Decoding the PITX2-controlled genetic network in atrial fibrillation

Steimle, Jeffrey D.; Canozo, Francisco Jose Grisanti; Park, Minjun; Kadow, Zachary A.; Samee, Md. Abul Hassan; Martin, James F.

doi:10.1172/jci.insight.158895

Cited by 11 publications

(9 citation statements)

References 110 publications

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“…7A). Marker genes for the LaCMs ( PITX2 and PANCR : PITX2-associated non-coding RNA) have been highlighted in human and mouse left atrial tissue ( see Bayraktar et al ) 36,37 , and are important in repressing the pacemaker gene programme in the left horn of the sinus venosus 28 . The PITX2-adjacent 4q25 locus is a well-known risk locus for atrial fibrillation 28,33 .…”

Section: Resultsmentioning

confidence: 99%

Multiomic analysis reveals developmental dynamics of the human heart in health and disease

Cranley,

Kanemaru,

Bayraktar

et al. 2024

Preprint

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Developmental dynamics encompass both the specification of cell types and their spatial organisation into multicellular niches. Here we harness the power of single-cell and spatial multiomics to unravel embryonic and foetal cardiac tissue niches, which lead to the development of a new tool, TissueTypist. We infer developmental cell trajectories, including evidence for lineage relationships based on shared somatic mutations, within first- and second-trimester human hearts. We reveal that cardiac-resident macrophages likely originate from the yolk sac, forming heterogeneous subsets. CX3CR1+ macrophages with a microglia-like profile localise in the sinoatrial node, which may contribute to axon guidance for the innervating autonomic neurons. Foetal pacemaker cells exhibit distinct characteristics compared to their adult counterparts, including the expression of genes that are known to promote parasympathetic innervation. By comparing somatic mutation profiles of cardiomyocytes, we identify an early branching point where pacemaker cells diverge from working cardiomyocytes. We highlight the enhancer-mediated gene regulatory networks governing atrial and ventricular cardiomyocyte specification. The maturation of atrial cardiomyocytes into distinct left and right phenotypes, driven by transcription factors linked to atrial septal defect genes, underscores the significance of this process for healthy heart development. In the ventricle, cellular and transcriptional gradients along both pseudotime and the transmural axis provide a new molecular understanding of myocardial compaction. Finally, generating data from Trisomy 21 hearts and comparing this with the euploid atlas, we reveal a reduced abundance of specific cell types including compact cardiomyocytes. Overall, this extensive dataset and our precomputed models will form a valuable resource for the field.

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Section: Resultsmentioning

confidence: 99%

Multiomic analysis reveals developmental dynamics of the human heart in health and disease

Cranley,

Kanemaru,

Bayraktar

et al. 2024

Preprint

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“…Bmp10, a conserved marker of aCM_Bmp10, is predominantly distributed in the heart that preserves cardiac function 12 . In contrast, the transcription factor Pitx2, which is expressed in aCM_Fabp5, is implicated in atrial brillation predisposition 13 . Besides Nppb, Ankyrin repeat domain 1 (Ankrd1) was found predominantly within vCM_Nppb, playing crucial roles in cardiogenesis, mechanosensing, and intracellular signaling 14 .…”

Section: Seven Subclusters Of Atrial and Ventricle Cardiomyocytesmentioning

confidence: 96%

The single-cell atlas of the heart reveals an unexpected erythrocyte-like cardiomyocyte

Shen

et al. 2022

Preprint

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Single-cell RNA sequencing (scRNA-seq) is widely used in cancer research and organ development since its powerful ability to analyze cellular heterogeneity. However, its application in cardiomyocytes is rare mainly because the cardiomyocytes are too large and fragile to withstand traditional single-cell approaches. Through designing the isolation procedure of neonatal mouse cardiac cells, we provide detailed cellular atlases of the heart at single-cell resolution across four different stages after birth. We have luckily obtained tens of thousands of cardiomyocytes, to our knowledge, the most extensive reference framework so far. Moreover, we have discovered unexpected erythrocytes-like cardiomyocyte-terminal cardiomyocytes, comprising more than a third of all the cardiomyocytes. Only a few genes are highly expressed in these cardiomyocytes. They are highly differentiated cardiomyocytes function as contraction pump. In addition, we have identified two cardiomyocyte-like conducting cells, lending support to the theory that the sinoatrial node pacemaker cells are specialized cardiomyocytes. Furthermore, we provide an initial blueprint for comprehensive interactions between cardiomyocytes and other cardiac cells. We linked specific cell types to adverse drug reactions and congenital heart diseases and analyzed the roles of cell subtypes in adverse drug reactions and cardiac diseases. These mouse cardiac cell atlas improves our understanding of the heart and provides a valuable reference in response to varying physiological conditions and diseases.

