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1.
Stem Cell Reports ; 18(11): 2138-2153, 2023 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-37863045

RESUMO

Congenital heart disease often arises from perturbations of transcription factors (TFs) that guide cardiac development. ISLET1 (ISL1) is a TF that influences early cardiac cell fate, as well as differentiation of other cell types including motor neuron progenitors (MNPs) and pancreatic islet cells. While lineage specificity of ISL1 function is likely achieved through combinatorial interactions, its essential cardiac interacting partners are unknown. By assaying ISL1 genomic occupancy in human induced pluripotent stem cell-derived cardiac progenitors (CPs) or MNPs and leveraging the deep learning approach BPNet, we identified motifs of other TFs that predicted ISL1 occupancy in each lineage, with NKX2.5 and GATA motifs being most closely associated to ISL1 in CPs. Experimentally, nearly two-thirds of ISL1-bound loci were co-occupied by NKX2.5 and/or GATA4. Removal of NKX2.5 from CPs led to widespread ISL1 redistribution, and overexpression of NKX2.5 in MNPs led to ISL1 occupancy of CP-specific loci. These results reveal how ISL1 guides lineage choices through a combinatorial code that dictates genomic occupancy and transcription.


Assuntos
Células-Tronco Pluripotentes Induzidas , Fatores de Transcrição , Humanos , Fatores de Transcrição/metabolismo , Miócitos Cardíacos , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Diferenciação Celular/genética , Proteína Homeobox Nkx-2.5/genética , Proteína Homeobox Nkx-2.5/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo
2.
Cell ; 185(5): 794-814.e30, 2022 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-35182466

RESUMO

Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease.


Assuntos
Fator de Transcrição GATA4/metabolismo , Cardiopatias Congênitas , Proteínas Nucleares/metabolismo , Oxirredutases/metabolismo , Fatores de Transcrição , Animais , Cardiopatias Congênitas/genética , Camundongos , Mutação , Proteômica , Proteínas com Domínio T/genética , Fatores de Transcrição/genética
3.
Cell Stem Cell ; 25(1): 87-102.e9, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31271750

RESUMO

Ectopic expression of combinations of transcription factors (TFs) can drive direct lineage conversion, thereby reprogramming a somatic cell's identity. To determine the molecular mechanisms by which Gata4, Mef2c, and Tbx5 (GMT) induce conversion from a cardiac fibroblast toward an induced cardiomyocyte, we performed comprehensive transcriptomic, DNA-occupancy, and epigenomic interrogation throughout the reprogramming process. Integration of these datasets identified new TFs involved in cardiac reprogramming and revealed context-specific roles for GMT, including the ability of Mef2c and Tbx5 to independently promote chromatin remodeling at previously inaccessible sites. We also find evidence for cooperative facilitation and refinement of each TF's binding profile in a combinatorial setting. A reporter assay employing newly defined regulatory elements confirmed that binding of a single TF can be sufficient for gene activation, suggesting that co-binding events do not necessarily reflect synergy. These results shed light on fundamental mechanisms by which combinations of TFs direct lineage conversion.


Assuntos
Fator de Transcrição GATA4/metabolismo , Fatores de Transcrição MEF2/metabolismo , Miócitos Cardíacos/fisiologia , Proteínas com Domínio T/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Reprogramação Celular , Montagem e Desmontagem da Cromatina , Epigênese Genética , Fator de Transcrição GATA4/genética , Fatores de Transcrição MEF2/genética , Aprendizado de Máquina , Camundongos , Ligação Proteica , Proteínas com Domínio T/genética , Ativação Transcricional
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