Developmental control of the DNA replication and transcription programs

Nordman, Jared; Li, Sharon; Eng, Thomas; MacAlpine, David M.; Orr‐Weaver, Terry L.

doi:10.1101/gr.114611.110

Cited by 78 publications

(136 citation statements)

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“…Most of these under-replicated regions correlate with marks of transcriptional repression (Sher et al, 2012). Interestingly, the degree and location of endoreplication-induced under-replication is dependent on tissue type, suggesting a role for under-replication in defining tissue identity (Nordman et al, 2011). However, underreplication can be blocked by mutation in a chromatin protein Suppressor of Under-Replication (SuUR) and SuUR mutant flies exhibit no obvious alteration of polyploid tissue function (Belyaeva et al, 1998).…”

Section: Consequences Of Defective Endoreplication During Developmentmentioning

confidence: 99%

“…In Drosophila, many endoreplicating cells fail to complete late S phase, leaving some genome regions dramatically under-replicated, including heterochromatic sequences (Gall et al, 1971;Lilly and Spradling, 1996). Using genomic deep-sequencing and chromatin immunoprecipitation approaches, recent studies of polyploid Drosophila genomes precisely defined a number of underreplicated regions also present in euchromatin (Nordman et al, 2011). Most of these under-replicated regions correlate with marks of transcriptional repression (Sher et al, 2012).…”

Section: Consequences Of Defective Endoreplication During Developmentmentioning

confidence: 99%

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Endoreplication and polyploidy: insights into development and disease

2013

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SummaryPolyploid cells have genomes that contain multiples of the typical diploid chromosome number and are found in many different organisms. Studies in a variety of animal and plant developmental systems have revealed evolutionarily conserved mechanisms that control the generation of polyploidy and have recently begun to provide clues to its physiological function. These studies demonstrate that cellular polyploidy plays important roles during normal development and also contributes to human disease, particularly cancer.Key words: Cancer, Endocycle, Endomitosis, Endoreplication, Genome instability IntroductionPolyploid cells, which contain multiples of the diploid genome equivalent, have been studied for many years, nearly as long as chromosomes themselves have been studied. Now, over a century after the discovery of polyploidy, we know much about the molecular mechanisms that generate cellular polyploidy, but comparably little regarding the physiological function of the polyploid state. This discrepancy exists despite the frequent occurrence of polyploid cells in most multicellular organisms, as well as in human cancers. An important aspect of deciphering the roles for polyploidy lies in understanding the regulation of endoreplication, a cell cycle variation that generates a polyploid genome by repeated rounds of DNA replication in the absence of cell division. Recent advances show that, although some differences exist in the diverse endoreplication programs found from protists to humans, core principles can be applied. New work in genetic model organisms has identified cases in which programmed endoreplication plays key roles in development. Furthermore, recent evidence indicates that endoreplication can confer genome instability, a major cancer-enabling property. In this Primer (see Box), we review such recent discoveries, focusing on work carried out in the past 3 years, and refer the reader to other comprehensive reviews on this topic Lee et al., 2009). From these new insights emerge unifying themes regarding endoreplication that hold promise of elucidating the advantages, as well as the potential disadvantages, of polyploidy. Endoreplication and developmentEndoreplication is typically studied in the context of endopolyploidy, which refers to the presence of polyploid cells in an otherwise diploid organism. Diverse levels of polyploidy occur throughout nature (Table 1). Although polyploidy is well appreciated in plants , many different animal tissues, including the skin, gut, placenta, liver, brain and blood have polyploid cells (Table 1) (Laird et al., 1980;Corash et al., 1989;Fox et al., 2010; Hedgecock and White, 1985;Melaragno et al., 1993;Sherman, 1972;Unhavaithaya and Orr-Weaver, 2012;Zanet et al., 2010). Interestingly, endoreplication is not limited to multi-cellular organisms, with examples described in ciliated protozoa (Yin et al., 2010) and even bacteria (Mendell et al., 2008).Two primary forms of endoreplication have been described: endocycling and endomitosis (Fig. 1). Endocycles are compos...

