Trends in Genetics
Volume 35, Issue 8, August 2019, Pages 589-600
Journal home page for Trends in Genetics

Review
Phase Separation as a Melting Pot for DNA Repeats

https://doi.org/10.1016/j.tig.2019.05.001Get rights and content

Highlights

  • The function and stability of rDNA repeats is intimately linked to the phase separation of various nucleolar factors.

  • By creating Cajal bodies or chromosome end shields, phase separation modulates the length of telomeres and their crosstalk with the DNA damage response.

  • Intersections between phase-separated nuclear compartments and factors encoded by mobile genetic elements impact genome stability and cellular lifespan.

  • Aberrant phase transition of factors linked to diseases, including cancer and neurodegeneration, intersects with repetitive DNA loci and their nuclear compartments.

Genome expression and stability are dependent on biological processes that control repetitive DNA sequences and nuclear compartmentalization. The phase separation of macromolecules has recently emerged as a major player in the control of biological pathways. Here, we summarize recent studies that collectively reveal intersections between phase separation, repetitive DNA elements, and nuclear compartments. These intersections modulate fundamental processes, including gene expression, DNA repair, and cellular lifespan, in the context of health and diseases such as cancer and neurodegeneration.

Section snippets

Repetitive DNA Loci, Heterochromatin, and Phase Separation

Genomes contain large amounts of repetitive DNA sequences that constitute, for example, >70% of the human genome [1]. Previously referred to as ‘junk’ DNA, these sequences, which comprise both coding and noncoding sequences, are now clearly vital for genome function. Key examples of repetitive DNA regions include the life-sustaining rDNA (see Glossary) loci, chromosome-protecting telomeres, and the genome-reorganizing transposable elements (TEs). Due to their vulnerability to DNA damage and

Roles of Phase Separation at rDNA Repeats and the Nucleolus

rDNA loci are spatially isolated from the rest of the nuclear DNA, forming one or a small number of membraneless nucleolar compartments. In human cells, rDNA is tandemly arranged across chromosomes 13, 14, 15, 21, and 22, with ~70 units per chromosome [18]. The rRNA genes within rDNA are transcribed by RNA polymerase I (Pol I) into a precursor ribosomal RNA (pre-rRNA), which undergoes processing and maturation into 18S, 5.8S, and 28S rRNAs as it migrates from the center to the periphery of the

Phase Separation Impacts Telomeres via Heterochromatin Modulation, Nuclear Compartmentalization, and DNA Repair Control

Telomeres are repetitive DNA sequences that are positioned at the ends of linear chromosomes to prevent their attrition and fusion. Recent evidence suggests that telomeres are regulated by phase separation-dependent mechanisms. For example, HP1, which phase separates and promotes the formation of liquid-like heterochromatin domains, is required for the establishment of telomeric silent chromatin 3., 4., 36.. This silencing is integral to the dynamic nature of telomere elongation. Specifically,

Transposable Elements, Nuclear Compartments, and Phase Separation

TEs are jumping genes that often drive genome reorganization. TEs can move through copy-and-paste (retrotransposons) and cut-and-paste (DNA transposons) mechanisms, with the former requiring an RNA intermediate [58]. Retrotransposons comprise up to 45% of the human genome, and their dysregulation is implicated in various diseases, including neurodegeneration and cancer, as well as aging 1., 59., 60.. Human autonomous long interspersed element 1 (LINE1) encodes two proteins, ORF1p and ORF2p,

Phase Separation and Repetitive DNA in Human Disease

Thus far, we have discussed connections between repetitive DNA loci and compartments that are phase separated and liquid like. However, phase separation can yield compartments with a range of physical properties. For example, the contents can range from low- to high-viscosity liquids and even solid-like structures. In some cases, phase-separated molecules can transition back and forth through these phases. In human disease, these phase separations and transitions can be defining pathological

Concluding Remarks

Here, we have highlighted crosstalks between phase separation, nuclear compartmentalization, and major repetitive DNA loci that are critical to genome organization, chromosome protection, and cellular lifespan. We speculate that DNA repeats are particularly susceptible to regulation by phase separation for two main reasons. First, DNA repeats form the bulk of eukaryotic genomes and represent a risk to genome stability. Phase separation may provide the cell with a broad and energy-efficient

Outstanding Questions

  • What are the signals controlling the phase separation or transition of factors that establish nuclear compartments critical to the regulation of repetitive DNA loci?

  • Following cell division, how does the cell coordinate chromosome folding or chromatin tethering to nuclear landmarks with the phase separation-driven genesis of nuclear compartments?

  • Can aging and diseases related to the dysfunction of repetitive DNA loci be countered or halted by using molecules that alter the phase separation

Acknowledgments

A.C.H is funded by a Doctoral Award (152283) from the Canadian Institutes of Health Research (CIHR). L.A.O. is funded by an Ontario Graduate Scholarship (OGS). This work was supported by grants to K.M. from the CIHR (388041, 399687) and Canada Research Chairs Program (CRC; 950-230661). We thank members of the Mekhail laboratory for fruitful discussions.

Glossary

Cajal body (CB)
subnuclear membraneless compartments that are the site of small nuclear RNA (snRNA) and small nucleolar RNA (snoRNA) modification and the assembly site of their respective RNPs.
Heterochromatin
epigenetic silencing mechanism where DNA is highly condensed, thereby inhibiting transcription at these regions. Heterochromatin can be either constitutive (consistently silent) or facultative (with gene expression potential).
Intrinsically disordered domain
polypeptide domain sequences that

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