Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Co-ordinate inhibition of autism candidate genes by topoisomerase inhibitors [Seq]

ABSTRACT: Topoisomerases are necessary for the expression of neurodevelopmental genes, and are mutated in some patients with autism spectrum disorder (ASD). We have studied the effects of inhibitors of Topoisomerase 1 (Top1) and Topoisomerase 2 (Top2) enzymes on mouse cortical neurons. We find that topoisomerases selectively inhibit long genes (>100kb), with little effect on all other gene expression. Using ChIPseq against RNA Polymerase II (Pol2) we show that the Top1 inhibitor topotecan blocks transcriptional elongation of long genes specifically. Many of the genes inhibited by topotecan are candidate ASD genes, leading us to propose that topoisomerase inhibition might contribute to ASD pathology. [Mouse] 5 biological replicates of transcriptome sequencing (RNAseq) from topotecan treated neurons and vehicle treated controls; Pol2 ChIPseq of topotecan and vehicle treated neurons [Human] Transcriptome sequencing (RNAseq) from topotecan treated neurons and vehicle treated control.

ORGANISM(S): Mus musculus

SUBMITTER: Chandri Yandava

PROVIDER: E-GEOD-43526 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Topoisomerases facilitate transcription of long genes linked to autism.

King Ian F IF Yandava Chandri N CN Mabb Angela M AM Hsiao Jack S JS Huang Hsien-Sung HS Pearson Brandon L BL Calabrese J Mauro JM Starmer Joshua J Parker Joel S JS Magnuson Terry T Chamberlain Stormy J SJ Philpot Benjamin D BD Zylka Mark J MJ

Nature 20130828 7465

Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically connected to ASD is unknown. Here we find that topotecan, a topoisomerase 1 (TOP1) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kilobases. Expression of long genes is also reduced after knockdown of ...[more]

PMID: 23995680

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Project description:Histone variants complement and integrate histone post-translational modifications in regulating transcription. The histone variant macroH2A1 (mH2A1) is almost three times the size of its canonical H2A counterpart due to the presence of a ~25kDa evolutionarily conserved non-histone macro domain. Strikingly, mH2A1 can mediate both gene repression and activation. However, the molecular determinants conferring these alternative functions remain elusive. Here, we report that mH2A1.2 is required for the activation of the myogenic gene regulatory network and muscle cell differentiation. H3K27 acetylation at prospective enhancers is exquisitely sensitive to mH2A1.2, indicating a role of mH2A1.2 in imparting enhancer activation. Both H3K27 acetylation and recruitment of the transcription factor Pbx1 at prospective enhancers are regulated by mH2A1.2. Overall, our findings indicate a role of mH2A1.2 in marking regulatory regions for activation. To establish the role of the histone variant mH2A1.2 in skeletal muscle differentiation we employed the mouse skeletal muscle C2C12 cell line and examined the genome wide distribution mH2A1.2 in myoblast (MB) and myotube (MT) (two replicates). We intersected the distribution of mH2A1.2 with active (H3K4me3 and H3K4me1 from published dataset, and H3K27ac, two replicates) and repressive (H3K27me3, two replicates) epigenetic marks in MB and MT. To gain insite on how chromatin accessibility is remodelled when muscle cells are induced to differentiate, we performed ATAC-seq in C2C12 MB and MT (2 replicates). We then evaluated whether mH2A1.2 was involved in conferring H3K27 acetylation during skeletal muscle differentiation by performing H3K27ac ChIP-seq (two replicates) upon mH2A1.2i in MB and MT. We also prefomred the ChIP-Seq for transcription factor Pbx1 in control and mH2A1.2i cells in MT to address the potential role of mH2A in recruitment of Pbx1. RNA-seq experiments were performed in control and mH2A1.2i C2C12 cells at the stage of MB and MT (three replicates). When mH2A1.2i C2C12 MB were induced to differentiate, a global effect on transcription was observed.

Dataset Information

Co-ordinate inhibition of autism candidate genes by topoisomerase inhibitors [Seq]

Publications

Topoisomerases facilitate transcription of long genes linked to autism.

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