betekintés - Developmental biology - # GATA6 Function in Early Human Cardiac Mesoderm Patterning

GATA6 Regulates Early Mesoderm Patterning and Cardiac Progenitor Cell Specification in Human Cardiogenesis

Q: How might the timing and positioning of GATA6-regulated mesoderm patterning events influence the specific types of congenital heart defects observed in patients with GATA6 mutations?

The timing and positioning of GATA6-regulated mesoderm patterning events are critical in determining the specific types of congenital heart defects (CHDs) observed in patients with GATA6 mutations. GATA6 plays a pivotal role during the early stages of cardiogenesis, particularly in the specification of cardiac progenitor cells (CPCs) and the patterning of precardiac mesoderm. Disruptions in these processes can lead to a reduced pool of CPCs, which are essential for the proper development of the heart. In patients with GATA6 haploinsufficiency, the early mesoderm patterning defects may lead to specific heart field progenitor populations being impaired. For instance, the second heart field (SHF), which contributes to structures such as the outflow tract (OFT), may be particularly affected due to the timing of GATA6's regulatory functions. If GATA6 is not adequately expressed during critical windows of mesoderm development, it can result in insufficient signaling through pathways like WNT and BMP, which are essential for the proper morphogenesis of cardiac structures. Consequently, this can manifest as specific defects such as OFT defects, septal defects, or other forms of CHD, as the precise timing and positioning of GATA6 activity dictate the fate of mesodermal progenitors and their subsequent differentiation into cardiac tissues.

Q: What are the potential mechanisms by which GATA6 interacts with chromatin remodeling complexes to promote accessibility of cardiac lineage-specific genes?

GATA6 is known to function as a pioneer transcription factor, which means it can bind to closed chromatin regions and facilitate their opening, thereby promoting accessibility to cardiac lineage-specific genes. One potential mechanism by which GATA6 interacts with chromatin remodeling complexes involves its binding to components of the SWI/SNF and NuRD complexes. These complexes are crucial for modifying chromatin structure and enhancing transcriptional activity. GATA6 may recruit chromatin remodeling complexes to specific genomic loci, where it binds to regulatory regions of cardiac lineage genes. For instance, the interaction of GATA6 with SWI/SNF complex members, such as SMARCA4, could facilitate the mobilization of nucleosomes, allowing transcriptional machinery to access the DNA and initiate gene expression. Additionally, GATA6's interaction with epigenetic regulators, such as histone deacetylases (HDACs) and other transcriptional co-regulators, may further modulate the chromatin landscape, promoting a permissive environment for cardiac gene expression. Moreover, GATA6's binding to EOMES and other transcription factors during early mesoderm patterning suggests a cooperative regulatory mechanism, where GATA6 not only influences chromatin accessibility but also coordinates the activity of other transcription factors to establish a cardiac-specific gene expression program. This multifaceted interaction with chromatin remodeling complexes is essential for the proper differentiation of cardiac progenitors and the subsequent development of the heart.

Q: Could modulating WNT and BMP signaling pathways during early human development be a therapeutic strategy for treating congenital heart defects associated with GATA6 haploinsufficiency?

Modulating WNT and BMP signaling pathways during early human development presents a promising therapeutic strategy for treating congenital heart defects (CHDs) associated with GATA6 haploinsufficiency. The study indicates that GATA6 is crucial for the regulation of these signaling pathways during the early stages of cardiogenesis, and its loss-of-function leads to dysregulation of WNT and BMP-related gene expression. By pharmacologically manipulating these pathways, such as through the use of WNT agonists like CHIR or by adjusting BMP concentrations, it may be possible to partially rescue the cardiac differentiation defects observed in GATA6 mutant cells. For instance, the study demonstrated that early treatment with CHIR and reduced BMP4 levels could improve the generation of cardiac mesoderm and enhance cardiomyocyte differentiation in GATA6-/- hESCs. This suggests that restoring the balance of WNT and BMP signaling could counteract the adverse effects of GATA6 haploinsufficiency. Furthermore, since WNT and BMP signaling are critical for mesoderm patterning and cardiac development, targeted interventions during these early developmental windows could potentially correct the underlying defects before they lead to irreversible heart malformations. Therefore, therapeutic strategies aimed at modulating these pathways could provide a novel approach to mitigate the impact of GATA6 mutations and improve outcomes for patients with associated CHDs.

Alapfogalmak

GATA6 is required for proper patterning of lateral and cardiac mesoderm during the earliest stages of human cardiogenesis, regulating the expression of genes involved in WNT and BMP signaling pathways.

Kivonat

This study investigates the role of the transcription factor GATA6 during the earliest stages of human cardiac development using in vitro differentiation of human embryonic stem cells (hESCs).

Key findings:

GATA6 loss-of-function severely impairs cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation.
The cardiac defects originate from early defects in lateral and cardiac mesoderm patterning, as GATA6 mutant hESCs fail to properly express genes involved in WNT and BMP signaling pathways required for this process.
GATA6 CUT&RUN analysis reveals GATA6 binding at regulatory regions of WNT and BMP target genes, suggesting direct transcriptional regulation.
GATA6 interacts with developmental transcription factors like EOMES and chromatin remodeling complexes, potentially regulating chromatin accessibility for cardiac lineage commitment.
Early modulation of WNT and BMP signaling can partially rescue the cardiac mesoderm and CM defects in GATA6 mutant hESCs, highlighting the importance of these pathways downstream of GATA6 during human cardiogenesis.

