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Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the RBFOX1 locus

ABSTRACT: Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the RBFOX1 locus

PROVIDER: PRJNA1013588 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25933737_1.fastq.gz	Fastqsanger.gz
	SRR25933737_2.fastq.gz	Fastqsanger.gz
	SRR25933738_1.fastq.gz	Fastqsanger.gz
	SRR25933738_2.fastq.gz	Fastqsanger.gz
	SRR25933439_1.fastq.gz	Fastqsanger.gz

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Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the RBFOX1 locus [cortex]

Project description:A long-standing goal of evolutionary biology is to decode how changes in gene regulatory networks contribute to human-specific traits. Human Accelerated Regions (HARs) are prime candidates for driving gene regulatory modifications in human development. The RBFOX1 locus is densely populated with HARs, providing a set of potential regulatory elements that could have changed its expression in the human lineage. Here we examined the role of RBFOX1-HARs using transgenic zebrafish reporter assays and identified fifteen transcriptional enhancers that are active in the developing nervous system, ten of which displayed differential expression between the human and chimpanzee sequences. The engineered loss of two selected RBFOX1-HARs in knockout mouse models increased Rbfox1 expression at specific developmental stages and tissues in the brain, influencing the expression and splicing of a high number of Rbfox1 target genes. Our results provided insight into the spatial and temporal changes in gene expression driven by RBFOX1-HARs.

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Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the RBFOX1 locus [midbrain]

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Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the RBFOX1 locus [cortex]

Project description:Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the RBFOX1 locus [cortex]

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Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the RBFOX1 locus [midbrain]

Project description:Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the RBFOX1 locus [midbrain]

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Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the <i>RBFOX1</i> locus.

Project description:A long-standing goal of evolutionary biology is to decode how changes in gene regulatory networks contribute to human-specific traits. Human accelerated regions (HARs) are prime candidates for driving gene regulatory modifications in human development. The RBFOX1 locus is densely populated with HARs, providing a set of potential regulatory elements that could have changed its expression in the human lineage. Here, we examined the role of RBFOX1-HARs using transgenic zebrafish reporter assays and identified 15 transcriptional enhancers that are active in the developing nervous system, 9 of which displayed differential activity between the human and chimpanzee sequences. The engineered loss of two selected RBFOX1-HARs in knockout mouse models modified Rbfox1 expression at specific developmental stages and tissues in the brain, influencing the expression and splicing of a high number of Rbfox1 target genes. Our results provided insight into the spatial and temporal changes in gene expression driven by RBFOX1-HARs.

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Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the RBFOX1 locus

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-21 | GSE242504 | GEO

RbFox1-Nestin hippocampus

Project description:Dysregulation of the brain-enriched RNA binding protein Rbfox1 has been linked to neurologic diseases such as epilepsy and autism spectrum disorders. However, it remains unexplored how distinct neuronal populations might contribute to neurologic dysfunction resulting from Rbfox1 loss. To examine these issues we profiled gene expression specifically in the hippocampus of wildtype and Rbfox1-/- mice. We identified transcripts whose expression was strongly Rbfox1-dependent and exhibited significant Rbfox1 binding in their 3’UTRs. One prominent target, Vamp1, was found to be specifically expressed in GABAergic interneurons. Both Vamp1 knockdown and Rbfox1 loss led to decreased synaptic transmission, and altered E/I balance in the Rbfox1-/- hippocampus, indicating that Vamp1 loss is a major component of the Rbfox1-/- physiological phenotype. The cytoplasmic isoform of Rbfox1 was sufficient to rescue Vamp1 expression in Rbfox1-/- neurons. We show that Rbfox1 binding in the Vamp1 3’UTR promotes its expression in part by antagonizing the brain-enriched microRNA-9. These results demonstrate that inhibitory neurons maintain specialized synaptic vesicle release machinery containing Vamp1 that is critically regulated by Rbfox1.

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Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels.

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Gene expression profiling of neurons with Rbfox1 and Rbfox3 knockdown and rescue with cytoplasmic or nuclear Rbfox1 isoform [RNA-seq]

Project description:Human genetic studies have identified the neuronal RNA binding protein, Rbfox1, as a candidate gene for autism spectrum disorders. While Rbfox1 functions as a splicing regulator in the nucleus, it is also alternatively spliced to produce cytoplasmic isoforms. To investigate cytoplasmic Rbfox1, we knocked down Rbfox proteins in mouse neurons and rescued with cytoplasmic or nuclear Rbfox1. Transcriptome profiling showed that nuclear Rbfox1 rescued splicing changes induced by knockdown, whereas cytoplasmic Rbfox1 rescued changes in mRNA levels. iCLIP-seq of subcellular fractions revealed that in nascent RNA Rbfox1 bound predominantly to introns, while cytoplasmic Rbox1 bound to 3' UTRs. Cytoplasmic Rbfox1 binding increased target mRNA stability and translation, and overlapped significantly with miRNA binding sites. Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism. Our results uncover a new Rbfox1 regulatory network and highlight the importance of cytoplasmic RNA metabolism to cortical development and disease. In this data set, we included the data from RNA-seq experiments. We performed RNA-seq to profile gene expression and splicing changes. The expression levels of Rbfox1 and Rbfox3 in cultured mouse hippocampal neurons were reduced by siRNAs. The reduction of Rbfox1 and 3 was rescued by expression of cytoplasmic or nuclear Rbfox1 splice isoform. The gene expression and splicing profiles were compared between different treatments. Eight samples were analyzed.

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Gene expression profiling of neurons with Rbfox1 and Rbfox3 knockdown and rescue with cytoplasmic or nuclear Rbfox1 isoform [RNA-seq]

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