A SIX6 reporter for studies of early optic development
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA743024 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15014540_1.fastq.gz | Fastqsanger.gz | |||
| SRR15014540_2.fastq.gz | Fastqsanger.gz | |||
| SRR15014541_1.fastq.gz | Fastqsanger.gz | |||
| SRR15014541_2.fastq.gz | Fastqsanger.gz | |||
| SRR15014542_1.fastq.gz | Fastqsanger.gz |
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Project description:Human pluripotent stem cells (PSCs) represent an exciting tool to investigate the mechanisms of human eye development and to build models of human retinal disease. When grown in 3D, these cells can self-organize into laminar organized retinas; however, significant variation in the size, shape and composition of individual organoids exists, and this variation can create challenges. Neither the microenvironment nor the timing of critical growth factors driving eye formation or retinogenesis are fully understood. To explore the dynamics of early retinal organoid development, we have developed a SIX6-GFP reporter line that enables the systematic optimization of early eye field development, allowing for the identification of conditions that favor optic development. We found that SIX6 expression in 3D optic structures is influenced by small molecules regulating SHH and WNT signaling in a dose and time dependent fashion. In addition, we demonstrated that hypoxic growth conditions favor SIX6 expression, and promote eye formation. The systematic optimization of these pathways leads to optic vesicles with robust SIX6 expression and global gene expression profiles consistent with a retinal identity. The use of stem cell derived human retinal organoids with a real time marker for retinogenesis, therefore, represents an important model for probing the mechanisms of early human eye development.
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Project description:SIX6 regulation in human optic vesicles is mediated by early microenvironmenta factors
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Project description:T cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy strongly affected by the abnormal activity of transcription factors. Here we report a high expression of developmental transcription factor SIX6 in TAL1 subtype of T-ALL. Our data indicates that this high expression is directly regulated by binding of TAL1 and GATA3 transcription factors into an upstream enhancer element. We also looked into the potential targets of SIX6 in T-ALL and Crispr-cas9 mediated knockout of SIX6 in Jurkat cells caused significant changes in the expression of multiple genes, including genes related to mTOR signaling. In two independent patient cohorts, the high SIX6 expression shows a trend of less favourable prognosis. However, the knockout of SIX6 was not enough to have an effect on proliferation, cell cycle or viability of the Jurkat cells and overexpression of SIX6 in the T-ALL zebrafish model didn’t influence the progression of the disease. Our results show that high expression of SIX6 has a trend towards a less favourable outcome, but SIX6 doesn’t have an independent oncogenic role in T-ALL.
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Project description:The different stages of the optic fissure can be clearly visualized by making sagittal sections through the mouse eye during early development which represent the optic fissure at open (E10.5), closing (E11.5) and fused (E12.5) states. Laser capture microdissection (LCM) was employed to dissect tissue from the margins of the optic fissure consisting of the outer (presumptive RPE) and inner (presumptive neurosensory retina) layers of the retina. An approximately square-shaped block of optic fissure (50 x 50 mm) was dissected from each side of the fissure. Two rounds of linear amplification were performed on RNA isolated from each of the samples prior to microarray hybridization. Expression data were gathered in biological triplicate at E10.5, E11.5 and duplicate at E12.5, each array representing pooled optic fissure tissue from three embryos from a single litter. Expression signals were ascertained from 45,101 probe sets and normalized across arrays. Keywords: Time course
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Project description:Purpose: the goal of this experiment was to identify differentially expressed genes in Six3 null, Six6 null and Six3;Six6 compound null retinas by RNAsequencing. Method: Retinas were dissected out from the following E13.5 mouse embryos: 1) WT (Six3F/F; Six6+/+); 2) Six3 KO (Six3F/F; CAGGCre-ERTM; Six6+/+); 3) Six6 KO (Six3F/F; Six6–/–); 4) DKO (Six3F/F; CAGGCre-ERTM; Six6–/–). RNA was then extracted from the retinas and profiled using RNAsequencing. Results: RNA isolated from three pairs of retinas for each genotype group (181.2-792 ng, RIN>9) was used for library preparation using KAPA RNA HyperPrep Kit with RiboErase. Sequencing was run on Illumina HiSeq 2500 in 100-bp single-end high-output mode in the Einstein Epigenomics Core Facility. About 30 million reads were generated for each sample. Each genotype group initially had three biological replicates, but one Six6 KO replicate was later removed due to over duplication. After trimming adapters with Trim Galore (v. 0.3.7), RNA-Seq reads were aligned back to mouse genome mm10 using Tophat (v. 2.0.13). The number of reads mapped back to each gene was calculated with HTseq (v.0.6.1) using Refseq gene annotation (downloaded from the UCSC genome browser in 03/17). The Cuffdiff in Cufflinks package (v. 2.2.1) was used to generate FPKM values. We identified 13498 transcripts with FPKM value >1 in at least one of samples. Deseq2 was used to determine the differentially expressed genes (DEGs) with FDR less than 0.05 as a cutoff.
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Project description:Regulation of retinal differentiation in mammals is not adequately understood. Using single-cell RNA sequencing of control and Six3 and Six6 compound-mutant mouse embryonic eye-cups, we identified cell clusters and developmental trajectories jointly regulated by transcription factor Six3 and its close paralog Six6. In control retinas, naïve retinal progenitor cells had two major trajectories leading to ciliary margin cells and retinal neurons, respectively. The ciliary margin trajectory was directly from naïve retinal progenitor cells at G1 phase whereas the neuronal trajectory was through a neurogenic state marked by Atoh7 expression. Upon Six3 and Six6 dual deficiencies, both naïve and neurogenic retinal progenitors were defective, ciliary margin differentiation was enhanced, and multi-lineage neuronal differentiation was disrupted. An ectopic neuronal trajectory lacking the Atoh7+ state led to ectopic neurons. Additionally, opposing gradients of Wnt and Fgf signaling were perturbed. Our findings provide deeper insight into molecular mechanisms underlying early retinal differentiation in mammals.
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2008-10-25 | E-GEOD-11862 | biostudies-arrayexpress
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