How the pluripotency Tx factor NANOG opens (remodels) chromatin

Both genetics (DNA, genes) and epigenetics (DNA-methylation, RNA-interference, histone modification, and chromatin remodeling) are the factors (along with environmental effects) that contribute to inheritance of most multifactorial traits. There are assays for detecting and studying variants/mutations in DNA (genome-wide association studies, whole-genome sequencing, and whole-genome exome sequencing), and some assays now available for epigenetic effects––in the cases of DNA-methylation and RNA-interference. Increasing numbers of studies are now focusing on ways to understand and develop assays for histone modification, and the least understood of all … is the phenomenon of chromatin remodeling.

The attached report concerns chromatin remodeling as it refers to regulation of gene expression. An open and decondensed chromatin organization is a defining property of pluripotency––i.e. the ability of a cell to develop into the three primary germ cell layers of the early embryo (endoderm, mesoderm, ectoderm) and therefore into all cells in the adult body, but not extra-embryonic tissues such as placenta. Embryonic stem (ES) cells, and induced pluripotent stem cells are characterized by their “pluripotency.”

Several epigenetic regulators have been implicated in maintaining an open chromatin organization, but how these processes are associated with the pluripotency network is unknown. In the attached paper, authors identified a new role for the transcription factor NANOG as a key regulator––connecting the pluripotency network with constitutive heterochromatin organization in mouse ES cells. Deletion of the Nanog gene leads to chromatin compaction and remodeling of heterochromatin domains. Forced expression of NANOG in epiblast stem cells is sufficient to decompact chromatin. NANOG is associated with satellite repeats within heterochromatin domains, contributing to an architecture ––characterized by highly dispersed chromatin fibers, low levels of H3K9me3 (trimethylation on Lys-9 of histone 3), and high major satellite transcription––and the strong trans-activation domain of NANOG is required for this organization.

The heterochromatin-associated protein SALL1 is a direct cofactor for NANOG. Loss of Sall1 recapitulates the Nanog-null phenotype, but loss of Sall1 can be circumvented through direct recruitment of the NANOG trans-activation domain to major satellites. These results establish a direct connection between the pluripotency network and chromatin organization. The findings emphasize that maintaining an open heterochromatin architecture is a highly regulated process in ES cells.

Genes Dev   2o16;  30:  1101-????

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