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Section: Consequences Of Defective Endoreplication During Developmentmentioning

confidence: 99%

Section: Consequences Of Defective Endoreplication During Developmentmentioning

confidence: 99%

Endoreplication and polyploidy: insights into development and disease

2013

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“…Thirty to 52 underreplicated (UR) regions 90-570 kb in length have been precisely mapped using DNA arrays (Belyakin et al 2005;Nordman et al 2011;Sher et al 2012). These UR zones correspond closely to regions of repressive chromatin, sparse replication origins, and mostly silent genes (Belyakin et al 2005;Pindyurin et al 2007;Filion et al 2010;Nordman et al 2011;Belyaeva et al 2012;Sher et al 2012;Maksimov et al 2013). The repressive chromatin state and late replication timing of UR regions are thought to be responsible for their susceptibility to incomplete replication.…”

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confidence: 99%

Incomplete replication generates somatic DNA alterations within Drosophila polytene salivary gland cells

2014

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DNA replication remains unfinished in many Drosophila polyploid cells, which harbor disproportionately fewer copies of late-replicating chromosomal regions. By analyzing paired-end high-throughput sequence data from polytene larval salivary gland cells, we define 112 underreplicated (UR) euchromatic regions 60-480 kb in size. To determine the effects of underreplication on genome integrity, we analyzed anomalous read pairs and breakpoint reads throughout the euchromatic genome. Each UR euchromatic region contains many different deletions 10-500 kb in size, while very few deletions are present in fully replicated chromosome regions or UR zones from embryo DNA. Thus, during endocycles, stalled forks within UR regions break and undergo local repair instead of remaining stable and generating nested forks. As a result, each salivary gland cell contains hundreds of unique deletions that account for their copy number reductions. Similar UR regions and deletions were observed in ovarian DNA, suggesting that incomplete replication, fork breakage, and repair occur widely in polytene cells. UR regions are enriched in genes encoding immunoglobulin superfamily proteins and contain many neurally expressed and homeotic genes. We suggest that the extensive somatic DNA instability described here underlies position effect variegation, molds the structure of polytene chromosomes, and should be investigated for possible functions.

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“…reduction in the expression of genes involved in DNA replication (10,42). It has been proposed that reduced expression of genes required for DNA replication leads to a slowed S phase and failure to replicate genomic regions normally replicated late in S phase (43), possibly leading to underreplication in these tissues.…”

Section: Tgcs Mksmentioning

confidence: 99%

“…All Drosophila polytene cells examined to date have a highly reduced copy number of heterochromatin as well as underreplicated euchromatic regions. These underreplicated regions outside of heterochromatin blocks can be either tissue specific or common to several tissues (10). Whereas gene amplification can be a strategy for robust expression of specific genes over a short developmental time, underreplication may conserve resources by avoiding replication of gene-poor regions of the genome.…”

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confidence: 99%

Fundamental differences in endoreplication in mammals and Drosophila revealed by analysis of endocycling and endomitotic cells

Sher

Stetina

Bell

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Throughout the plant and animal kingdoms specific cell types become polyploid, increasing their DNA content to attain a large cell size. In mammals, megakaryocytes (MKs) become polyploid before fragmenting into platelets. The mammalian trophoblast giant cells (TGCs) exploit their size to form a barrier between the maternal and embryonic tissues. The mechanism of polyploidization has been investigated extensively in Drosophila , in which a modified cell cycle—the endocycle, consisting solely of alternating S and gap phases—produces polyploid tissues. During S phase in the Drosophila endocycle, heterochromatin and specific euchromatic regions are underreplicated and reduced in copy number. Here we investigate the properties of polyploidization in murine MKs and TGCs. We induced differentiation of primary MKs and directly microdissected TGCs from embryonic day 9.5 implantation sites. The copy number across the genome was analyzed by array-based comparative genome hybridization. In striking contrast to Drosophila , the genome was uniformly and integrally duplicated in both MKs and TGCs. This was true even for heterochromatic regions analyzed by quantitative PCR. Underreplication of specific regions in polyploid cells is proposed to be due to a slower S phase, resulting from low expression of S-phase genes, causing failure to duplicate late replicating genomic intervals. We defined the transcriptome of TGCs and found robust expression of S-phase genes. Similarly, S-phase gene expression is not repressed in MKs, providing an explanation for the distinct endoreplication parameters compared with Drosophila . Consistent with TGCs endocycling rather than undergoing endomitosis, they have low expression of M-phase genes.

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Developmental control of the DNA replication and transcription programs

Cited by 78 publications

References 35 publications

Endoreplication and polyploidy: insights into development and disease

Endoreplication and polyploidy: insights into development and disease

Incomplete replication generates somatic DNA alterations within Drosophila polytene salivary gland cells

Fundamental differences in endoreplication in mammals and Drosophila revealed by analysis of endocycling and endomitotic cells

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