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“…Single nuclei (sn) were isolated according to previous methods 20 . The snRNA-Seq libraries were generated using the 10x Genomics Chromium Single Cell 3' v3 reagent kit and the sequencing was performed by Novogene.…”

Section: Single Nuclei Rna-seqmentioning

confidence: 99%

“…Gene expression was converted to Uniform Manifold Approximation and Projection (UMAP) and clusters were detected using Scanpy 21 . Cell types were annotated using cell markers of murine heart previously reported 20,23 . Differentially expressed genes were determined using the Seurat R package 24 FindMarkers function, with significance achieved for FDR<0.05 and fold change exceeding 1.5-fold.…”

Section: Single Nuclei Rna-seqmentioning

confidence: 99%

Fibroblast-specific inflammasome activation predisposes to atrial fibrillation

2023

Preprint

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Background: Recent work has shown that the NLR-family-pyrin-domain-containing 3 (NLRP3) inflammasome is expressed in cardiomyocytes and when specifically activated causes atrial electrical remodeling and arrhythmogenicity. Whether the NLRP3-inflammasome system is functionally important in cardiac fibroblasts (FBs) remains controversial. In this study, we sought to uncover the potential contribution of FB NLRP3-inflammasome signaling to the control of cardiac function and arrhythmogenesis. Methods: Digital-PCR was performed to determine the expression of NLRP3-pathway components in FBs isolated from human biopsy samples of AF and sinus rhythm patients. NLRP3-system protein expression was determined by immunoblotting in atria of canines with electrically maintained AF. Using the inducible, resident fibroblast (FB)-specific Tcf21-promoter-Cre system (Tcf21iCre as control), we established a FB-specific knockin (FB-KI) mouse model with FB-restricted expression of constitutively active NLRP3. Cardiac function and arrhythmia susceptibility in mice were assessed by echocardiography, programmed electrical stimulation, and optical mapping studies. Results: NLRP3 and IL1B were upregulated in atrial FBs of patients with persistent AF. Protein levels of NLRP3, ASC, and pro-Interleukin-1b were increased in atrial FBs of a canine AF model. Compared with the control mice, FB-KI mice exhibited enlarged left atria (LA) and reduced LA contractility, a common determinant of AF. The FBs from FB-KI mice were more transdifferentiated, migratory, and proliferative compared to the FBs from control mice. FB-KI mice showed increased cardiac fibrosis, atrial gap junction remodeling, and reduced conduction velocity, along with increased AF susceptibility. These phenotypic changes were supported by single nuclei (sn)RNA-seq analysis, which revealed enhanced extracellular matrix remodeling, impaired communication among cardiomyocytes, and altered metabolic pathways across multiple cell types. Conclusions: Our results show that the FB-restricted activation of the NLRP3-inflammasome system leads to fibrosis, atrial cardiomyopathy, and AF. Activation of NLRP3-inflammasome in resident FBs exhibits cell-autonomous function by increasing the activity of cardiac FBs, fibrosis, and connexin remodeling. This study establishes the NLRP3-inflammasome as a novel FB-signaling pathway contributing to AF pathogenesis.

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Decoding the PITX2-controlled genetic network in atrial fibrillation

Cited by 11 publications

References 110 publications

Multiomic analysis reveals developmental dynamics of the human heart in health and disease

Multiomic analysis reveals developmental dynamics of the human heart in health and disease

The single-cell atlas of the heart reveals an unexpected erythrocyte-like cardiomyocyte

Fibroblast-specific inflammasome activation predisposes to atrial fibrillation

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