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Restructuring of chromatin architecture is an essential process for establishing cell type-specific gene regulatory programs in eukaryotic cells including cardiomyocytes^–. Supporting its importance, recent studies have reported that a substantial number of mutations discovered in congenital heart disease (CHD) patients reside in genes encoding chromatin remodeling factors^–; yet, how chromatin structure reorganizes to assemble gene regulatory networks crucial for controlling human cardiomyocyte development remains to be elucidated. Here, through comprehensively analyzing high-resolution genomic maps that detail the dynamic changes of chromatin architecture, chromatin accessibility and modifications, and gene expression during human pluripotent stem cell (PSC) cardiomyocyte differentiation, we reveal novel molecular insights into how human PSC chromatin architecture is iteratively remodeled to build gene regulatory networks directing cardiac lineage specification. Specifically, we uncover a new class of human PSC-specific topologically associating domain (TAD) that is created by the active transcription of the primate-specific endogenous retrotransposon HERV-H. Silencing of specific HERV-Hs during the initial stages of human PSC differentiation or by genome-editing results in the elimination of corresponding TAD boundaries and reduced transcription of genes upstream of HERV-Hs. Supporting their role in maintaining pluripotency, we discovered that deletion of specific HERV-Hs leads to more efficient human PSC cardiomyocyte differentiation. Using chromatin interaction maps from these analyses, we also assigned potential …