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Non-coding variants alter Gata2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis

ABSTRACT: Non-coding variants alter Gata2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis

PROVIDER: PRJNA925501 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23098564.fastq.gz	Fastqsanger.gz
	SRR23098565.fastq.gz	Fastqsanger.gz
	SRR23098566.fastq.gz	Fastqsanger.gz
	SRR23098567.fastq.gz	Fastqsanger.gz
	SRR23098568.fastq.gz	Fastqsanger.gz

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Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Project description:Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

| S-EPMC10335940 | biostudies-literature

Non-coding variants alter Gata2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis

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

2023-04-04 | GSE223274 | GEO

Gene expression differences between Gata2cko and wt mouse rhombomere 1

Project description:During development, rhombomere 1 gives rise to a multitude of cell types, including serotonergic as well as glutamatergic neurons that populate the raphe nuclei. Transcription factor Gata2 has been shown to regulate the development of the serotonergic neurons in the rhombomere 1. To further understand the role and targets of Gata2 in the rhombomere 1 during development, we used cDNA microarrays to compare gene expression in the embryonic day 12.5 (E12.5) rhombomere 1 tissues extracted from wild-type and Gata2 mutant embryos.

2016-11-01 | GSE89354 | GEO

Anti-NR2F1 scCUT&Tag on FAC-sorted Isl1MN-GFP rhombomere 4 neurons from wildtype and HCFP1 Fam5snv/snv E10.5 mouse embryos

Project description:We found hereditary congenital facial paralysis type 1 (HCFP1) is caused by variants that duplicate or change cis regulatory elements (cREs) controlling the neuronal expression of the GATA2 transcription factor. The single nucleotide variants (SNVs) alter a previously uncharacterized cis regulatory element (we named cRE2). A subset of these variants disrupted a consensus sequence for the COUP transcription factor family (NR2F1 and NR2F2). We performed low-input scCUT&Tag with antibodies against NR2F1 and found it bound to the predicted cRE2 sequence in embryonic mouse rhombomere 4 motor neurons in vivo. We generated an HCFP1 SNV mouse model that harbored Mm10:Chr6:88,224,892 A>G in the NR2F1 binding site (Fam5snv/snv) and found it disrupted NR2F1 binding in vivo.

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Hoxb1 mutant mRNA levels in rhombomere 4 at E10.5

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Single cell RNA sequencing (scRNAseq) on mouse embryonic cranial motor neurons and surrounding tissue from wildtype and HCFP1 cRE1dup/+ mice.

Project description:We found hereditary congenital facial paralysis type 1 (HCFP1) is caused by variants that duplicate or change cis regulatory elements (cREs) controlling the neuronal expression of the GATA2 transcription factor. We generated an HCFP1 mouse model in which tandem copies of the human version of a GATA2 regulatory element we term cRE1 were inserted proximal to the mouse cRE1 (cRE1dup/+; hg19: chr3:128,175,708-128,176,563). We report the use of single cell RNA sequencing (scRNAseq) for transcriptomic analysis of developing rhombomere 4(r4)-derived wild type (WT) and cRE1dup/+ facial branchial motor neurons (FBMNs) and inner ear efferent neurons (IEEs), as well as surrounding tissue, from embryos aged 9.5-12.5 post coitus (E9.5-12.5).

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Project description:Hoxb1 is required for proper specification of rhombomere 4 and the facial motor neurons. This study analyzed gene expression in the corresponding hindbrain segment of E10.5 mutant embryos. Several genetic pathways were found altered, including transcription factors such as Phox2b, Gata3, Nkx2-2 and Nkx6-1. Experiment Overall Design: Each of the three mutant and control samples was an independent biological replicate. Pools of r4 segments from multiple embryos were snap frozen on dry ice and stored at -80ÂºC. Total RNA was isolated, processed with standard Affymetrix protocols and hybridized to GeneChip Mouse Expression Sets 430A.

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| PRJEB76254 | ENA

Hoxb1 gene expressing Hox-A1 protein: Altered transcriptional profile in rhombomere 4 at E10.5

Project description:This study analyzed mRNA profiles in rhombomere 4 of E10.5 mouse knock-in embryos expressing either normal endogenous Hox-B1 protein or the paralogous Hox-A1 protein from the Hoxb1 locus. The Hox-A1 protein was found to be detectably less efficacious than Hox-B1 in promoting neurogenesis in the basal plate of rhombomere 4 and its transcriptional profile shared several similarities with the Hoxb1 mutant. Keywords: gene swap, knock-in, hindbrain development, rhombomere 4

2006-08-28 | GSE5124 | GEO

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Project description:GATA2 Deficiency

| PRJNA684644 | ENA