Discovering miRNA regulatory networks in Holt-Oram Syndrome using a Zebrafish model
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE64466 | GEO | 2016/04/24
SECONDARY ACCESSION(S): PRJNA271069
REPOSITORIES: GEO
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Project description:MicroRNAs (miRNAs) are small non-coding RNAs that play an important role in the post-transcriptional regulation of gene expression. miRNAs are involved in the regulation of many biological processes such as differentiation, apoptosis, and cell proliferation. miRNAs are expressed in embryonic, postnatal, and adult hearts, and they have a key role in the regulation of gene expression during cardiovascular development and disease. Aberrant expression of miRNAs is associated with abnormal cardiac cell differentiation and dysfunction. Tbx5 is a member of the T-box gene family, which acts as transcription factor involved in the vertebrate heart development. Alteration of Tbx5 level affects the expression of hundreds of genes. Haploinsufficiency and gene duplication of Tbx5 are at the basis of the cardiac abnormalities associated with Holt-Oram syndrome (HOS). Recent data indicate that miRNAs might be an important part of the regulatory circuit through which Tbx5 controls heart development. Using high-throughput technologies, we characterized genome-widely the miRNA and mRNA expression profiles in WT- and Tbx5-depleted zebrafish embryos at two crucial developmental time points, 24 and 48 h post fertilization (hpf). We found that several miRNAs, which are potential effectors of Tbx5, are differentially expressed; some of them are already known to be involved in cardiac development and functions, such as miR-30, miR-34, miR-190, and miR-21. We performed an integrated analysis of miRNA expression data with gene expression profiles to refine computational target prediction approaches by means of the inversely correlation of miRNA-mRNA expressions, and we highlighted targets, which have roles in cardiac contractility, cardiomyocyte proliferation/apoptosis, and morphogenesis, crucial functions regulated by Tbx5. This approach allowed to discover complex regulatory circuits involving novel miRNAs and protein coding genes not considered before in the HOS such as miR-34a and miR-30 and their targets.
| S-EPMC4943955 | biostudies-literature
Project description:To investigate the complex regulatory networks disrupted in Holt-Oram Syndrome, we characterized genome-widely the miRNA and mRNA expression profiles in WT and Tbx5 depleted zebrafish embryos at two development time points, 24 and 48 hpf.
2016-04-24 | GSE64426 | GEO
Project description:To investigate the complex regulatory networks disrupted in Holt-Oram Syndrome, we characterized genome-widely the miRNA and mRNA expression profiles in WT and Tbx5 depleted zebrafish embryos at two development time points, 24 and 48 hpf.
2016-04-24 | GSE64465 | GEO
Project description:Discovering miRNA regulatory networks in Holt-Oram Syndrome using a Zebrafish model
| PRJNA271069 | ENA
Project description:Holt-Oram Syndrome (HOS) is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene, a transcription factor capable of regulating hundreds of cardiac-specific genes through complex transcriptional networks. Here we show that, in zebrafish, modulation of a single miRNA is sufficient to rescue the morphogenetic defects generated by HOS. The analysis of miRNA-seq profiling revealed a decreased expression of miR-19a in Tbx5-depleted zebrafish embryos compared to the wild type. We revealed that the transcription of the miR-17-92 cluster, which harbors miR-19a, is induced by Tbx5 and that a defined dosage of miR-19a is essential for the correct development of the heart. Importantly, we highlighted that miR-19a replacement is able to rescue cardiac and pectoral fin defects and to increase the viability of HOS zebrafish embryos. We further observed that miR-19a replacement shifts the global gene expression profile of HOS-like zebrafish embryos towards the wild type condition, confirming the ability of miR-19a to rescue the Tbx5 phenotype. In conclusion our data demonstrate the importance of Tbx5/miR-19a regulatory circuit in heart development and provide a proof of principle that morphogenetic defects associated with HOS can be rescued by transient miRNA modulation.
| S-EPMC4677400 | biostudies-literature
Project description:Holt-Oram syndrome (HOS) is a rare monogenic disorder characterized by upper limb abnormalities, congenital heart defects and/or conduction abnormalities. It is determined by mutations of TBX5 gene and is inherited in an autosomal dominant manner. Penetrance is complete, but variable expressivity is present, which gives sometimes diagnostic difficulties. Our case is a young adult with a personal history of preaxial polydactyly operated in infancy, multiple cardiac malformations (atrial septal defect, bicuspid aortic valve, left ventricular non-compaction) and radiologic findings consistent with HOS. Family history is negative for HOS. In conclusion, we present a case of HOS diagnosed in the adult period to highlight the diagnostic problems for the proband and the family and the importance of an early diagnostic.
| S-EPMC6188042 | biostudies-literature
Project description:The regulative role of miRNAs in Holt-Oram Syndrome is investigated in a zebrafish model.
