Fish-Ing for Enhancers in the Heart

Parisi, Costantino; Vashisht, Shikha; Winata, Cecilia Lanny

doi:10.3390/ijms22083914

Cited by 7 publications

(5 citation statements)

References 207 publications

(293 reference statements)

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“…To interrogate the in vivo enhancer potential of the identified CNEs, we performed transgenic reporter assays in zebrafish, a well‐established model for the study of human enhancer function (Parisi et al, 2021). To this purpose, corresponding human sequences of the identified CNEs were cloned into a Tol2 reporter vector containing a cfos minimal promoter and EGFP cassette (Fisher et al, 2006) (Table S2).…”

Section: Resultsmentioning

confidence: 99%

Identification of ancestral gnathostome Gli3 enhancers with activity in mammals

Ali,

Abrar,

Hussain

et al. 2023

Dev Growth Differ

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Abnormal expression of the transcriptional regulator and hedgehog (Hh) signaling pathway effector Gli3 is known to trigger congenital disease, most frequently affecting the central nervous system (CNS) and the limbs. Accurate delineation of the genomic cis‐regulatory landscape controlling Gli3 transcription during embryonic development is critical for the interpretation of noncoding variants associated with congenital defects. Here, we employed a comparative genomic analysis on fish species with a slow rate of molecular evolution to identify seven previously unknown conserved noncoding elements (CNEs) in Gli3 intronic intervals (CNE15–21). Transgenic assays in zebrafish revealed that most of these elements drive activities in Gli3 expressing tissues, predominantly the fins, CNS, and the heart. Intersection of these CNEs with human disease associated SNPs identified CNE15 as a putative mammalian craniofacial enhancer, with conserved activity in vertebrates and potentially affected by mutation associated with human craniofacial morphology. Finally, comparative functional dissection of an appendage‐specific CNE conserved in slowly evolving fish (elephant shark), but not in teleost (CNE14/hs1586) indicates co‐option of limb specificity from other tissues prior to the divergence of amniotes and lobe‐finned fish. These results uncover a novel subset of intronic Gli3 enhancers that arose in the common ancestor of gnathostomes and whose sequence components were likely gradually modified in other species during the process of evolutionary diversification.

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Section: Resultsmentioning

confidence: 99%

Identification of ancestral gnathostome Gli3 enhancers with activity in mammals

Ali,

Abrar,

Hussain

et al. 2023

Dev Growth Differ

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show abstract

“…SHSY5Y cells) and assess the target gene expression. Moreover, testing the functionality of the active enhancers in zebra fish can provide further insight into tissue-specificity and in vivo activity patterns during development [9, 44]. Finally, as we only searched for CNVs in the active enhancers, we strongly suggest screening these regions for other types of variations in genetically undiagnosed patients in order to discover novel genetic variants.…”

Section: Discussionmentioning

confidence: 99%

Identification and copy number variant analysis of enhancer regions of genes causing spinocerebellar ataxia

Ghorbani,

de Boer,

Fokkens

et al. 2023

Preprint

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Currently, routine diagnostics for spinocerebellar ataxia (SCA) consist of analyses that look for polyQ repeat expansions and conventional variations affecting the proteins encoded by known SCA genes. Despite all the effort, ~40% of the patients still remain without a genetic diagnosis after routine tests. Increasing evidence suggests that variations in the enhancer regions of genes involved in neurodegenerative disorders can also be disease-causing. Since the enhancers of SCA genes are not yet known, it remains to be determined whether variations in these regions are a cause of SCA. In this pilot project, we aimed to identify the enhancers of the SCA genesATXN1,ATXN3,TBPandITPR1in human cerebellum using 4C-seq experiments, publicly available datasets, reciprocal 4C-seq and luciferase assays. We then screened these enhancers for copy number variants (CNVs) in a cohort of genetically undiagnosed SCA patients. We identified two active enhancers for each of the four SCA genes in human cerebellar tissue. In addition, forTBPandITPR1, we observed interactions between the putative enhancers of each gene. CNV analysis did not reveal any CNVs in the active enhancers of the four SCA genes in any of the genetically undiagnosed SCA patients. However, in one patient, we noted a CNV deletion with unknown clinical significance near one of the active enhancers ofITPR1. These results not only reveal elements involved in regulation of SCA genes, they can also lead to the discovery of novel SCA-causing genetic variants. As enhancer variations are increasingly recognized to cause brain disorders, screening the enhancers ofATXN1,ATXN3,TBPandITPR1for variations other than CNVs and identifying and screening enhancers of other SCA genes might elucidate the genetic cause in genetically undiagnosed patients.

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“…In this direction, Yuan et al [50] engineered a green fluorescent protein (GFP) reporter line of zebrafish which is driven by murine Smarcd3 enhancer (Smarcd3-F6), because its activity is detected in early gastrulating mouse mesoderm [56][57][58]. Smarcd3 is also known as Baf60c in humans, a component of the Notch signaling pathway, which regulates cardiac looping morphology or left-right asymmetry [59], remodels chromatin to regulate gene expression for heart development and function [60,61], and determines the fate of cardiomyocyte cells [62].…”

Section: Epigenomic Mapping Of Zebrafish Reveals New Insights Into Cardiac Developmentmentioning

confidence: 99%

Advances in Cardiac Development and Regeneration Using Zebrafish as a Model System for High-Throughput Research

Francoeur

Sen

2021

JDB

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Heart disease is the leading cause of death in the United States and worldwide. Understanding the molecular mechanisms of cardiac development and regeneration will improve diagnostic and therapeutic interventions against heart disease. In this direction, zebrafish is an excellent model because several processes of zebrafish heart development are largely conserved in humans, and zebrafish has several advantages as a model organism. Zebrafish transcriptomic profiles undergo alterations during different stages of cardiac development and regeneration which are revealed by RNA-sequencing. ChIP-sequencing has detected genome-wide occupancy of histone post-translational modifications that epigenetically regulate gene expression and identified a locus with enhancer-like characteristics. ATAC-sequencing has identified active enhancers in cardiac progenitor cells during early developmental stages which overlap with occupancy of histone modifications of active transcription as determined by ChIP-sequencing. CRISPR-mediated editing of the zebrafish genome shows how chromatin modifiers and DNA-binding proteins regulate heart development, in association with crucial signaling pathways. Hence, more studies in this direction are essential to improve human health because they answer fundamental questions on cardiac development and regeneration, their differences, and why zebrafish hearts regenerate upon injury, unlike humans. This review focuses on some of the latest studies using state-of-the-art technology enabled by the elegant yet simple zebrafish.

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Fish-Ing for Enhancers in the Heart

Cited by 7 publications

References 207 publications

Identification of ancestral gnathostome Gli3 enhancers with activity in mammals

Identification of ancestral gnathostome Gli3 enhancers with activity in mammals

Identification and copy number variant analysis of enhancer regions of genes causing spinocerebellar ataxia

Advances in Cardiac Development and Regeneration Using Zebrafish as a Model System for High-Throughput Research

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