Liquid-liquid phase separation in subcellular assemblages and signaling pathways: Chromatin modifications induced gene regulation for cellular physiology and functions including carcinogenesis

• Published in: Biochimie 2024-08, Vol.223, p.74-97
• Main Authors: Chakraborty, Subhajit, Mishra, Jagdish, Roy, Ankan, Niharika, Manna, Soumen, Baral, Tirthankar, Nandi, Piyasa, Patra, Subhajit, Patra, Samir Kumar
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Carcinogenesis - genetics; Carcinogenesis - metabolism; Chromatin - genetics; Chromatin - metabolism; Chromatin Assembly and Disassembly; Condensate; Enzymatic reaction; Epigenesis, Genetic; Epigenetics; Humans; IDR-LCR; Liquid-liquid phase separation; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Organelles - genetics; Organelles - metabolism; Phase Separation; Signal Transduction
• ISSN: 0300-9084; 1638-6183; 1638-6183
• DOI: 10.1016/j.biochi.2024.05.007

Liquid-liquid phase separation (LLPS) describes many biochemical processes, including hydrogel formation, in the integrity of macromolecular assemblages and existence of membraneless organelles, including ribosome, nucleolus, nuclear speckles, paraspeckles, promyelocytic leukemia (PML) bodies, Cajal bodies (all exert crucial roles in cellular physiology), and evidence are emerging day by day. Also, phase separation is well documented in generation of plasma membrane subdomains and interplay between membranous and membraneless organelles. Intrinsically disordered regions (IDRs) of biopolymers/proteins are the most critical sticking regions that aggravate the formation of such condensates. Remarkably, phase separated condensates are also involved in epigenetic regulation of gene expression, chromatin remodeling, and heterochromatinization. Epigenetic marks on DNA and histones cooperate with RNA-binding proteins through their IDRs to trigger LLPS for facilitating transcription. How phase separation coalesces mutant oncoproteins, orchestrate tumor suppressor genes expression, and facilitated cancer-associated signaling pathways are unravelling. That autophagosome formation and DYRK3-mediated cancer stem cell modification also depend on phase separation is deciphered in part. In view of this, and to linchpin insight into the subcellular membraneless organelle assembly, gene activation and biological reactions catalyzed by enzymes, and the downstream physiological functions, and how all these events are precisely facilitated by LLPS inducing organelle function, epigenetic modulation of gene expression in this scenario, and how it goes awry in cancer progression are summarized and presented in this article. [Display omitted] •LLPS defines macromolecular assemblies, membraneless organelles and biochemical processes.•IDR, LCR, lncRNA and multivalent domain-motif interactions drive LLPS formation.•LLPS regulates chromatin organization and gene expression.•LLPS influence cancer, cancer associated signaling, autophagy and apoptosis.•Machine learning is applicable to predict phase separation and multiple interactions in LLPS.