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The dynamic regulatory architecture of human cardiac differentiation

ABSTRACT: Transcription factors (TFs) control the precise timing of gene programs during lineage commitment. A key challenge is to define the dynamic regulatory architecture of TFs in human development. Here, we systematically perturb 1983 transcription factors (TFs) during cardiomyocyte differentiation of human stem cells. Our analysis links TFs to multiscale gene expression phenotypes, and nominates TFs regulating cardiomyocyte differentiation and the balance of cell fate commitment across cardiac lineages. Architecturally, we identify MYOCD and TBX18 as highly connected hub TFs serving as regulatory interfaces for stage-specific developmental gene programs. More generally, co-regulation analysis identifies dynamic TF-TF interactions between MEF2 family TFs and members of the Polycomb Repressive 1 complex during cardiac differentiation. Finally, we develop a deep learning transformer model to accurately predict perturbed TFs driving altered regulatory networks in patient-derived transcriptomes. Together, this reference map represents a foundational platform to understand how developmental networks are structured, to model TF function, and to interpret disease variants and mechanisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330353 | GEO | 2026/05/13

REPOSITORIES: GEO

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