Research
A conserved function for pericentromeric satellite DNA
Our recent work indicates that satellite DNAs are critical for compartmentalizing the entire genome within a single nucleus – a defining feature of eukaryotes (Jagannathan et al, eLife, 2018). We addressed the role of satellite DNA by studying chromocenters, nuclear foci that consist of clustered pericentromeric satellite DNA from multiple chromosomes (Figure 1). Although observed widely across eukaryotes, no function had been attributed to chromocenters. We have shown that chromocenters in both Drosophila and mouse are formed by conserved satellite DNA binding proteins, which bundle pericentromeric satellite DNA from multiple chromosomes. Disrupting chromocenters by mutating satellite DNA-binding proteins resulted in the defective genome compartmentalization in the form of micronuclei and loss of cellular viability. We propose a model wherein bundling of pericentromeric satellite DNAs by satellite DNA-binding proteins is essential to compartmentalize the entire genome within a single nucleus (Figure 1). This is the first work describing an essential and conserved role for satellite DNA in maintaining cellular viability.
Figure 1 - Model of chromocenter formation and function. Pericentromeric satellite DNA repeats (pink) from multiple chromosomes are bundled together by the D1/HMGA1 satellite DNA binding proteins (gray). Chromocenter disruption results in micronuclei, which form by budding out of the primary nucleus during interphase.
What’s next?
1. Characterizing the molecular mechanism by which satellite DNA-binding proteins recognize and bundle Mb-long stretches of satellite DNA from multiple chromosomes
2. What are the events that link chromocenter disruption to micronuclei formation?
The modular mechanism of chromocenter formation in Drosophila
In our model, sequence-specific satellite DNA binding proteins bind and bundle chromosomes into chromocenters. However, most eukaryotes (including humans and Drosophila) possess multiple distinct satellite DNA repeats. This raises the question as to how all chromosomes, each containing a distinct set of satellite DNA repeats, are bundled into chromocenters. Using Drosophila melanogaster, a model organism containing 17 distinct satellite DNAs constituting ~30% of the genome, we have identified that multiple sequence-specific satellite DNA binding proteins bundle chromosomes containing their cognate pericentromeric satellite DNA (Figure 2). Moreover, dynamic interactions between these satellite DNA binding proteins ensures the compartmentalization of all chromosomes within a single nucleus (Figure 2). While loss of an individual satellite DNA-binding protein resulted in tissue-specific defects, simultaneous mutation of multiple satellite DNA-binding proteins resulted in widespread micronuclei formation and cell death, revealing a critical requirement for chromocenters (and thus satellite DNA) in fundamental cell biology external page (Jagannathan*, Cummings* and Yamashita, eLife, 2019).
Figure 2. Modular mechanism of chromocenter formation in Drosophila melanogaster. Modules of D1 - AATAT and Prod - AATAACATAG associate with each other to bundle the entire chromosome complement into chromocenters.
What’s next?
1. Identifying and characterizing novel satellite DNA-binding proteins in Drosophila species
2. Is there a tissue-specific repertoire of satellite DNA-binding proteins in Drosophila melanogaster?
Determining the consequences of satellite DNA divergence in interspecies hybrids
Although satellite DNAs are known to diverge rapidly between species, whether these repeats contribute to hybrid incompatibility and/or sterility has not been tested and the underlying cellular defects remain unidentified. Our model for satellite DNA function predicts defective chromocenter formation in hybrids that contain divergent satellite DNAs. As a result, we hypothesize that the inability to compartmentalize the chromosomes of two different species within a single nucleus is a fundamental defect causing hybrid incompatibility (Figure 3). We are excited to test this hypothesis in Drosophila melanogaster and it’s sibling species, where we have recently mapped the divergent satellite DNA repeats external page (Jagannathan*, Watase*, Warsinger-Pepe* and Yamashita, G3, 2017).
Figure 3. Proposed model of chromocenter disruption in hybrids. In this model, species-specific satellite DNA repeats cannot be bundled into chromocenters in hybrids, resulting in micronuclei formation and cell death.
What’s next?
1. Determining whether chromocenter disruption and micronuclei are observed in interspecies hybrids
2. Can restoring chromocenters in hybrids rescue hybrid incompatibility and/or sterility?