About this Research Topic

Background

Cell biologists have long recognized, looking through classical light microscopes, organelles that are either membrane-bound or membrane-less. Recent progress in the development of biophysical analytical approaches has crossed paths with macromolecule condensates in cells. These cellular condensates, or liquid-like droplets, are formed by liquid-liquid phase separation (LLPS). During eukaryotic evolution, cells gained membrane-bound organelles such as nuclei, mitochondria, and endoplasmic reticula, where lipid membranes separate organelle matrices from the cytoplasm. Such membrane-bound organelles enable the segregation of certain factors, including proteins and metabolites, in their proper locations and provide selective trafficking between inside and outside of the nucleus.

Although it seemed that the presence of a physical boundary, such as a nuclear membrane, was the only way compartments could be formed and provide trafficking control within cells, cells, in fact, have another option: LLPS. LLPS define distinct compartments to efficiently organize cellular processes by concentrating on certain factors in their proper location without interfering with one another in the complex and the heterogeneous environment within a cell. Accumulating evidence demonstrates that these LLPS-mediated molecular compartments are required for signal transduction, regulation of gene expression, stress response, and many other aspects of cellular physiology.

LLPS is reversible, unlike aggregates, and appear to be in a viscoelastic-dynamic fluid state, which gives them plasticity and flexibility. Aberrant regulation of LLPS is often found in neurological and developmental diseases and human genetics offers more information about the physiological roles of LLPS. Moreover, the relevance of LLPS is not restricted only to eukaryotic cells, but also to bacteria and to the origins of life.

More and more cell biologists now recognize that many of the membrane-less organelles observed in cells are formed by LLPS caused by interactions between proteins and nucleic acids. LLPS is driven by self-interaction of intrinsically disordered low complexity protein regions as well as multivalent interaction between proteins and nucleic acids. LLPS is also regulated by posttranslational modifications and molecular chaperones. However, little is known about the mechanisms of formation and regulation of LLPS. In contrast to conventional biomolecular interactions, weak, transient and multivalent interactions drive LLPS formation. To better understand the unconventional behavior of LLPS-forming macromolecules, technical advancement of biophysical analytical approaches is desired; this promising list includes nuclear magnetic resonance (NMR), small angle X-ray scattering (SAXS), small angle neutron scattering (SANS), cryogenic electron microscopy (cryo-EM), high-speed atomic force microscopy (HS-AFM), and optogenetics, among others.

The aims of this Research Topic are to update the current understanding and future directions of biological phase separation. The scope covers all relevant technologies and topics, from molecular and cellular studies to animal and human research. We will gladly consider original research articles, reviews, perspectives, and commentaries related to all facets of biological phase separation. We welcome contributions that cover, but are not limited to, the following topics and keywords:
• liquid-like droplets, hydrogels, membrane-less organelles
• intrinsically disordered low complexity proteins, cross-β polymers, Prions, amyloids
• origins of life, coacervates, protocells
• gene transcription, super-enhancers, genome replication, DNA repair, epigenetics
• metabolism, enzyme chain reaction, activation/inactivation
• RNA granules, stress response, stem cell maintenance
• nucleocytoplasmic transport, nuclear pores
• autophagy, proteasomes, proteostasis
• regulators of LLPS: posttranslational modifications, molecular chaperones
• technical advancements and theories required to properly study biological phase separation

Keywords: Phase Separation, RNA granules, intrinsically disordered low complexity proteins, liquid-like droplets, membraneless organelles

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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