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Genome-wide maps of chromatin state in E12.5 forebrain tissues

ABSTRACT: The histone methyltransferase complex PRC2 is a crucial chromatin modifier and controls key steps in developmental transitions and cell fate choices. Mutations in PRC2 core subunits are found in Weaver syndrome with craniofacial defects, intellectual disabilities, and often macrocephaly, but its pathogenicity and molecular mechanism are unknown. Here, we examined the role of PRC2/Eed in neural stem/progenitor cells (NSPCs) during cortical neurogenesis We found that Eed is highly expressed in embryonic cerebral cortex and specific deletion of Eed in forebrain reduced the number of upper layer neurons but not deeper layer neurons and ultimately contributed to abnormal cortical development. In addition, our results revealed that PRC2/Eed regulated Hedgehog signaling pathway through activation of Gli3 not dependent on H3K27me3 but H3K27ac. What?s more, Increased Gli3 in NSPCs could reduce Gli1 expression and contribute to the defects of cortical neurogenesis caused by Eed deletion. Finally, Hedgehog signaling activation with small molecule SAG or genetic inactivation of Ptch1 could partially rescue the cortical neurogenesis defects in vivo after Eed depletion. In general, we identified a novel PRC2/Eed-Gli3-Gli1 regulatory axis that is critical for normal cortical neurogenesis. Our findings define a critical function for PRC2/Eed in cortical development and shed light on the genetic basis of intellectual disabilities of neural developmental disorders caused by PRC2/Eed mutation.

ORGANISM(S): Mus musculus

PROVIDER: GSE169401 | GEO | 2022/09/21

REPOSITORIES: GEO

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Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type and EedcKO Forebrain Transcriptomes

Project description:The histone methyltransferase complex PRC2 is a crucial chromatin modifier and controls key steps in developmental transitions and cell fate choices. Mutations in PRC2 core subunits are found in Weaver syndrome with craniofacial defects, intellectual disabilities, and often macrocephaly, but its pathogenicity and molecular mechanism are unknown. Here, we examined the role of PRC2/Eed in neural stem/progenitor cells (NSPCs) during cortical neurogenesis We found that Eed is highly expressed in embryonic cerebral cortex and specific deletion of Eed in forebrain reduced the number of upper layer neurons but not deeper layer neurons and ultimately contributed to abnormal cortical development. In addition, our results revealed that PRC2/Eed regulated Hedgehog signaling pathway through activation of Gli3 not dependent on H3K27me3 but H3K27ac. What?s more, Increased Gli3 in NSPCs could reduce Gli1 expression and contribute to the defects of cortical neurogenesis caused by Eed deletion. Finally, Hedgehog signaling activation with small molecule SAG or genetic inactivation of Ptch1 could partially rescue the cortical neurogenesis defects in vivo after Eed depletion. In general, we identified a novel PRC2/Eed-Gli3-Gli1 regulatory axis that is critical for normal cortical neurogenesis. Our findings define a critical function for PRC2/Eed in cortical development and shed light on the genetic basis of intellectual disabilities of neural developmental disorders caused by PRC2/Eed mutation.

2022-09-21 | GSE169395 | GEO

RNA-Seq analysis of wild-type and Hdac3-null E16.5 neurospheres and P0 cerebral cortex

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2019-06-25 | GSE133195 | GEO

Single cell transcriptomics of the cerebral cortex in mice lacking the PRC2 gene Eed

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2019-11-15 | PXD005598 | Pride

Metabolic control of adult neural stem cell activity by FASN-dependent lipogenesis

