The modular mechanism of chromocenter formation in Drosophila

A central principle underlying the ubiquity and abundance of pericentromeric satellite DNA repeats in eukaryotes has remained poorly understood. Previously we proposed that the interchromosomal clustering of satellite DNAs into nuclear structures known as chromocenters ensures encapsulation of all chromosomes into a single nucleus (Jagannathan et al., 2018). Chromocenter disruption led to micronuclei formation, resulting in cell death. Here we show that chromocenter formation is mediated by a ‘modular’ network, where associations between two sequence-specific satellite DNA-binding proteins, D1 and Prod, bound to their cognate satellite DNAs, bring the full complement of chromosomes into the chromocenter. D1 prod double mutants die during embryogenesis, exhibiting enhanced phenotypes associated with chromocenter disruption, revealing the universal importance of satellite DNAs and chromocenters. Taken together, we propose that associations between chromocenter modules, consisting of satellite DNA binding proteins and their cognate satellite DNA, package the Drosophila genome within a single nucleus.

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The modular mechanism of chromocenter formation in Drosophila

10.1101/481820 ◽

2018 ◽

Author(s):

Madhav Jagannathan ◽

Ryan Cummings ◽

Yukiko M. Yamashita

Keyword(s):

Dna Binding ◽

Satellite Dna ◽

Binding Proteins ◽

Dna Binding Proteins ◽

Dna Repeats ◽

Satellite Dnas ◽

Modular Network ◽

Full Complement ◽

Single Nucleus ◽

Nuclear Structures

AbstractA central principle underlying the ubiquity and abundance of pericentromeric satellite DNA repeats in eukaryotes has remained poorly understood. In our previous study (Jagannathan et al., 2018), we proposed that the interchromosomal clustering of satellite DNAs into nuclear structures known as chromocenters ensures encapsulation of all chromosomes into a single nucleus. Chromocenter disruption led to micronuclei formation, resulting in cell death. Here we show that chromocenter formation is mediated by a ‘modular’ network, where interactions between two sequence-specific satellite DNA-binding proteins, D1 and Prod, bound to their cognate satellite DNAs, bring the full complement of chromosomes into the chromocenter. D1 prod double mutants die during embryogenesis, exhibiting enhanced phenotypes associated with chromocenter disruption, revealing the universal importance of satellite DNAs and chromocenters. Taken together, we propose that interactions between chromocenter modules, consisting of satellite DNA binding proteins and their cognate satellite DNA, package the Drosophila genome within a single nucleus.

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A conserved function for pericentromeric satellite DNA

10.1101/245589 ◽

2018 ◽

Author(s):

Madhav Jagannathan ◽

Ryan Cummings ◽

Yukiko M. Yamashita

Keyword(s):

Cell Death ◽

Dna Binding ◽

Satellite Dna ◽

Interphase Nucleus ◽

Underlying Mechanism ◽

Dna Binding Proteins ◽

Eukaryotic Cells ◽

Evolutionarily Conserved ◽

Full Complement ◽

Single Nucleus

AbstractA universal and unquestioned characteristic of eukaryotic cells is that the genome is divided into multiple chromosomes and encapsulated in a single nucleus. However, the underlying mechanism to ensure such a configuration is unknown. Here we provide evidence that pericentromeric satellite DNA, which is often regarded as junk, is a critical constituent of the chromosome, allowing the packaging of all chromosomes into a single nucleus. We show that the multi AT-hook satellite DNA binding proteins, D. melanogaster D1 and mouse HMGA1, play an evolutionarily conserved role in bundling pericentromeric satellite DNA from heterologous chromosomes into ‘chromocenters’, a cytological association of pericentromeric heterochromatin. Defective chromocenter formation leads to micronuclei formation due to budding off of interphase nucleus and cell death. We propose that chromocenter and satellite DNA serves a fundamental role to achieve the universal characteristic of eukaryotic cells: full complement of the genome within a single nucleus.

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Genetic and epigenetic control of the spatial organization of the genome

Molecular Biology of the Cell ◽

10.1091/mbc.e16-03-0149 ◽

2017 ◽

Vol 28 (3) ◽

pp. 364-369 ◽

Cited By ~ 9

Author(s):

Jason Brickner

Keyword(s):

Gene Expression ◽

Dna Binding ◽

Chromatin Structure ◽

Binding Sites ◽

Spatial Organization ◽

Binding Proteins ◽

Dna Binding Proteins ◽

Adaptive Function ◽

Nuclear Structures ◽

Eukaryotic Genomes

Eukaryotic genomes are spatially organized within the nucleus by chromosome folding, interchromosomal contacts, and interaction with nuclear structures. This spatial organization is observed in diverse organisms and both reflects and contributes to gene expression and differentiation. This leads to the notion that the arrangement of the genome within the nucleus has been shaped and conserved through evolutionary processes and likely plays an adaptive function. Both DNA-binding proteins and changes in chromatin structure influence the positioning of genes and larger domains within the nucleus. This suggests that the spatial organization of the genome can be genetically encoded by binding sites for DNA-binding proteins and can also involve changes in chromatin structure, potentially through nongenetic mechanisms. Here I briefly discuss the results that support these ideas and their implications for how genomes encode spatial organization.

