whereas overexpression of CTCF promotes the myelination program. We find that CTCF establishes chromatin interaction loops between enhancer and promoter regulatory elements and promotes expression of a key pro-myelinogenic factor EGR2. In addition, CTCF interacts with SUZ12, a component of polycomb-repressive-complex 2 (PRC2), to repress the transcriptional program associated with negative regulation of Schwann cell maturation. Together, our findings reveal a dual role of CTCF-dependent chromatin organization in promoting myelinogenic programs and recruiting chromatin-repressive complexes to block Schwann cell differentiation inhibitors to control peripheral myelination and repair.
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Project description:Suz12 exon 4 encodes 23 amino acids (aa 129–152 in SUZ12-L) that partially overlap with the WD-binding domain 1 (WDB1, 110–145). We reasoned that exon 4 skipping might alter the structure of SUZ12 and, possibly, PRC2 composition. To explore this possibility, we generated ESCs that lack the Suz12 exon 4 via CRISPR-Cas9–induced deletion. In addition, to rule out any biases due to the expression levels and/or SUZ12 epitope masking, we generated Suz12 knockout (KO) ESCs (herein, KO) in which Suz12 expression was subsequently rescued by re-introducing either the Suz12-L or Suz12-S mouse isoform fused to a triple-Flag tag under the regulation of a CAG promoter (KO+L/S; Figures S2H–S2K). We performed SUZ12 immunoprecipitation coupled with mass spectrometry (IP-MS) in the WT and ∆ex4 clones to compare their interactomes and with a flag antibody in the KO and rescue cell lines. As expected, no peptides corresponding to exon 4 were retrieved in ∆ex4 samples, while the rest of the sequence displayed similar coverage. Comparison of interactors in the two conditions revealed that SUZ12 binding to AEBP2 and JARID2 was strongly reduced in ∆ex4 cells with respect to WT cells, whereas SUZ12 binding to most core components or to PRC2.1-specific factors was unchanged or only slightly increased . These observations were confirmed by SUZ12 IP followed by Western blot (WB). Flag IP-MS in rescue cells confirmed that, while the long isoform was able to correctly form comparable amounts of both PRC2.1 and PRC2.2 subtypes, interaction of the SUZ12-S with PRC2.2-specific factors was drastically reduced.
2024-03-18 | PXD046660 | Pride
Project description:Long noncoding RNAs (lncRNAs) are emerging as important regulators of cellular functions, but their roles in myelination in the CNS remain undefined. Through de novo transcriptome reconstruction at multiple stages, we establish dynamic expression profiles of lncRNAs during oligodendrocyte lineage progression and uncover a cohort of oligodendrocyte-enriched lncRNAs. Co-expression network analysis reveals a cohort of lncRNAs is linked to protein-coding genes associated with oligodendrocyte maturation. We identify a conserved chromatin-associated oligodendrocyte-restricted lncRNA, lncOL1. Overexpression of lncOL1 promotes oligodendrocyte differentiation in the developing brain, whereas genetic inactivation of lncOL1 causes defects in myelination and remyelination in the CNS. We further show that lncOL1 interacts with Suz12, a component of polycomb repressive complex 2, to promote oligodendrocyte differentiation in part through Suz12-mediated silencing of a differentiation inhibitory network that antagonizes OL maturation. Together, our findings demonstrate lncRNAs as a key layer of the genetic circuitry that controls CNS myelination and myelin repair.
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Project description:Long noncoding RNAs (lncRNAs) are emerging as important regulators of cellular functions, but their roles in myelination in the CNS remain undefined. Through de novo transcriptome reconstruction at multiple stages, we establish dynamic expression profiles of lncRNAs during oligodendrocyte lineage progression and uncover a cohort of oligodendrocyte-enriched lncRNAs. Co-expression network analysis reveals a cohort of lncRNAs is linked to protein-coding genes associated with oligodendrocyte maturation. We identify a conserved chromatin-associated oligodendrocyte-restricted lncRNA, lncOL1. Overexpression of lncOL1 promotes oligodendrocyte differentiation in the developing brain, whereas genetic inactivation of lncOL1 causes defects in myelination and remyelination in the CNS. We further show that lncOL1 interacts with Suz12, a component of polycomb repressive complex 2, to promote oligodendrocyte differentiation in part through Suz12-mediated silencing of a differentiation inhibitory network that antagonizes OL maturation. Together, our findings demonstrate lncRNAs as a key layer of the genetic circuitry that controls CNS myelination and myelin repair.
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Project description:Long noncoding RNAs (lncRNAs) are emerging as important regulators of cellular functions, but their roles in myelination in the CNS remain undefined. Through de novo transcriptome reconstruction at multiple stages, we establish dynamic expression profiles of lncRNAs during oligodendrocyte lineage progression and uncover a cohort of oligodendrocyte-enriched lncRNAs. Co-expression network analysis reveals a cohort of lncRNAs is linked to protein-coding genes associated with oligodendrocyte maturation. We identify a conserved chromatin-associated oligodendrocyte-restricted lncRNA, lncOL1. Overexpression of lncOL1 promotes oligodendrocyte differentiation in the developing brain, whereas genetic inactivation of lncOL1 causes defects in myelination and remyelination in the CNS. We further show that lncOL1 interacts with Suz12, a component of polycomb repressive complex 2, to promote oligodendrocyte differentiation in part through Suz12-mediated silencing of a differentiation inhibitory network that antagonizes OL maturation. Together, our findings demonstrate lncRNAs as a key layer of the genetic circuitry that controls CNS myelination and myelin repair.
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Project description:Polycomb Repressive Complex 2 (PRC2) plays an essential role in development by catalysing trimethylation of histone H3 lysine 27 (H3K27me3), resulting in gene repression. PRC2 consists of two sub-complexes, PRC2.1 and PRC2.2, in which the PRC2 core associates with distinct ancillary subunits such as MTF2 and JARID2, respectively. Both MTF2, present in PRC2.1, and JARID2, present in PRC2.2, play a role in core PRC2 recruitment to target genes in mouse embryonic stem cells (mESCs). However, it remains unclear how these distinct sub-complexes cooperate to establish H3K27me3 domains. Here, we combine a range of Polycomb mutant mESCs with chemical inhibition of PRC2 catalytic activity, to systematically dissect their relative contributions to PRC2 binding to target loci. We find that PRC2.1 and PRC2.2 mediate two distinct paths for recruitment, with mutually reinforced binding. Part of the cross-talk between PRC2.1 and PRC2.2 occurs via their catalytic product H3K27me3, which is bound by the PRC2 core-subunit EED, thereby mediating a positive feedback. Strikingly, removal of either JARID2 or H3K27me3 only has a minor effect on PRC2 recruitment, whereas their combined ablation largely attenuates PRC2 recruitment. This strongly suggests an unexpected redundancy between JARID2 and EED-H3K27me3-mediated recruitment of PRC2. Furthermore, we demonstrate that all core PRC2 recruitment occurs through the combined action of MTF2-mediated recruitment of PRC2.1 to DNA and PRC1-mediated recruitment of JARID2-containing PRC2.2. Both axes of binding are supported by EED-H3K27me3 positive feedback, but to a different degree. Finally, we provide evidence that PRC1 and PRC2 mutually reinforce reciprocal binding. Together, these data disentangle the interdependent and cooperative interactions between Polycomb complexes that are important to establish Polycomb repression at target sites.
2021-09-22 | PXD020684 | Pride