Gene Silencing Determines Eventual Stem Cell Fate

Sequestration of certain portions of the genome in close proximity to the wall of the nucleus in a stem cell determines whether genes in this region (the nuclear lamina) are expressed, which controls future cellular identity and function.

Progenitor stem cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. Investigators at the University of Pennsylvania (Philadelphia, USA) worked with heart stem cells to study the mechanism that causes certain areas of the genome to become bound to the nuclear membrane and the ramifications of being bound in this location.

The investigators reported in the October 12, 2017, online edition of the journal Cell that a histone deacetylase (Hdac3) protein organized heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Hdac3 tethered peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells released genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescued myogenesis - allowing continued reproduction as stem cells - in progenitors otherwise lacking Hdac3.

This data demonstrated that nuclear lamina-chromatin interactions influenced cardiac progenitor cell differentiation. The investigators proposed that organogenesis was achieved through dynamic spatial reorganization of chromatin, including coordinated sequestration and/or release of genomic regions harboring key developmental genes from the nuclear lamina.

"The basis of this study is understanding the ability of a cell to respond to molecular cues to correctly become one cell type or another," said senior author, Dr. Rajan Jain, assistant professor of cardiovascular medicine at the University of Pennsylvania. "We wanted to know how that is achieved, step by step, because stem cells, capable of becoming any cell type in the body, give rise to cardiac muscle cells. Our work suggests that a cell defines its identity by storing away in an inaccessible closet the critical genes and programs necessary for it to mature into another cell type. In other words, a cell is "who" it is because it has silenced "who" it is not. We asked: Does this choreographed control of DNA availability contribute to a cell becoming a certain type?"

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