The Dynamic Partnership of Polycomb and Trithorax in Brain Development and Diseases

Kuehner, Janise N.; Yao, Bing

doi:10.3390/epigenomes3030017

Cited by 14 publications

(11 citation statements)

References 207 publications

(249 reference statements)

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“…Our spatio-temporal transcriptomic and epigenomic analysis provides an in-depth view into the strikingly different regulatory landscape present in the anterior versus posterior regions of the CNS, and the profound importance of PRC2 in estab-lishing and driving these differences. Previous studies show that the role of PRC2 in gating A-P gene expression is integral for mouse, fly, and zebrafish development (8,43,44). Our work extends upon this, revealing that the FB genes dysregulated in the developing mouse PRC2 mutant CNS are also selectively expressed during human FB embryonic development, underscoring the evolutionary conservation of brain development across bilateria.…”

Section: Prc2 Inactivation Causes Extensive Direct and Indirect Effectssupporting

confidence: 76%

Integrated gene landscapes uncover multi-layered roles of repressive histone marks during mouse CNS development

Mora

Rakar

Cobeta

et al. 2021

Preprint

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A prominent aspect of most, if not all, central nervous systems (CNSs) is that anterior regions (brain) are larger than posterior ones (spinal cord). Studies in Drosophila and mouse have revealed that the Polycomb Repressor Complex 2 (PRC2) acts by several mechanisms to promote anterior CNS expansion. However, it is unclear if PRC2 acts directly and/or indirectly upon key downstream genes, what the full spectrum of PRC2 action is during embryonic CNS development and how PRC2 integrates with the epigenetic landscape. We removed PRC2 function from the developing mouse CNS, by mutating the key gene Eed, and generated spatio-temporal transcriptomic data. We developed a bioinformatics workflow that incorporates standard statistical analyses with machine learning to integrate the transcriptomic response to PRC2 inactivation with epigenetic information from ENCODE. This multi-variate analysis corroborates the central involvement of PRC2 in anterior CNS expansion, and reveals layered regulation via PRC2. These findings uncover a differential logic for the role of PRC2 upon functionally distinct gene categories that drive CNS anterior expansion. To support the analysis of emerging multi-modal datasets, we provide a novel bioinformatics package that can disentangle regulatory underpinnings of heterogeneous biological processes.

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Section: Prc2 Inactivation Causes Extensive Direct and Indirect Effectssupporting

confidence: 76%

Integrated gene landscapes uncover multi-layered roles of repressive histone marks during mouse CNS development

Mora

Rakar

Cobeta

et al. 2021

Preprint

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“…More than a quarter of these repressed TSSs also overlapped known polycomb targets 19 possibly reflecting dysregulation of the BAF/PRC relationship. Given the well-established antagonistic roles of BAF and PRCs in regulating neuronal differentiation 20 – 22 , this result suggests that promoter-specific loss of chromatin accessibility in KO cells is possibly linked to β-actin-dependent disruption of BRG1 binding.…”

Section: Resultsmentioning

confidence: 78%

β-actin dependent chromatin remodeling mediates compartment level changes in 3D genome architecture

et al. 2021

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Abstractβ-actin is a crucial component of several chromatin remodeling complexes that control chromatin structure and accessibility. The mammalian Brahma-associated factor (BAF) is one such complex that plays essential roles in development and differentiation by regulating the chromatin state of critical genes and opposing the repressive activity of polycomb repressive complexes (PRCs). While previous work has shown that β-actin loss can lead to extensive changes in gene expression and heterochromatin organization, it is not known if changes in β-actin levels can directly influence chromatin remodeling activities of BAF and polycomb proteins. Here we conduct a comprehensive genomic analysis of β-actin knockout mouse embryonic fibroblasts (MEFs) using ATAC-Seq, HiC-seq, RNA-Seq and ChIP-Seq of various epigenetic marks. We demonstrate that β-actin levels can induce changes in chromatin structure by affecting the complex interplay between chromatin remodelers such as BAF/BRG1 and EZH2. Our results show that changes in β-actin levels and associated chromatin remodeling activities can not only impact local chromatin accessibility but also induce reversible changes in 3D genome architecture. Our findings reveal that β-actin-dependent chromatin remodeling plays a role in shaping the chromatin landscape and influences the regulation of genes involved in development and differentiation.

