Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA265110 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1633881.fastq.gz | Fastqsanger.gz | |||
| SRR1633882.fastq.gz | Fastqsanger.gz | |||
| SRR1633883.fastq.gz | Fastqsanger.gz | |||
| SRR2039656.fastq.gz | Fastqsanger.gz | |||
| SRR2039657.fastq.gz | Fastqsanger.gz |
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Project description:Microphthalmos is a rare congenital anomaly characterized by reduced eye size and visual deficits of variable degrees. Sporadic and hereditary microphthalmos has been associated to heterozygous mutations in genes fundamental for eye development. Yet, many cases are idiopathic or await the identification of molecular causes. Here we show that haploinsufficiency of Meis1, a transcription factor with an evolutionary conserved expression in the embryonic trunk, brain and sensory organs, including the eye, causes microphthalmic traits and visual impairment, in adult mice. In the trunk, Meis1 acts as a cofactor for genes of the Hox complex, mostly binding to Hox-Pbx target sequence on the DNA. By combining the analysis of Meis1 loss-of-function and conditional Meis1 functional rescue with ChIPseq and RNAseq approaches, we show that during the development of the optic cup, an Hox-free region, Meis1 binds instead to Hox/Pbx-independent Meis binding site, and coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating the expression of components of the Notch signalling pathway. Meis1 also controls the activity of genes responsible for human microphthalmia and eye patterning so that in Meis1-/- embryos, the eye size is reduced and boundaries among the different eye territories are shifted or blurred. We thus propose that Meis1 is at the core of a genetic network implicated in microphthalmia, itself representing an additional candidate for syndromic cases of these ocular malformations. Transcriptomics and Meis1 Occupancy analysis on mouse isolated optic cups and ChIP data for histone methylation marks were obtained from about 100 eyes of E10.5 CD1 embryos.
2015-08-27 | E-GEOD-62786 | biostudies-arrayexpress
Project description:Microphthalmos is a rare congenital anomaly characterized by reduced eye size and visual deficits of variable degrees. Sporadic and hereditary microphthalmos has been associated to heterozygous mutations in genes fundamental for eye development. Yet, many cases are idiopathic or await the identification of molecular causes. Here we show that haploinsufficiency of Meis1, a transcription factor with an evolutionary conserved expression in the embryonic trunk, brain and sensory organs, including the eye, causes microphthalmic traits and visual impairment, in adult mice. In the trunk, Meis1 acts as a cofactor for genes of the Hox complex, mostly binding to Hox-Pbx target sequence on the DNA. By combining the analysis of Meis1 loss-of-function and conditional Meis1 functional rescue with ChIPseq and RNAseq approaches, we show that during the development of the optic cup, an Hox-free region, Meis1 binds instead to Hox/Pbx-independent Meis binding site, and coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating the expression of components of the Notch signalling pathway. Meis1 also controls the activity of genes responsible for human microphthalmia and eye patterning so that in Meis1-/- embryos, the eye size is reduced and boundaries among the different eye territories are shifted or blurred. We thus propose that Meis1 is at the core of a genetic network implicated in microphthalmia, itself representing an additional candidate for syndromic cases of these ocular malformations.
2015-08-27 | GSE62786 | GEO
Project description:Genetic perturbations influencing early eye development can result in microphthalmia, anophthalmia and coloboma (MAC). Over 100 genes are associated with MAC, but little is known about common disease mechanisms. In this study, we generated induced pluripotent stem cell (iPSC) derived optic vesicles (OVs) from two unrelated microphthalmia patients and healthy controls. At day 20, 35 and 50 microphthalmia patient OV diameters were significantly smaller, recapitulating the ‘small eye’ phenotype. RNA-seq analysis revealed upregulation of apoptosis-initiating and extracellular matrix (ECM) genes at day 20 and 35. Western blot and immunohistochemistry revealed increased expression of lumican, nidogen and collagen type IV, suggesting ECM overproduction. Increased apoptosis was observed in microphthalmia OVs with reduced pH3+ cells confirming decreased cell proliferation at day 35. Pharmacological inhibition of caspase-8 activity with Z-IETD-FMK decreased apoptosis in one patient model, highlighting a potential therapeutic approach. These data reveal shared pathophysiological mechanisms contributing to a microphthalmia phenotype.
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Project description:Anophthalmia, microphthalmia and coloboma (AMC) comprise a spectrum of developmental eye disorders, accounting for approximately 20% of childhood visual impairment. While non-coding regulatory sequences are increasingly recognised as contributing to disease burden, characterising their impact on gene function and phenotype remains challenging. Furthermore, little is known of the nature and extent of their contribution to AMC phenotypes. We identified two families with variants in or near MAB21L2. The first proband, with microphthalmia and coloboma, had a likely pathogenic missense variant (c.338G>C; p.[Trp113Ser]), segregating within the family. The second individual, presenting with microphthalmia, had an ~113.5kb homozygous deletion 19.38kb upstream of MAB21L2. Modelling the deletion led to transient small lens and coloboma in zebrafish, and microphthalmia and coloboma in Xenopus tropicalis. Conservation analysis identified 15 non-genic conserved elements (CE) within the deleted region, while ChIP-seq data from mouse embryonic stem cells demonstrated one of these (CE14) binds OTX2, a protein with an established role in eye development. Targeted disruption of CE14 in Xenopus tropicalis recapitulated an ocular coloboma phenotype, supporting its role in eye development. Together, our data provides insights into regulatory mechanisms underlying eye development, and highlights the importance of non-coding sequences as a source of genetic diagnoses in AMC.
