Dosage compensation in high resolution: global up-regulation through local recruitment
- Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland
This extract was created in the absence of an abstract.
Dosage compensation solves the chromosomal imbalance that is a result of sexual determination by sex chromosomes. It equalizes gene expression between the homogametic (XX) and heterogametic (XY) sexes and thus needs to selectively modify expression from the X chromosome in a sex-specific manner without affecting transcription on the autosomes. Various strategies have evolved in different organisms to achieve this balance, and their study has contributed significantly to our understanding of transcriptional gene regulation of whole chromosomes and established several paradigms of epigenetic control (Lucchesi 1998; Stuckenholz et al. 1999; Akhtar 2003).
In mammals, dosage compensation is accomplished by inactivating one copy of the X chromosome in females via an epigenetic process of allele-specific modification of chromatin and DNA. In Drosophila, dosage compensation is achieved not by repression but by increasing the transcription specifically on the single male X chromosome (Hamada et al. 2005; Straub et al. 2005). Genetic screens for male-specific lethality (MSL) identified five protein-coding genes that are required for dosage compensation: Msl 1-3, male absent on the first (mof), and maleless (mle). Subsequent biochemical characterizations suggested that these proteins, together with two noncoding RNAs (roX1 and roX2), form what has been termed the dosage compensation complex (DCC) (for review, see Bashaw and Baker 1996; Gilfillan et al. 2004). Complex formation only occurs in males, as translation of the MSL-2 protein is inhibited in females.
A first evidence for chromatin as a target in dosage compensation came from the observation of higher levels of histone H4K16 acetylation on the hyperactivated X detected by immunostaining (Turner et al. 1992). One of the msl genes, MOF, is a histone acetyl-transferase (HAT) that acetylates H4 at Lys 16 and is able to cause derepression of chromatinized templates in vitro and in vivo (Akhtar and Becker 2000). Thus, …