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A conserved function for pericentromeric satellite DNA

eLife ◽

10.7554/elife.34122 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 29

Author(s):

Madhav Jagannathan ◽

Ryan Cummings ◽

Yukiko M Yamashita

Keyword(s):

Dna Damage ◽

Cell Death ◽

Satellite Dna ◽

Interphase Nucleus ◽

Underlying Mechanism ◽

Dna Binding Proteins ◽

Eukaryotic Cells ◽

Evolutionarily Conserved ◽

Full Complement ◽

Single Nucleus

A universal and unquestioned characteristic of eukaryotic cells is that the genome is divided into multiple chromosomes and encapsulated in a single nucleus. However, the underlying mechanism to ensure such a configuration is unknown. Here, we provide evidence that pericentromeric satellite DNA, which is often regarded as junk, is a critical constituent of the chromosome, allowing the packaging of all chromosomes into a single nucleus. We show that the multi-AT-hook satellite DNA-binding proteins, Drosophila melanogaster D1 and mouse HMGA1, play an evolutionarily conserved role in bundling pericentromeric satellite DNA from heterologous chromosomes into ‘chromocenters’, a cytological association of pericentromeric heterochromatin. Defective chromocenter formation leads to micronuclei formation due to budding from the interphase nucleus, DNA damage and cell death. We propose that chromocenter and satellite DNA serve a fundamental role in encapsulating the full complement of the genome within a single nucleus, the universal characteristic of eukaryotic cells.

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Defective satellite DNA clustering into chromocenters underlies hybrid incompatibility in Drosophila

10.1101/2021.04.16.440167 ◽

2021 ◽

Author(s):

Madhav Jagannathan ◽

Yukiko M Yamashita

Keyword(s):

Satellite Dna ◽

Rapid Evolution ◽

Dna Binding Proteins ◽

Dna Repeats ◽

Hybrid Cells ◽

Entire Genome ◽

Closely Related Species ◽

Hybrid Incompatibility ◽

Cluster Satellite ◽

Single Nucleus

Although rapid evolution of pericentromeric satellite DNA repeats is theorized to promote hybrid incompatibility (HI), how divergent repeats affect hybrid cells remains poorly understood. Recently, we demonstrated that sequence-specific DNA-binding proteins cluster satellite DNA from multiple chromosomes into chromocenters, thereby bundling chromosomes to maintain the entire genome in a single nucleus. Here we show that ineffective clustering of divergent satellite DNA in the cells of Drosophila hybrids results in chromocenter disruption, associated micronuclei formation and tissue atrophy. We further demonstrate that previously identified HI factors trigger chromocenter disruption and micronuclei in hybrids, linking their function to a conserved cellular process. Together, we propose a unifying framework that explains how the widely observed satellite DNA divergence between closely related species can cause reproductive isolation.

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Non-B-Form DNA Is Enriched at Centromeres

Molecular Biology and Evolution ◽

10.1093/molbev/msy010 ◽

2018 ◽

Vol 35 (4) ◽

pp. 949-962 ◽

Cited By ~ 38

Author(s):

Sivakanthan Kasinathan ◽

Steven Henikoff

Keyword(s):

Dna Binding ◽

Satellite Dna ◽

Binding Sites ◽

Binding Proteins ◽

Dna Binding Proteins ◽

Genetic Characteristics ◽

Dna Structures ◽

Centromere Function ◽

General Basis ◽

Human And Mouse

AbstractAnimal and plant centromeres are embedded in repetitive “satellite” DNA, but are thought to be epigenetically specified. To define genetic characteristics of centromeres, we surveyed satellite DNA from diverse eukaryotes and identified variation in <10-bp dyad symmetries predicted to adopt non-B-form conformations. Organisms lacking centromeric dyad symmetries had binding sites for sequence-specific DNA-binding proteins with DNA-bending activity. For example, human and mouse centromeres are depleted for dyad symmetries, but are enriched for non-B-form DNA and are associated with binding sites for the conserved DNA-binding protein CENP-B, which is required for artificial centromere function but is paradoxically nonessential. We also detected dyad symmetries and predicted non-B-form DNA structures at neocentromeres, which form at ectopic loci. We propose that centromeres form at non-B-form DNA because of dyad symmetries or are strengthened by sequence-specific DNA binding proteins. This may resolve the CENP-B paradox and provide a general basis for centromere specification.

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Non-B-form DNA structures mark centromeres

10.1101/209023 ◽

2017 ◽

Cited By ~ 1

Author(s):

Sivakanthan Kasinathan ◽

Steven Henikoff

Keyword(s):

Dna Binding ◽

Satellite Dna ◽

Binding Sites ◽

Binding Proteins ◽

Dna Binding Proteins ◽

Genetic Characteristics ◽

Dna Structures ◽

Centromere Function ◽

General Basis ◽

Human And Mouse

AbstractAnimal and plant centromeres are embedded in repetitive “satellite” DNA, but are thought to be epigenetically specified. To define genetic characteristics of centromeres, we surveyed satellite DNA from diverse eukaryotes and identified variation in <10-bp dyad symmetries predicted to adopt non-B-form conformations. Organisms lacking centromeric dyad symmetries had binding sites for sequence-specific DNA binding proteins with DNA bending activity. For example, human and mouse centromeres are depleted for dyad symmetries, but are enriched for non-B DNA and are associated with binding sites for the conserved DNA-binding protein CENP-B, which is required for artificial centromere function but is paradoxically non-essential. We also detected dyad symmetries and predicted non-B-form DNA structures at neocentromeres, which form at ectopic loci. We propose that centromeres form at non-B-form DNA because of dyad symmetries or are strengthened by sequence-specific DNA binding proteins. Our findings resolve the CENP-B paradox and provide a general basis for centromere specification.

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