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“…More than a quarter of these repressed TSSs also overlapped known polycomb targets (19) possibly reflecting dysregulation of the BAF/PRC relationship. Given the well-established antagonistic roles of BAF and PRCs in regulating neuronal differentiation (20)(21)(22), this result suggests that promoter-specific loss of chromatin accessibility in KO cells is possibly linked to β-actin-dependent disruption of BRG1 binding.…”

Section: β-Actin Loss Induces Dosage-dependent Changes In Chromatin Amentioning

confidence: 80%

β-actin dependent chromatin remodeling mediates compartment level changes in 3D genome architecture

Mahmood

Xie

Said

et al. 2020

Preprint

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β-actin is a crucial component of several chromatin remodeling complexes that control chromatin structure and accessibility. The mammalian Brahma-associated factor (BAF) is one such complex that plays essential roles in development and differentiation by regulating the chromatin state of critical genes and opposing the repressive activity of polycomb repressive complexes (PRCs). While previous work has shown that β-actin loss can lead to extensive changes in gene expression and heterochromatin organization, it is not known if changes in β-actin levels can directly influence chromatin remodeling activities of BAF and polycomb proteins. Here we conduct a comprehensive genomic analysis of β-actin knockout mouse embryonic fibroblasts (MEFs) using ATAC-Seq, HiC-seq, RNA-Seq and ChIP-Seq of various epigenetic marks. We demonstrate that β-actin levels can affect the complex interplay between chromatin remodelers such as BAF/BRG1 and EZH2 in a dosage-dependent manner. Our results show that changes in β-actin levels and associated chromatin remodeling activities can not only impact local chromatin accessibility but also induce reversible changes in 3D genome architecture. Our findings support a novel role for β-actin-dependent chromatin remodeling in shaping the chromatin landscape and regulating genes involved in development and differentiation. METHODSCell culture: WT, KO and HET mouse embryonic fibroblasts (MEFs) (from the lab of Dr. Christophe Ampe, University of Gent, Belgium) were maintained and cultured with Dulbecco's modified Eagle medium (DMEM) with high glucose, 10% fetal bovine serum (FBS) and 100 units/mL penicillin and 100 μg/mL streptomycin, in a humidified incubator with 5% CO2 at 37⁰C. The KO(Mm) and KO(Hs) cells with GFP and NLS-β actin re-introduced into KO cells were generated by retroviral transduction as described in (2). ATAC-Seq:Samples with 50,000 cells per condition were shipped in frozen medium (DMEM with 50 % FBS and 10% DMSO) on dry ice to Novogene (Beijing, China). All subsequent processing was performed by Novogene using standard DNA extraction and library preparation protocols. Cell nuclei were isolated, mixed with Tn5 Transposase with two adapters and tagmentation was performed for 30 minutes at 37⁰C. The fragmented DNA was purified and amplified with limited PCR cycle using index primers. Libraries were prepared according to recommended Illumina NovaSeq6000 protocols. All ATAC-Seq processing was performed by Novogene (Beijing, China). ChIP-Seq:ChIP-Seq for BRG1, H3K9me3 and H3K27me3 was performed as described in (2). For EZH2 ChIP-Seq, Mouse Embryonic fibroblasts were crosslinked using 1% formaldehyde (Sigma cat. No. F8775) for 10 minutes followed by quenching with 0.125 M Glycine for 5 minutes and lysis with lysis buffer 1 -LB1-(50 mM Hepes KOH pH 7.5, 10 mM NaCl, 1mM EDTA, 10% glycerol, 0.5% NP-40, 0.25% Triton X-100). Nuclei were pelleted, collected and washed using lysis buffer 2 -LB2-(10 mM Tris HCl pH 8, 200 mM NaCl, 1mM EDTA, 0.5 mM EGTA). This was followed by lysis using lysis buf...

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The Dynamic Partnership of Polycomb and Trithorax in Brain Development and Diseases

Cited by 14 publications

References 207 publications

Integrated gene landscapes uncover multi-layered roles of repressive histone marks during mouse CNS development

Integrated gene landscapes uncover multi-layered roles of repressive histone marks during mouse CNS development

β-actin dependent chromatin remodeling mediates compartment level changes in 3D genome architecture

β-actin dependent chromatin remodeling mediates compartment level changes in 3D genome architecture

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