One step closer – Does phase separation drive heterochromatin establishment?

Liquid-liquid phase separation is currently a hot topic under chromatin biologists. Different chromatin states might form immiscible, separated compartments within the nucleus that allow only particular cellular processes to occur within. Recently, Manuel Guthmann, Adam Burton and Maria-Elena Torres Padilla, Director from the Institute of Epigenetics and Stem Cells (IES) of the Helmholtz Zentrum München, published their findings in EMBO Reports that suggest phase separation as a key driver for heterochromatin formation in the early mouse embryo.

Source: EMBOpress Synopsis

In multicellular organisms, such as humans, DNA carrying the hereditary information is packaged into a structure called chromatin. While packaging of the DNA is necessary to fit the genomic material into tiny nuclei, it is also is a way to regulate DNA accessibility for cellular processes that require DNA as template, such as transcription. Functionally, chromatin states can be classified into two states: eu- and heterochromatin. Heterochromatin was considered to be not functional at first, since it appeared as regions of the nucleus that did not decondense during mitosis. However, nowadays it is known that heterochromatin is the characteristic structure of centromeres or telomeres and necessary for gene repression. Heterochromatin protein 1 (HP1) proteins are key components of heterochromatin formation. Recent findings have suggested that HP1α accumulation leads to nucleation of immiscible phase separated compartment enabling heterochromatin formation to occur within. During germ cell and early embryonic development, a significant rearrangement and reprogramming of heterochromatin occurs. The mechanisms behind are thus far elusive since HP1α is not expressed until the late 2-cell stage.To shed light into the biophysical properties and the mechanisms underlying heterochromatin formation, M. Guthmann and colleagues investigated the potential of the 148 most relevant heterochromatic proteins to contribute to heterochromatin phase separation. Therefore, they analyzed each protein for its intrinsically disordered domains (IDRs) and determined a disorder score for each protein by calculating the percentage disorder, the mean disorder and the length of disordered segments. IDRs are structural features of protein domains thought to promote phase separation. In comparison to other nuclear proteins, heterochromatic proteins had a significantly higher disorder score suggesting that they have a higher potential to phase separate. Furthermore, by analyzing the expression patterns of the heterochromatic proteins during mouse preimplantation development, Guthmann et al. could investigate for the first time the dynamics of phase separation in the mouse embryo. Their findings suggest that heterochromatin and its potential to phase separate mature gradually during the early period of mammalian development.Altogether, the work of Guthmann and colleagues creates an exciting foundation for future research aiming to unravel if and when phase separation regulates heterochromatin formation, especially during early embryonic development.

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