Intravenous NeuroD1 Gene Therapy Rescues Neurovascular Impairment After Ischemic Stroke
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ABSTRACT:
PROVIDER: PRJNA975940 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24727014_1.fastq.gz | Fastqsanger.gz | |||
| SRR24727014_2.fastq.gz | Fastqsanger.gz | |||
| SRR24727015_1.fastq.gz | Fastqsanger.gz | |||
| SRR24727015_2.fastq.gz | Fastqsanger.gz |
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Project description:Intravenous NeuroD1 Gene Therapy Rescues Neurovascular Impairment After Ischemic Stroke
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Project description:NeuroD1 encodes a basic helix-loop-helix transcription factor involved in the development of neural and endocrine structures. NeuroD1 mRNA is highly abundant in the adult mammalian pineal gland and exhibits a developmental expression pattern similar to the retina. This is consistent with the common evolutionary origin of pinealocytes and retinal photoreceptors. Pinealocytes and retinal photoreceptors express a shared set of phototransduction genes and submammalian pinealocytes are photosensitive. In contrast to the retina, the pineal gland is a relatively homogeneous structure, composed 95% of pinealocytes. This makes the pineal gland a particularly useful model for understanding photoreceptor cell biology. The loss of NeuroD1 in the retina results in progressive photoreceptor degeneration and the molecular mechanisms underlying this retinal degeneration phenotype remain unknown. Similarly, the role that NeuroD1 plays in the pineal gland is unknown. To determine the function of NeuroD1 in the pineal gland and retina, a Cre/loxP recombination strategy was used to selectively target a NeuroD1 floxed allele and generate NeuroD1 conditional knockout (cKO) mice. Tissue specificity was conferred using Cre recombinase expressed under the control of the promoter of Crx, a transcription factor selectively expressed in the pineal gland and retina. Pineal and retinal tissues from two-month-old NeuroD1 cKO and control animals were used in microarray studies to identify candidate genes responsible for the photoreceptor degeneration phenotype. The Cre/loxP recombination strategy was used to target a NeuroD1 floxed allele and generate NeuroD1 conditional knockout mice (NeuroD1floxed::Crx-Cre+/-). NeuroD1 floxed mice (NeuroD1floxed::Crx-Cre-/-) served as the controls. Pineal glands and retinas from two-month-old control and conditional knockout mice were collected at ZT6 and ZT20. 3 pools of 6 pineal glands per genotype and respective time of day were collected for each sample. Similarly, 3 pools of 6 retinas each were also collected. RNA from each pool was extracted and hybridized on the Affymetrix Mouse 430 2.0 array.
2012-07-25 | E-GEOD-35396 | biostudies-arrayexpress
Project description:Cell fate specification relies on the action of critical transcription factors that become available at distinct stages of embryonic development. One such factor is NeuroD1, which is essential for eliciting the neuronal development program and possesses the ability to reprogram other cell types into neurons. Given this capacity, it is important to understand its targets and the mechanism underlying neuronal specification. Here, we show that NeuroD1 directly binds regulatory elements of neuronal genes that are developmentally silenced by epigenetic mechanisms. This targeting is sufficient to initiate events that confer transcriptional competence, including reprogramming of transcription factor landscape, conversion of heterochromatin to euchromatin and increased chromatin accessibility, indicating potential pioneer factor ability of NeuroD1. The transcriptional induction of neuronal fate genes is maintained via epigenetic memory despite a transient NeuroD1 induction during neurogenesis. Our study not only reveals the NeuroD1-dependent gene regulatory program driving neurogenesis but also increases our understanding of how cell-fate specification during development involves a concerted action of transcription factors and epigenetic mechanisms. 1. Ectopic NeuroD1 was induced for 48 hours (+Dox) in ES cells for checking initiation of neuronal transcriptional program in comparison to uninduced condition (-Dox) 2. ChIP-seq was performed after 24 hours of NeuroD1 induction in ES cells.
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Project description:Cell-fate specification relies on a close cooperation of distinct transcription factors and their crosstalk with the epigenetic landscape during embryonic development. NeuroD1 is known to be essential for eliciting neurogenesis and is able to reprogram other cell types into neurons. Despite progress, its global impact on the epigenome and cooperativity with other transcription factors during neurogenesis remains unknown. Here we show that despite NeuroD1 binding and a gain of active chromatin, only sites that show high local density of adjacent bHLH motifs, higher minor groove width and propeller twist as well as enrichment of another novel bHLH motif were able to get transcriptionally induced. Transcription factor activity analysis on the epigenome timecourse following NeuroD1 induction further identified this bHLH factor among top factors that gained activity during this process. Importantly, this bHLH factor was induced simultaneously to NeuroD1 as cells transit from an apical to a basal progenitor state during cortical development. Moreover, this bHLH factor interacts with NeuroD1 and co-occupies NeuroD1 target distinct genomic regions. We further show that the loss of this bHLH factor during cortical development severely impairs neurogenesis. Our study not only reveals the mechanistic basis underlying a productive transcriptional response of NeuroD1 during neurogenesis but also identified a novel bHLH transcription factor that partners with NeuroD1 and plays a critical role during cortical development.
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