2015-10-01 | GSE69690 | GEO
Project description:BACKGROUND: Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterised by upper limb anomalies and congenital heart defects. We present epidemiological and clinical aspects of HOS patients using data from EUROCAT (European Surveillance of Congenital Anomalies) registries. METHODS: The study was based on data collected during 1990-2011 by 34 registries. The registries are population-based and use multiple sources of information to collect data on all types of birth using standardized definitions, methodology and coding. Diagnostic criteria for inclusion in the study were the presence of radial ray abnormalities and congenital heart disease (CHD), or the presence of either radial ray anomaly or CHD, with family history of HOS. RESULTS: A total of 73 cases of HOS were identified, including 11 (15.1%) TOPFA and 62 (84.9%) LB. Out of 73 HOS cases, 30.8% (20/65) were suspected prenatally, 55.4% (36/65) at birth, 10.7% (7/65) in the first week of life, and 3.1% (2/65) in the first year of life. The prenatal detection rate was 39.2% (20/51), with no significant change over the study period. In 55% (11/20) of prenatally detected cases, parents decided to terminate pregnancy. Thumb anomalies were reported in all cases. Agenesis/hypoplasia of radius was present in 49.2% (30/61), ulnar aplasia/hypoplasia in 24.6% (15/61) and humerus hypoplasia/phocomelia in 42.6% (26/61) of patients. Congenital heart defects (CHD) were recorded in 78.7% (48/61) of patients. Isolated septal defects were present in 54.2 (26/48), while 25% (12/48) of patients had complex/severe CHD. The mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births. CONCLUSIONS: HOS is a rare genetic condition showing regional variation in its prevalence. It is often missed prenatally, in spite of the existence of major structural anomalies. When discovered, parents in 45% (9/20) of cases opt for the continuation of pregnancy. Although a quarter of patients have severe CHD, the overall first week survival is very good, which is important information for counselling purposes.
| S-EPMC4245183 | biostudies-literature
Project description:BackgroundThe Holt-Oram Syndrome (HOS) or the Heart-Hand syndrome is considered as an overt autosomal hereditary disease with a complete influential effect and variable expression that emerges due to a genetic mutation. It can be vividly characterized by heart disorders and deficiencies in hand structure. Despite the existing genetic heterogeneity, the variable integration between HOS and the T-BX5 gene from the T-BOX Gene Complex has been observed during which various mutations have been reported in the affected patients. The T-BOX Gene Complex is located on chromosome 12 (12 q 24.1), and is able to encode a copying factor. That has a conservative motive with 180 amino acids. The deficiencies in only 1/3 of patients have been observed caused by the mutation of this gene.Case reportThis case was a 10-year-old child with hand disorders, incomplete growth of clavicle, moving problems in elbow joint and shoulder, disorder in ventricle and auricle walls. The disease was diagnosed as HOS, based on clinical examination and drawing the family tree diagram. It was impossible to investigate molecular mutation due to inaccessibility to the patient.ConclusionBy investigating the family members and their deficiencies and imaging disorder variables according to different reports as well as parents' state of health, the HOS can be defined as an overt heredity resulting from a new mutation in the germinating layer of sexual cells in one of the parents. There is a weak possibility that the disease results from a mosaic mutation in the male parent's testicle or the female parent's ovum. In this case, the probability for the disease to be repeated in parents' next children will be guessed between 1 and 50%.
| S-EPMC3347849 | biostudies-literature
Project description:Holt-Oram syndrome (HOS), characterized by heart and forelimb defects, is caused by mutations in the T-box transcription factor, TBX5. While much has been done to elucidate TBX5’s transcriptional mechanisms in animal and human induced pluripotent stem cell (iPSC) models, transcriptomics from HOS patient tissue is lacking.
2024-12-16 | GSE261014 | GEO