Transcriptional control of a whole chromosome: emerging models for dosage compensation

Abstract

Males and females of many animal species differ in their sex-chromosome karyotype, and this creates imbalances between X-chromosome and autosomal gene products that require compensation. Although distinct molecular mechanisms have evolved in three highly studied systems, they all achieve coordinate regulation of an entire chromosome by differential RNA-polymerase occupancy at X-linked genes. High-throughput genome-wide methods have been pivotal in driving the latest progress in the field. Here we review the emerging models for dosage compensation in mammals, flies and nematodes, with a focus on mechanisms affecting RNA polymerase II activity on the X chromosome.

Figure 1

Comparison of three modes of dosage compensation. (a) Dosage compensation is required to balance gene expression between sexes and between autosomes and sex chromosomes. In mammals (top), one of the two X chromosomes is inactivated in females (blue color for silencing) to balance expression, but X-chromosome upregulation is also required in both males and females to balance expression from diploid autosomes (red color for upregulation). In fruitflies (middle), the two-fold upregulation of the male X chromosome is sufficient to balance expression between sexes and relative to autosomes. In nematode hermaphrodites (XX) (bottom), downregulation of both copies of the X chromosome is superimposed upon upregulation of X chromosomes in both sexes, to balance autosomal expression levels. (b) Distinct complexes (DCC) are involved in dosage compensation in different species, but similarities have been proposed in the targeting and spreading of the various DCCs along the target chromosomes. The models propose that binding occurs at distinct nucleation sites (top) and spreads to additional target sites (bottom), which may be distant in the linear sequence of the chromosome, in addition to local spreading (dashed arrows) of the deposited epigenetic marks around primary target sites. This scheme is meant to highlight common principles, although of course there are species-specific differences, as detailed in the main text.

Figure 2

Metagene visualization of dosage compensation. Dosage-compensation mechanisms have a small effect in magnitude (approximately two-fold) but are observed over a large number of genes (entire chromosomes). For these characteristics, genome-wide experimental methods are particularly useful, because visualizing the average effect over many genes is a commonly adopted solution. Metagene profiles are average summaries of a quantitative score derived from genomic data, plotted against relative coordinates over gene loci. Metagene profiles can be plotted relative to a single position (top), for example, around the transcription start site (TSS), or relative to the gene body (middle and bottom), with scaling of the distance between the TSS and 3′ end for multiple genes (Box 3). In mammals (top), analysis of Pol II occupancy in the active (Xa) and the inactive (Xi) shows the lack of Pol II recruitment at the TSS of genes on the inactive X. In male fruitflies (middle), an average relative increase in elongating Pol II density on X versus autosomes has been reported, and this effect is lost after RNA-interference (RNAi) knockdown of key components of the dosage-compensation complex (MSL). In hermaphrodite nematodes (bottom), mutants for the sdc-2 component of the dosage-compensation complex shows approximately double density in Pol II recruited to X-linked genes.

Figure 3

Modulation of Pol II transcription within the context of distinct dosage-compensation models. The three mechanisms of transcription regulation (upregulation, downregulation and X inactivation, left) culminate in changes in chromatin composition, histone modifications and Pol II occupancy on the respective X chromosomes (right). A central question is whether these changes are mediated through gene-specific or chromosome-wide, higher-order mechanisms (depicted within the nucleus at the center of the diagram). In fruitflies, dosage compensation probably occurs via gene-by-gene upregulation of an entire chromosome, in which increased levels of H4K16ac within gene bodies directly facilitates pausing release and elongation by RNA Pol II. In nematodes, dosage compensation is achieved by a reduction of Pol II recruitment to the promoters of X-linked genes, driven by a chromosome-restructuring condensin complex. In addition, specific histone modifications (such as increased H4K20me1 and decreased H4K16ac) may also contribute to transcriptional downregulation on the X chromosome. Most importantly, the discrepancies between DCC targeting and dosage compensation suggest that in nematodes compensation occurs through selective sensitivity to chromosome-wide, long-distance regulation. In mammals, X inactivation (Xi) is probably accomplished by exclusion of RNA Pol II from Xi genes. In general, X inactivation is associated with global changes in chromatin accessibility and an increase of inactive chromatin marks such as H3K27me3, H4K20me1, H3K9me2 and H3K9me3, macroH2A and DNA methylation, as well as a decrease of active chromatin marks, such as H3K4me2 and H3K4me3 and histone acetylation. The question of whether local or global enrichment of the repressive factors is an initial event driving RNA Pol II exclusion from Xi genes remains unanswered. Black nucleosomes indicate inactive chromatin.