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  • Review Article
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Dosage compensation in Drosophila melanogaster: epigenetic fine-tuning of chromosome-wide transcription

Nature Reviews Genetics volume 13, pages 123–134 (2012)Cite this article

Subjects

Key Points

  • Dosage compensation is an epigenetic mechanism that balances gene expression from unequally distributed sex chromosomes between the sexes and in relation to the diploid autosomes. In Drosophila melanogaster, this is achieved by twofold upregulation of transcription from the single male X chromosome.

  • The modification of chromatin structure is a general principle of dosage compensation systems in various organisms. Concomitant with the evolution of sex chromosomes, pre-existing epigenetic regulators are often adapted for this novel task.

  • In D. melanogaster males, the dosage compensation complex (DCC) uses the histone acetyltransferase MOF for global hyperacetylation of X-linked chromatin at histone H4 at lysine 16 (H4K16ac). The H4K16ac modification prevents chromatin compaction and is generally associated with enhanced DNA accessibility and transcription.

  • Recognition of the X chromosome by the DCC involves the dynamic interplay between male sex lethal (MSL) proteins, male-specific RNAs on the X (roXs), and a limited number of X-specific DNA sequence elements. The DCC spreads from these high-affinity binding sites (HASs) to the transcribed regions of active genes, where it recognizes features of active chromatin such as transcription coupled histone marks.

  • The DCC induces substantial alterations in the local and long-range structure of X-linked chromatin. The resulting permissive conditions within the X-chromosomal territory create a uniquely active compartment, leading to activation even of autosomal genes that get translocated in this environment.

  • The exact mechanism of transcriptional activation remains enigmatic to date. Traditionally, transcription elongation is thought to be enhanced by H4K16ac in the transcribed regions of genes, and recent evidence supports this idea. However, some data suggest that transcriptional initiation as well as the release of paused Pol II from gene promoters might also be targeted by the dosage compensation mechanism.

Abstract

Dosage compensation is an epigenetic mechanism that normalizes gene expression from unequal copy numbers of sex chromosomes. Different organisms have evolved alternative molecular solutions to this task. In Drosophila melanogaster, transcription of the single male X chromosome is upregulated by twofold in a process orchestrated by the dosage compensation complex. Despite this conceptual simplicity, dosage compensation involves multiple coordinated steps to recognize and activate the entire X chromosome. We are only beginning to understand the intriguing interplay between multiple levels of local and long-range chromatin regulation required for the fine-tuned transcriptional activation of a heterogeneous gene population. This Review highlights the known facts and open questions of dosage compensation in D. melanogaster.

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Figure 1: Composition and localization of the dosage compensation complex.
Figure 2: DCC nucleation and spreading.
Figure 3: The X-chromosome territory represents a uniquely active compartment.
Figure 4: Hypothetical models of transcriptional regulation by the DCC.

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Acknowledgements

We thank members of the laboratory for critical reading. This work was supported by the EU-funded network of excellence 'EpiGeneSys' awarded to A.A.

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  1. Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108, Freiburg im Breisgau, Germany

    Thomas Conrad & Asifa Akhtar

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Glossary

Chromosomal aneuploidy

The presence of an abnormal number of chromosomes, either more or less than the diploid number. Associated with cell and organismal inviability, cancer and birth defects.

Training data sets

The known examples of an object (for example, an exon) that are used to train prediction algorithms, so that they learn the rules for predicting an object. They can be positive training sets (consisting of true objects, such as exons) or negative training sets (consisting of false objects, such as pseudoexons).

CXC domain

A frequent protein structure module, characterized by the occurrence of one to three CXC motifs amino-terminal to a CX4CXCX6CX4–5CX2C sequence. A general role of CXC domains for DNA binding has been proposed.

Fluorescence recovery after photobleaching

(FRAP). In this technique, a laser pulse is used to bleach fluorescently labelled molecules (such as an ectopically expressed GFP fusion protein) within a restricted volume of the cell. The increase of fluorescence signal within the bleached area is then measured over time to determine diffusion rates of the labelled molecules.

30-nanometre fibres

(30 nm fibres). A helical arrangement of adjacent nucleosomes, which is believed to be the first level of chromatin compaction and appears as fibres of ~30 nm diameter in electron micrographs.

Fluorescence in situ hybridization

(FISH). A technique that uses fluorescently labelled hybridization probes to determine the abundance of RNA species or the spatial organization of genomic loci in fixed cells.

Chromosome territory

A domain of the nucleus occupied by a pair of homologous chromosomes.

Stochastic

Probabilistic; governed by chance.

Self-organizing

A process in which pattern at the global level of a system emerges solely from numerous interactions among the lower-level components of the system. The rules specifying interactions among the system's components are executed using only local information, without reference to the global pattern.

Global run-on sequencing

(GRO-seq). A method for the genome-wide mapping of the position, amount and orientation of transcriptionally engaged RNA polymerases.

Hit-and-run

Targeting mechanism in which a DNA-binding protein undergoes repeated random and short-lived interactions with DNA until it encounters its cognate binding sequence.

Deterministic

Not governed by stochastic processes.

Chromosome conformation capture

(3C). A technique that is used to study the long-distance interactions between genomic regions, which in turn can be used to study the three-dimensional architecture of chromosomes within a cell nucleus.

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Conrad, T., Akhtar, A. Dosage compensation in Drosophila melanogaster: epigenetic fine-tuning of chromosome-wide transcription. Nat Rev Genet 13, 123–134 (2012). https://doi.org/10.1038/nrg3124

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