Biogenesis and function of nuclear bodies

Abstract

Nuclear bodies including nucleoli, Cajal bodies, nuclear speckles, Polycomb bodies, and paraspeckles are membraneless subnuclear organelles. They are present at steady-state and dynamically respond to basic physiological processes as well as to various forms of stress, altered metabolic conditions and alterations in cellular signaling. The formation of a specific nuclear body has been suggested to follow a stochastic or ordered assembly model. In addition, a seeding mechanism has been proposed to assemble, maintain, and regulate particular nuclear bodies. In coordination with noncoding RNAs, chromatin modifiers and other machineries, various nuclear bodies have been shown to sequester and modify proteins, process RNAs and assemble ribonucleoprotein complexes, as well as epigenetically regulate gene expression. Understanding the functional relationships between the 3D organization of the genome and nuclear bodies is essential to fully uncover the regulation of gene expression and its implications for human disease.

Figure 1

Diversity of nuclear bodies. The cartoon represents the landscape of an interphase mammalian cell nucleus. The nucleus is enclosed by a double membrane structure called the nuclear envelope, which is contiguous with the rough endoplasmic reticulum and serve as a physical barrier to separate nuclear contents from cytoplasm. The nuclear envelope is interrupted in places by nuclear pore complexes controlling the nucleocytoplasmic transport. Under the inner face of the nuclear envelope, the nuclear lamina provides mechanical support and participates in chromatin organization. The nucleus contains the vast majority of the cell's genetic material organized as multiple chromosomes. Interphase chromosomes occupy distinct chromosome territories. Chromatin fibers and loops from the same chromosome territory and from neighboring chromosome territories can make contact and intermingle in cis and trans. The interchromatin space is very organized, highly dynamic, and harbors multiple nuclear bodies, such as Cajal bodies, clastosomes, histone locus bodies, nuclear speckles, nucleoli, paraspeckles, perinucleolar compartments, PML-nuclear bodies, and Polycomb bodies. The nucleolus is composed of fibrillar centers, dense fibrillar component and granular components and is surrounded by perinucleolar heterochromatin.

Figure 2

Mechanisms of nuclear body assembly. (a) The formation of a nuclear body can occur via a stochastic assembly mechanism in which multiple pathways can be followed to assemble a nuclear body (top), or a hierarchically ordered mechanism in which only one or limited number of pathways are followed to assemble a nuclear body (bottom). (b) The seeding model of nuclear body assembly. RNAs or proteins serve as seeds (shown in red) to nucleate the formation of a nuclear body. The subsequent steps after the initial seeding event could be either stochastic or ordered. If they are completely random (top), the seeding model still differs from the stochastic model because the seeding component is hierarchically different from the other components. If they are tightly ordered (bottom), the seeding model becomes an ordered mechanism.

Figure 3

Conceptual frameworks of how nuclear bodies function. Here, we summarize the common themes of how nuclear bodies may function in the nucleus. However, many nuclear bodies combine multiple mechanisms to perform their diverse cellular functions. (a) Reaction site. Nuclear bodies can concentrate the substrates and enzymes in a confined volume, thereby enhancing the specificity and efficiency of biological reactions. For example, nucleoli serve as pre-rRNA synthesis and processing factories and CBs promote the modification of snRNAs and the assembly of snRNPs, by enriching RNAs and proteins required for these processes. (b) Hub. Nuclear bodies can act as hot spots to activate or repress gene expression by recruiting gene loci. For example, the perinucleolar heterochromatin recruits Xi and imprinted regions to establish and maintain their epigenetic heterochromatin state. Nuclear bodies can also recruit multiple gene loci to stabilize their interactions and subsequently regulate their expression. For example, in Drosophila PcG bodies harbor Hox genes interactions. (c) Storage/modification site. Nuclear bodies can store and recycle proteins and RNAs. For example, paraspeckles retain some A-to-I hyperedited mRNAs. Nuclear bodies can also modify the components being stored. For example, a nuclear speckle-associated kinase can regulate the phosphorylation state of SR proteins and PcG bodies act as sumoylation centers for several nuclear proteins.