Specific genomic cues regulate Cajal body assembly

Abstract

The assembly of specialized sub-nuclear microenvironments known as nuclear bodies (NBs) is important for promoting efficient nuclear function. In particular, the Cajal body (CB), a prominent NB that facilitates spliceosomal snRNP biogenesis, assembles in response to genomic cues. Here, we detail the factors that regulate CB assembly and structural maintenance. These include the importance of transcription at nucleating gene loci, the grouping of these genes on human chromosomes 1, 6 and 17, as well as cell cycle and biochemical regulation of CB protein function. We also speculate on the correlation between CB formation and RNA splicing levels in neurons and cancer. The timing and location of these specific molecular events is critical to CB assembly and its contribution to genome function. However, further work is required to explore the emerging biophysical characteristics of CB assembly and the impact upon subsequent genome reorganization.

Membraneless nuclear organelles and the search for phases within phases

“…Small changes in the valency of the interactions between their primary components transforms these constituents from a solution state to a condensate state. Once these multivalent molecules reach a local concentration above the threshold level, they assemble into complex polymers and undergo LLPS to promote body formation (Sawyer, Hager, & Dundr, ). Recent modeling of plant phytochrome MLO formation suggests this is a two‐step process, consisting of an initial rapid macroparticle formation step and slow macroparticle aggregation into mature droplets (Grima et al, ).…”

“…For example, the constitutively expressed and highly transcribed spliceosomal RNU1 and RNU2 gene arrays may act as the primary nucleation sites for the formation of the Cajal body (Frey, Bailey, Weiner, & Matera, ; Frey & Matera, ; Wang et al, ), cell cycle‐dependent transcription of replication‐dependent major ( HIST1 ) and minor ( HIST2 ) histone gene arrays triggers histone locus body (HLB) formation and enlargement in S‐phase, and the transcription of the long noncoding RNA (lncRNA) NEAT1 initiates the formation of paraspeckles (Mao et al, ; Shevtsov & Dundr, ). MLO assembly is likely orchestrated by an initial RNA seeding event that provides a structural platform to subsequently trigger recruitment and retention of building blocks, including RBPs, by random self‐organization (Sawyer, Hager, & Dundr, ). In the sections below, we summarize the evidence implicating RNA as a crucial mediator of MLO self‐organization.…”

“…The Cajal body is an excellent example of how protein posttranslational modifications and RNA expression cooperate to promote self‐organizing droplet formation (Dundr, ; Hebert & Poole, ; Machyna et al, ; Sawyer, Hager, & Dundr, ; Wang et al, ). The Cajal body has long been known to exhibit an interesting ultrastructure, as early transmission electron microscopy studies reported inclusions resembling tangled web of coiled threads, leading to its original name: the coiled body (Monneron & Bernhard, ).…”

Cajal body function in genome organization and transcriptome diversity

“…Using a combination of advanced multicolor microscopic mapping tools and high-throughput sequencing techniques, we explored the specific clustering network, consisting of distant chromosomal targeting regions proximal to CBs [30]. Chromosomes that associate frequently with CBs display higher CB target gene density than other size-matched chromosomes (human chromosomes 1, 6 and 17 vs. 2, 7 and 18) [64]. Physical associations between specific chromosomes and CBs also correlate with major and minor spliceosomal snRNA gene clusters, such as the U1 and U2 snRNA gene arrays on chromosomes 1 and 17, respectively.…”

“…A clue can be found in the localization of most NBs, as they are predominantly situated in the interchromatin space at the periphery of CTs where multiple chromosomes frequently intermingle [65]. Transcriptional activation of large ubiquitously expressed gene arrays, such as the U1 and U2 snRNA arrays [64], triggers the nucleation and formation of a CB. Subsequently, other highly expressed U snRNA genes, which are positioned at the periphery of their host CT, or even looped out of the domain, associate with the growing CB.…”