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Project description:Vertebrate eye is derived from the neuroepithelium, surface ectoderm, and extracellular mesenchyme. Eye-specified neuroepithelium forms the optic cup in which spatial separation of three domains is established, namely, the region of multipotent retinal progenitor cells (RPCs), the ciliary margin zone (CMZ) possessing both neurogenic and non-neurogenic potential, and the optic disc (OD), the interface between the optic stalk and the neuroretina. Here, we show by genetic ablation in the developing optic cup that Meis1 and Meis2 homeobox genes function redundantly to maintain the retinal progenitor pool while they simultaneously suppress the expression of genes characteristic of CMZ and OD fates. Furthermore, we demonstrate that Meis transcription factors bind the regulatory regions of RPC-, CMZ-, and OD-specific genes, thus providing a mechanistic insight into the Meis-dependent gene regulatory network. Our work uncovers the essential role of Meis1 and Meis2 as regulators of cell fate competence and guardians of spatial territories in the vertebrate eye.
2021-02-17 | E-MTAB-10112 | biostudies-arrayexpress
Project description:Vertebrate eye is derived from the neuroepithelium, surface ectoderm, and extracellular mesenchyme. Eye-specified neuroepithelium forms the optic cup in which spatial separation of three domains is established, namely, the region of multipotent retinal progenitor cells (RPCs), the ciliary margin zone (CMZ) possessing both neurogenic and non-neurogenic potential, and the optic disc (OD), the interface between the optic stalk and the neuroretina. Here, we show by genetic ablation in the developing optic cup that Meis1 and Meis2 homeobox genes function redundantly to maintain the retinal progenitor pool while they simultaneously suppress the expression of genes characteristic of CMZ and OD fates. Furthermore, we demonstrate that Meis transcription factors bind the regulatory regions of RPC-, CMZ-, and OD-specific genes, thus providing a mechanistic insight into the Meis-dependent gene regulatory network. Our work uncovers the essential role of Meis1 and Meis2 as regulators of cell fate competence and guardians of spatial territories in the vertebrate eye.
2021-02-17 | E-MTAB-9143 | biostudies-arrayexpress
Project description:Meis1 encodes a TALE family homeodomain protein that was first identified as a common retroviral integration site in mouse BHX2 myeloid leukemia. It functions as a DNA binding co-factor of Hox proteins through interacting with Pbx, a member of another TALE family protein. Moreover, Meis1 homozygous knockout mice are embryonic lethal, showing significant defects in vasculogenesis, eye development and hematopoiesis. Severe defects were also observed in adult hematopoiesis by conditional inactivation of Meis1 in vivo. Meis1 is critical to maintain the balance between enter and exit from cell cycles of hematopoietic stem cells (HSCs), indicating that Meis1 regulates self-renewal and quiescence of HSCs.
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Project description:The clustered homeobox proteins play crucial roles in development, hematopoiesis and leukemia yet the targets they regulate and their mechanisms of action are poorly understood. Here, we identified the binding sites for Hoxa9 and the Hox cofactor Meis1 on a genome-wide level and profiled their associated epigenetic modifications and transcriptional targets. Hoxa9 and the Hox cofactor Meis1 co-bind at hundreds of highly evolutionarily-conserved sites, most of which are distant from transcription start sites. These sites show high levels of histone H3K4 monomethylation and CBP/P300 binding characteristic of enhancers. Furthermore, a subset of these sites shows enhancer activity in transient transfection assays. Many Hoxa9 and Meis1 binding sites are also bound by PU.1 and other lineage-restricted transcription factors previously implicated in establishment of myeloid enhancers. Conditional Hoxa9 activation is associated with CBP/P300 recruitment, histone acetylation and transcriptional activation of a network of proto-oncogenes including Erg, Flt3, Lmo2, Myb and Sox4. Collectively this work suggests that Hoxa9 regulates transcription by interacting with enhancers of genes important for hematopoiesis and leukemia. To identify the genome-wide binding sites for Hoxa9 and the Hox cofactor Meis1
2011-12-04 | E-GEOD-33509 | biostudies-arrayexpress
Project description:Meis1 encodes a TALE family homeodomain protein that was first identified as a common retroviral integration site in mouse BHX2 myeloid leukemia. It functions as a DNA binding co-factor of Hox proteins through interacting with Pbx, a member of another TALE family protein. Moreover, Meis1 homozygous knockout mice are embryonic lethal, showing significant defects in vasculogenesis, eye development and hematopoiesis. Severe defects were also observed in adult hematopoiesis by conditional inactivation of Meis1 in vivo. Meis1 is critical to maintain the balance between enter and exit from cell cycles of hematopoietic stem cells (HSCs), indicating that Meis1 regulates self-renewal and quiescence of HSCs. Total RNA was isolated from KSL cells obtained from poly(I:C)-treated Mx1-Cre Meis1fl/fl and sham-treated Meis1fl/fl mice.
2013-12-01 | E-GEOD-38336 | biostudies-arrayexpress