Project description:Mechanisms controlling the proliferative activity of neural stem/progenitor cells (NSPCs) play a pivotal role to ensure life-long neurogenesis in the mammalian brain. How metabolic programs are coupled with NSPC activity remains unknown. Here we show that fatty acid synthase (FASN), the key enzyme of de novo lipogenesis, is highly active in adult NSPCs and that conditional deletion of FASN in NSPCs impairs adult neurogenesis. The rate of de novo lipid synthesis and subsequent proliferation of NSPCs is regulated by Spot14, a gene we found to be selectively expressed in low proliferating adult NSPCs. Spot14 reduces the availability of malonyl-CoA, which is an essential substrate for FASN to fuel lipogenesis. Thus, we here identified a functional coupling between the regulation of lipid metabolism and adult NSPC proliferation. 6 samples were analyzed. Spot14+: Spot14 GFP positive mouse neural stem cell, 3 biological rep Spot14-: Spot14 GFP negative mouse neural stem cell, 3 biological rep

2012-11-02 | E-GEOD-27391 | biostudies-arrayexpress

FASN-dependent metabolism links neurogenic stem/progenitor cell activity to intellectual disability

Project description:Failure of neural stem/progenitor cell (NSPC) activity and subsequently neurogenesis during brain development has been linked to cognitive impairment and intellectual disability. However, it remains unclear if changes in metabolism, recently discovered as a key regulator of somatic stem cell activity, contribute to altered neurogenesis and cognitive deficits in humans. To investigate a link between NSPC-associated lipid metabolism and brain development, we generated mice and human embryonic stem cells (hESCs) mimicking a variant in fatty acid synthase (FASN; R1819W), a metabolic regulator of rodent NSPC activity recently identified in humans with intellectual disability. Mice homozygous for the FASN R1812W variant have impaired hippocampal NSPC activity associated with cognitive impairment due to presumed toxic accumulation of lipids in NSPCs and subsequent lipogenic ER stress. Human NSPCs homozygous for the FASN R1819W variant show reduced rates of proliferation in embryonic 2D cultures and 3D forebrain regionalized organoids, revealing that the functional significance of lipid metabolism for neurogenic proliferation of progenitors is conserved between rodents and humans. By taking a disease modeling approach, using mouse and human tissue genome engineering, our data provide genetic evidence for a link between altered lipid metabolism, NSPC activity and brain function.

2020-03-18 | GSE115851 | GEO

Repression of the soma-specific transcriptome by Polycomb-repressive complex 2 promotes male germ cell development

Project description:Polycomb-repressive complex 2 (PRC2) catalyzes the methylation of histone H3 Lys27 (H3K27) and functions as a critical epigenetic regulator of both stem cell pluripotency and somatic differentiation, but its role in male germ cell development is unknown. Using conditional mutagenesis to remove the core PRC2 subunits EED and SUZ12 during male germ cell development, we identified a requirement for PRC2 in both mitotic and meiotic germ cells. We observed a paucity of mutant spermatogonial stem cells (SSCs), which appears independent of repression of the known cell cycle inhibitors Ink4a/Ink4b/Arf. Moreover, mutant spermatocytes exhibited ectopic expression of somatic lamins and an abnormal distribution of SUN1 proteins on the nuclear envelope. These defects were coincident with abnormal chromosome dynamics, affecting homologous chromosome pairing and synapsis. We observed acquisition of H3K27me3 on stage-specific genes during meiotic progression, indicating a requirement for PRC2 in regulating the meiotic transcriptional program. Together, these data demonstrate that transcriptional repression of soma-specific genes by PRC2 facilitates homeostasis and differentiation during mammalian spermatogenesis. Examination of two different types of histone modifications (H3K27me3 and H3K4me3) in spermatocytes at two different stages of development (P12 and P17) and the DNA binding protein, EED, in spermatocytes at one stage of development, P17. At P12, there was a single replicate of H3K27me3, H3K4me3 and input. At P17, there were two replicates of H3K27me3, H3K4me3 and input and a single replicate for EED.

2014-10-01 | E-GEOD-61902 | biostudies-arrayexpress

Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells

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.

2020-08-07 | PXD014290 | Pride

Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells

2021-09-22 | PXD020684 | Pride

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