Activating the right gene at the right time and place is essential for development. Emerging evidence suggests that this process is regulated by the mesoscale compartmentalization of the gene-control machinery, RNA polymerase II and its cofactors, within biomolecular condensates. Coupling gene activity to the reversible and dynamic process of condensate formation is proposed to enable the robust and precise changes in gene-regulatory programs during signaling and development. The macromolecular features that enable condensates and the regulatory pathways that control them are dysregulated in disease, highlighting their importance for normal physiology. In this review, we will discuss the role of condensates in gene activation; the multivalent features of protein, RNA, and DNA that enable reversible condensate formation; and how these processes are utilized in normal and disease biology. Understanding the regulation of condensates promises to provide novel insights into how organization of the gene-control machinery regulates development and disease.
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http://dx.doi.org/10.1016/j.devcel.2020.09.005 | DOI Listing |
Unlabelled: Biomolecular condensates organize cellular environments and regulate key processes such as transcription. We previously showed that full-length androgen receptor (AR-FL), a major oncogenic driver in prostate cancer (PCa), forms nuclear condensates upon androgen stimulation in androgen-sensitive PCa cells. Disrupting these condensates impairs AR-FL transcriptional activity, highlighting their functional importance.
View Article and Find Full Text PDFUnlabelled: Compartmentalization of the nucleus into heterochromatin and euchromatin is highly conserved across eukaryotes. Constitutive heterochromatin (C-Het) constitutes a liquid-like condensate that packages the repetitive regions of the genome through the enrichment of histone modification H3K9me3 and recruitment of its cognate reader protein Heterochromatin Protein-1 (HP1a). The ability for well-ordered nucleosome arrays and HP1a to independently form biomolecular condensates suggests that the emergent material properties of C-Het compartments may contribute to its functions such as force-buffering, dosage-dependent gene silencing, and selective permeability.
View Article and Find Full Text PDFPRX Life
June 2024
Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA.
Biomolecular condensates are dynamic intracellular entities defined by their sequence- and composition-encoded material properties. During aging, these properties can change dramatically, potentially leading to pathological solidlike states, the mechanisms of which remain poorly understood. Recent experiments reveal that the aging of condensates involves a complex interplay of solvent depletion, strengthening of sticker links, and the formation of rigid structural segments such as beta fibrils.
View Article and Find Full Text PDFImmunohorizons
January 2025
Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, United States.
Antibody (Ab) crosslinking of HLA class II (HLA II) molecules on the surface of endothelial cells (ECs) triggers proliferative and prosurvival intracellular signaling, which are implicated in promoting chronic Ab-mediated rejection (cAMR). Despite the importance of cAMR in transplant medicine, the mechanisms involved remain incompletely understood. Here, we examined the regulation of yes-associated protein (YAP) nuclear cytoplasmic localization and phosphorylation in human ECs challenged with Abs that bind HLA II, which are strongly associated with cAMR.
View Article and Find Full Text PDFBiomacromolecules
January 2025
Department of Applied Chemistry, Kyung Hee University, Yongin, Gyeonggi 17104, South Korea.
This study proposes fluorenylmethoxycarbonyl (Fmoc)-protected single amino acids (Fmoc-AAs) as a minimalistic model system to investigate liquid-liquid phase separation (LLPS) and the elusive liquid-to-solid transition of condensates. We demonstrated that Fmoc-AAs exhibit LLPS depending on the pH and ionic strength, primarily driven by hydrophobic interactions. Systematic examination of the conditions under which each Fmoc-AA undergoes LLPS revealed distinct residue-dependent trends in the critical concentrations and phase behavior.
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