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C. elegans development (Gro-Seq)

ABSTRACT: Despite highly conserved chromatin states and cis-regulatory elements, studies of metazoan genomes reveal that gene organization and the strategies to control mRNA expression can vary widely among animal species. C. elegans gene regulation is often assumed to be similar to that of other model organisms, yet evidence suggests the existence of distinct molecular mechanisms to pattern the developmental transcriptome, including extensive post-transcriptional RNA control pathways, widespread splice leader (SL) trans-splicing of pre-mRNAs, and the organization of genes into operons. Here, we performed ChIP-seq for histone modifications in highly synchronized embryos cohorts representing three major developmental stages, with the goal of better characterizing whether the dynamic changes in embryonic mRNA expression are accompanied by changes to the chromatin state. We were surprised to find that thousands of promoters are persistently marked by active histone modifications, despite a fundamental restructuring of the transcriptome. We employed global run-on sequencing using a long-read nanopore format to map nascent RNA transcription across embryogenesis, finding that the invariant open chromatin regions are persistently transcribed by Pol II at all stages of embryo development, even though the mature mRNA is not produced. By annotating our nascent RNA sequencing reads into directional transcription units, we find extensive evidence of polycistronic RNA transcription genome-wide, suggesting that nearby genes in C. elegans are linked by shared transcriptional regulatory mechanisms. We present data indicating that the sharing of cis-regulatory sequences has constrained C. elegans gene positioning and likely explains the remarkable retention of syntenic gene pairs over long evolutionary timescales.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE140864 | GEO | 2020/05/05

REPOSITORIES: GEO

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Project description:<p>Non-coding elements in our genomes that play critical roles in complex disease are frequently marked by highly unstable RNA species. Sequencing nascent RNAs attached to an actively transcribing RNA polymerase complex can identify unstable RNAs, including those templated from gene-distal enhancers (eRNAs). However, nascent RNA sequencing techniques remain challenging to apply in some cell lines and especially to intact tissues, limiting broad applications in fields such as cancer genomics and personalized medicine. Here we report the development of chromatin run-on and sequencing (ChRO-seq), a novel run-on technology that maps the location of RNA polymerase using virtually any frozen tissue sample, including samples with degraded RNA that are intractable to conventional RNA-seq. We used ChRO-seq to develop the first maps of nascent transcription in 23 human glioblastoma (GBM) brain tumors and patient derived xenografts. Remarkably, >90,000 distal enhancers discovered using the signature of eRNA biogenesis within primary GBMs closely resemble those found in the normal human brain, and diverge substantially from GBM cell models. Despite extensive overall similarity, 12% of enhancers in each GBM distinguish normal and malignant brain tissue. These enhancers drive regulatory programs similar to the developing nervous system and are enriched for transcription factor binding sites that specify a stem-like cell fate. These results demonstrate that GBMs largely retain the enhancer landscape associated with their tissue of origin, but selectively adopt regulatory programs that are responsible for driving stem-like cell properties. We also identified enhancers and their associated transcription factors that regulate genes characteristic of each known GBM subtype, and discovered a core group of transcription factors that control the expression of genes associated with clinical outcomes. This study uncovers new insights into the molecular etiology of GBM and introduces ChRO-seq which can now be used to map regulatory programs contributing to a variety of complex diseases.</p>

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C. elegans development (Gro-Seq)

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