Abstract
Most genes along the male single X chromosome in Drosophila are hypertranscribed about two-fold relative to each of the two female X chromosomes. This is accomplished by the MSL (male-specific lethal) complex that acetylates histone H4 at lysine 16. The MSL complex contains two large noncoding RNAs, roX1 (RNA on X) and roX2, that help target chromatin modifying enzymes to the X. The roX RNAs are functionally redundant but differ in size, sequence, and transcriptional control. We wanted to find out how roX1 production is regulated. Ectopic DC can be induced in wild-type (roX1+ roX2+) females if we provide a heterologous source of MSL2. However, in the absence of roX2, we found that roX1 expression failed to come on reliably. Using an in situ hybridization probe that is specific only to endogenous roX1, we found that expression was restored if we introduced either roX2 or a truncated but functional version of roX1. This shows that pre-existing roX RNA is required to positively autoregulate roX1 expression. We also observed massive cis spreading of the MSL complex from the site of roX1 transcription at its endogenous location on the X chromosome. We propose that retention of newly assembled MSL complex around the roX gene is needed to drive sustained transcription and that spreading into flanking chromatin contributes to the X chromosome targeting specificity. Finally, we found that the gene encoding the key male-limited protein subunit, msl2, is transcribed predominantly during DNA replication. This suggests that new MSL complex is made as the chromatin template doubles. We offer a model describing how the production of roX1 and msl2, two key components of the MSL complex, are coordinated to meet the dosage compensation demands of the male cell.
Highlights
Some long noncoding RNAs have the ability to recruit chromatin modifying enzymes to specific genes thereby controlling their expression [1]
A large ribonucleoprotein complex that consists of two large noncoding RNA, roX1 and roX2, and at least five MSL chromatin-modifying proteins is responsible
We propose that this mechanism is essential for ensuring sustained dosage compensation in males and perhaps for bursts of new MSL complex at each cell cycle
Summary
Some long noncoding RNAs have the ability to recruit chromatin modifying enzymes to specific genes thereby controlling their expression [1]. The roX RNAs assemble into a complex containing at least five MSL protein subunits that bind actively transcribed genes along the male X chromosome, but not autosomes or the two X chromosomes in females [4]. This has been termed the dosage compensation complex or the MSL complex. One function of the complex is acetylation of histone H4 at lysine 16, carried out by the MOF (males absent on first) histone acetyltransferase resulting in an essential ,two-fold increase in transcription [5,6,7,8] Another modification is ubiquitylation of histone H2B at K34 by the MSL2 RING finger protein [9]
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