These findings provide insights into how GATA6 haploinsufficiency can lead to congenital heart defects and co-occurring organ defects in humans by disrupting the earliest stages of precardiac mesoderm patterning.

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biorxiv.org

Statisztikák

"GATA6 is required for the development of multiple mesoderm and endoderm derived organs and some CHD patients with heterozygous GATA6 mutations have comorbidities including pancreatic agenesis, neonatal diabetes, or congenital diaphragmatic hernia."
"GATA6 knockout (KO) mice exhibit early embryonic arrest during primitive streak formation due to defects in visceral endoderm."
"GATA6 heterozygous mutant mice develop heart abnormalities including bicuspid aortic valve and heart rhythm abnormalities."

Idézetek

"GATA6 loss-of-function hESCs had a profound impairment in cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation due to early defects during the mesendoderm and lateral mesoderm patterning stages."
"Profiling by RNA-seq and CUT&RUN identified genes of the WNT and BMP programs regulated by GATA6 during early mesoderm patterning."
"Interactome analysis detected GATA6 binding with developmental transcription factors and chromatin remodelers suggesting cooperative regulation of cardiac lineage gene accessibility."

Főbb Kivonatok

GATA6 regulates WNT and BMP programs to pattern precardiac mesoderm during the earliest stages of human cardiogenesis

by Bisson,J. A.... : www.biorxiv.org 07-11-2024

https://www.biorxiv.org/content/10.1101/2024.07.09.602666v1

Mélyebb kérdések

How might the timing and positioning of GATA6-regulated mesoderm patterning events influence the specific types of congenital heart defects observed in patients with GATA6 mutations?

The timing and positioning of GATA6-regulated mesoderm patterning events are critical in determining the specific types of congenital heart defects (CHDs) observed in patients with GATA6 mutations. GATA6 plays a pivotal role during the early stages of cardiogenesis, particularly in the specification of cardiac progenitor cells (CPCs) and the patterning of precardiac mesoderm. Disruptions in these processes can lead to a reduced pool of CPCs, which are essential for the proper development of the heart.
In patients with GATA6 haploinsufficiency, the early mesoderm patterning defects may lead to specific heart field progenitor populations being impaired. For instance, the second heart field (SHF), which contributes to structures such as the outflow tract (OFT), may be particularly affected due to the timing of GATA6's regulatory functions. If GATA6 is not adequately expressed during critical windows of mesoderm development, it can result in insufficient signaling through pathways like WNT and BMP, which are essential for the proper morphogenesis of cardiac structures. Consequently, this can manifest as specific defects such as OFT defects, septal defects, or other forms of CHD, as the precise timing and positioning of GATA6 activity dictate the fate of mesodermal progenitors and their subsequent differentiation into cardiac tissues.

What are the potential mechanisms by which GATA6 interacts with chromatin remodeling complexes to promote accessibility of cardiac lineage-specific genes?

GATA6 is known to function as a pioneer transcription factor, which means it can bind to closed chromatin regions and facilitate their opening, thereby promoting accessibility to cardiac lineage-specific genes. One potential mechanism by which GATA6 interacts with chromatin remodeling complexes involves its binding to components of the SWI/SNF and NuRD complexes. These complexes are crucial for modifying chromatin structure and enhancing transcriptional activity.
GATA6 may recruit chromatin remodeling complexes to specific genomic loci, where it binds to regulatory regions of cardiac lineage genes. For instance, the interaction of GATA6 with SWI/SNF complex members, such as SMARCA4, could facilitate the mobilization of nucleosomes, allowing transcriptional machinery to access the DNA and initiate gene expression. Additionally, GATA6's interaction with epigenetic regulators, such as histone deacetylases (HDACs) and other transcriptional co-regulators, may further modulate the chromatin landscape, promoting a permissive environment for cardiac gene expression.
Moreover, GATA6's binding to EOMES and other transcription factors during early mesoderm patterning suggests a cooperative regulatory mechanism, where GATA6 not only influences chromatin accessibility but also coordinates the activity of other transcription factors to establish a cardiac-specific gene expression program. This multifaceted interaction with chromatin remodeling complexes is essential for the proper differentiation of cardiac progenitors and the subsequent development of the heart.

Could modulating WNT and BMP signaling pathways during early human development be a therapeutic strategy for treating congenital heart defects associated with GATA6 haploinsufficiency?

Modulating WNT and BMP signaling pathways during early human development presents a promising therapeutic strategy for treating congenital heart defects (CHDs) associated with GATA6 haploinsufficiency. The study indicates that GATA6 is crucial for the regulation of these signaling pathways during the early stages of cardiogenesis, and its loss-of-function leads to dysregulation of WNT and BMP-related gene expression.
By pharmacologically manipulating these pathways, such as through the use of WNT agonists like CHIR or by adjusting BMP concentrations, it may be possible to partially rescue the cardiac differentiation defects observed in GATA6 mutant cells. For instance, the study demonstrated that early treatment with CHIR and reduced BMP4 levels could improve the generation of cardiac mesoderm and enhance cardiomyocyte differentiation in GATA6-/- hESCs. This suggests that restoring the balance of WNT and BMP signaling could counteract the adverse effects of GATA6 haploinsufficiency.
Furthermore, since WNT and BMP signaling are critical for mesoderm patterning and cardiac development, targeted interventions during these early developmental windows could potentially correct the underlying defects before they lead to irreversible heart malformations. Therefore, therapeutic strategies aimed at modulating these pathways could provide a novel approach to mitigate the impact of GATA6 mutations and improve outcomes for patients with associated CHDs.