RSF Governs Silent Chromatin Formation via Histone H2Av Replacement

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Abstract
Human remodeling and spacing factor (RSF) consists of a heterodimer of Rsf-1 and hSNF2H, a counterpart of Drosophila ISWI. RSF possesses not only chromatin remodeling activity but also chromatin assembly activity in vitro. While no other single factor can execute the same activities as RSF, the biological significance of RSF remained unknown. To investigate the in vivo function of RSF, we generated a mutant allele of Drosophila Rsf-1 (dRsf-1). The dRsf-1 mutant behaved as a dominant suppressor of position effect variegation. In dRsf-1 mutant, the levels of histone H3K9 dimethylation and histone H2A variant H2Av were significantly reduced in an euchromatic region juxtaposed with heterochromatin. Furthermore, using both genetic and biochemical approaches, we demonstrate that dRsf-1 interacts with H2Av and the H2Av-exchanging machinery Tip60 complex. These results suggest that RSF contributes to histone H2Av replacement in the pathway of silent chromatin formation. As DNA is packaged into chromatin in the nucleus, every DNA transaction requires alteration of the chromatin structure. RSF, a heterodimer of Rsf-1 and ISWI/SNF2H, is a unique chromatin remodeling factor that can assemble regularly spaced nucleosome arrays without the aid of histone chaperons, but its biological function is not clear. Using Drosophila melanogaster as a model organism, we investigated the in vivo role of RSF in gene expression. The loss of RSF function reduces the levels of histone variant H2Av and histone H3-K9 methylation, and suppresses silencing of transcription in an euchromatic region neighboring the centromeric heterochromatin. We also observed that Rsf-1 interacts with histone H2Av and the H2Av-exchanging machinery Tip60 complex. Based on these findings, we propose that RSF plays a role in silent chromatin formation by promoting histone H2Av replacement.

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