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PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in Split Hand/Foot Malformation

ABSTRACT: PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in Split Hand/Foot Malformation

PROVIDER: PRJNA899096 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22221231_1.fastq.gz	Fastqsanger.gz
	SRR22221231_2.fastq.gz	Fastqsanger.gz
	SRR22221232_1.fastq.gz	Fastqsanger.gz
	SRR22221232_2.fastq.gz	Fastqsanger.gz
	SRR22221233_1.fastq.gz	Fastqsanger.gz

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PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in Split Hand/Foot Malformation

Project description:Split Hand/Foot Malformation (SHFM) is a rare limb abnormality with clefting of the fingers and/or toes. For many patients, the genetic etiology is unknown. Through whole exome and targeted sequencing, we detected three novel variants in a transcription factor, PRDM1 that arose de novo in families with SHFM or segregated with the phenotype. PRDM1 has been shown to be required for limb development; however, its role is not well understood, and it is unclear how the PRDM1 variants affect protein function. Using transient and stable overexpression rescue experiments in zebrafish, we show that the variants have reduced function compared to wildtype PRDM1 likely due to disruption of the proline/serine-rich and DNA-binding zinc finger domains. Through expression assays, RNA-seq, and CUT&RUN in isolated pectoral fin cells, we demonstrate that Prdm1a directly binds to and regulates genes required for limb induction, outgrowth, and anterior/posterior patterning, such as fgfr1a, dlx5a, dlx6a, and smo. Together, these results improve our understanding of the role of PRDM1 in the limb gene regulatory network and help predict the pathogenicity of PRDM1 variants in humans

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Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation

Project description:We describe an 18-month-old male (BAB7221)with split-hand malformation. Custom high-density array and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother (BAB7219), the fetus (BAB7218) and her later born son (BAB7221). This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother (BAB8247). High density custom aCGH detecting all 6 individuals in the family

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Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [4C-seq]

Project description:Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigated the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice resulted in restructuring of the chromatin architecture. This led to an ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern. Artificial repositioning of the AER-specific enhancers of Fgf8 was sufficient to induce misexpression of Lbx1 and Btrc. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression and dosage in the developing limb. Our results reveal new insights into the molecular mechanism underlying SHFM3 and provide novel conceptual framework for how genomic rearrangements can cause gene misexpression and disease.

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Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [scRNA-seq]

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Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3

Project description:Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3

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Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [RNA-seq]

Project description:Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [RNA-seq]