GATA6 mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm

Sharma, Arun; Wasson, Lauren; Willcox, Jon A. L.; Morton, Sarah U.; Gorham, Joshua M.; DeLaughter, Daniel M.; Neyazi, Meraj; Schmid, Manuel; Agarwal, Radhika; Jang, Min Young; Toepfer, Christopher N.; Ward, Tarsha; Kim, Yuri; Pereira, Alexandre C.; DePalma, Steven R.; Tai, Angela; Kim, Seongwon; Conner, David A.; Bernstein, Daniel; Gelb, Bruce D.; Chung, Wendy K.; Goldmuntz, Elizabeth; Porter, George A.; Tristani‐Firouzi, Martin; Srivastava, Deepak; Seidman, Jonathan G.; Seidman, Christine E.

doi:10.7554/elife.53278

Cited by 34 publications

(33 citation statements)

References 90 publications

(123 reference statements)

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“…Interestingly, GATA6 mutations were also found to be an important cause of pancreatic abnormalities (hypoplasia and agenesis) and associated type 1 diabetes mellitus (87,165). GATA6 was recently shown to function as a pioneer factor in cardiac development, regulating transcriptional activation of critical genes associated with the development of the heart as well as endodermal lineages, pancreas and diaphragm (167). These findings illuminated the molecular mechanisms for diverse developmental defects such as cardiac outflow tract defects, pancreas and diaphragm dysgenesis in patients with distinct GATA6 variants.…”

Section: Transcription Factorsmentioning

confidence: 99%

Genetics of congenital heart disease: a narrative review of recent advances and clinical implications

Yasuhara¹,

Garg²

2021

Transl Pediatr

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Congenital heart disease (CHD) is the most common human birth defect and remains a leading cause of mortality in childhood. Although advances in clinical management have improved the survival of children with CHD, adult survivors commonly experience cardiac and non-cardiac comorbidities, which affect quality of life and prognosis. Therefore, the elucidation of genetic etiologies of CHD not only has important clinical implications for genetic counseling of patients and families but may also impact clinical outcomes by identifying at-risk patients. Recent advancements in genetic technologies, including massively parallel sequencing, have allowed for the discovery of new genetic etiologies for CHD. Although variant prioritization and interpretation of pathogenicity remain challenges in the field of CHD genomics, advances in single-cell genomics and functional genomics using cellular and animal models of CHD have the potential to provide novel insights into the underlying mechanisms of CHD and its associated morbidities. In this review, we provide an updated summary of the established genetic contributors to CHD and discuss recent advances in our understanding of the genetic architecture of CHD along with current challenges with the interpretation of genetic variation. Furthermore, we highlight the clinical implications of genetic findings to predict and potentially improve clinical outcomes in patients with CHD.

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Section: Transcription Factorsmentioning

confidence: 99%

Genetics of congenital heart disease: a narrative review of recent advances and clinical implications

Yasuhara¹,

Garg²

2021

Transl Pediatr

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“…GATA3 has been found to bind nucleosomal DNA and induce chromatin accessibility through the recruitment of SWI/SNF chromatin remodeling complexes in breast cancer cells ( Takaku et al, 2016 ; Tanaka et al, 2020 ). GATA6 was recently shown to function as a pioneer factor in cardiac development, with perturbations in chromatin accessibility identified when hiPSCs with clinically relevant GATA6 mutations were differentiated to cardiac myocytes ( Sharma et al, 2020 ). Several reports have identified GATA motifs to be enriched in chromatin that becomes accessible during definitive endoderm formation ( Cernilogar et al, 2019 ; Genga et al, 2019 ; Lee et al, 2019 ; Meers et al, 2019 ); however, the active contributions of GATA factors to the altered accessibility at these loci have not been investigated.…”

Section: Introductionmentioning

confidence: 99%

GATA6 defines endoderm fate by controlling chromatin accessibility during differentiation of human-induced pluripotent stem cells

et al. 2021

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GATA6 defines endoderm fate by controlling chromatin accessibility during differentiation of human-induced pluripotent stem cells Graphical abstract Highlights d Newly accessible chromatin in definitive endoderm is enriched for GATA motifs d Definitive endoderm patterning is significantly perturbed in GATA6 À/À cells d GATA6 interacts with multiple chromatin remodeling complexes d GATA6-dependent patterning commonly precedes the onset of gene expression

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“…The conditional inactivation of Gata6 in cardiac neural crest cells results in failed OFT septation [58], and CHD patients with GATA6 mutations have OFT malformations [59][60][61], demonstrating a role for GATA6 in CTD. TBX1 is critical for normal pharyngeal arch development, and both reductions and increases in TBX1 levels increase the risk of pharyngeal arch birth defects.…”

Section: Discussionmentioning

confidence: 99%

Variants in a cis-regulatory element of TBX1 in conotruncal heart defect patients impair GATA6-mediated transactivation

Jiang

Liu

et al. 2021

Orphanet J Rare Dis

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Background TBX1 (T-box transcription factor 1) is a major candidate gene that likely contributes to the etiology of velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS). Although the haploinsufficiency of TBX1 in both mice and humans results in congenital cardiac malformations, little has been elucidated about its upstream regulation. We aimed to explore the transcriptional regulation and dysregulation of TBX1. Methods Different TBX1 promoter reporters were constructed. Luciferase assays and electrophoretic mobility shift assays (EMSAs) were used to identify a cis-regulatory element within the TBX1 promoter region and its trans-acting factor. The expression of proteins was identified by immunohistochemistry and immunofluorescence. Variants in the cis-regulatory element were screened in conotruncal defect (CTD) patients. In vitro functional assays were performed to show the effects of the variants found in CTD patients on the transactivation of TBX1. Results We identified a cis-regulatory element within intron 1 of TBX1 that was found to be responsive to GATA6 (GATA binding protein 6), a transcription factor crucial for cardiogenesis. The expression patterns of GATA6 and TBX1 overlapped in the pharyngeal arches of human embryos. Transfection experiments and EMSA indicated that GATA6 could activate the transcription of TBX1 by directly binding with its GATA cis-regulatory element in vitro. Furthermore, sequencing analyses of 195 sporadic CTD patients without the 22q11.2 deletion or duplication identified 3 variants (NC_000022.11:g.19756832C > G, NC_000022.11:g.19756845C > T, and NC_000022.11:g. 19756902G > T) in the non-coding cis-regulatory element of TBX1. Luciferase assays showed that all 3 variants led to reduced transcription of TBX1 when incubated with GATA6. Conclusions Our findings showed that TBX1 might be a direct transcriptional target of GATA6, and variants in the non-coding cis-regulatory element of TBX1 disrupted GATA6-mediated transactivation.

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GATA6 mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm

Cited by 34 publications

References 90 publications

Genetics of congenital heart disease: a narrative review of recent advances and clinical implications

Genetics of congenital heart disease: a narrative review of recent advances and clinical implications

GATA6 defines endoderm fate by controlling chromatin accessibility during differentiation of human-induced pluripotent stem cells

Variants in a cis-regulatory element of TBX1 in conotruncal heart defect patients impair GATA6-mediated transactivation

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