Dynamic reorganization of nuclear architecture during human cardiogenesis

Abstract

While chromosomal architecture varies among cell types, little is known about how this organization is established or its role in development. We integrated Hi-C, RNA-seq and ATAC-seq during cardiac differentiation from human pluripotent stem cells to generate a comprehensive profile of chromosomal architecture. We identified active and repressive domains that are dynamic during cardiogenesis and recapitulate in vivo cardiomyocytes. During differentiation, heterochromatic regions condense in cis. In contrast, many cardiac-specific genes, such as TTN (titin), decompact and transition to an active compartment coincident with upregulation. Moreover, we identify a network of genes, including TTN, that share the heart-specific splicing factor, RBM20, and become associated in trans during differentiation, suggesting the existence of a 3D nuclear splicing factory. Our results demonstrate both the dynamic nature in nuclear architecture and provide insights into how developmental genes are coordinately regulated.One Sentence SummaryThe three-dimensional structure of the human genome is dynamically regulated both globally and locally during cardiogenesis.

Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells

“…Consistent with recent reports describing loss of TADs during ESC differentiation 23 , 28 , we also observed that the number of TADs decreased as hESCs differentiated into ventricular cardiomyocytes using multiple TAD-calling algorithms 5 , 10 , 29 ( Supplementary Fig. 4a , b , c ).…”

Decoding the Heart through Next Generation Sequencing Approaches

“…Their analyses showed that in differentiating hESCs, heterochromatin regions pack more tightly within cis chromosome territories (intra-chromosomal contacts), whereas inter-chromosomal interactions (trans) are likely to occur between active regions localized in the proximity of cardiac-specific genes, such as titin ( TTN ). In general, collective results from RNA-seq, ATAC-seq, and Hi-C revealed that changes in chromatin accessibility occurred concomitantly with changes in RNA expression and large scale genome organization [ 27 ].…”