The NSL complex regulates housekeeping genes in Drosophila

• Published in: PLoS genetics 2012-06, Vol.8 (6), p.e1002736-e1002736
• Main Authors: Lam, Kin Chung, Mühlpfordt, Friederike, Vaquerizas, Juan M, Raja, Sunil Jayaramaiah, Holz, Herbert, Luscombe, Nicholas M, Manke, Thomas, Akhtar, Asifa
• Format: Article
• Language: English
• Subjects: Acetylation; Animal genetics; Animals; Binding Sites; Biology; Chromatin; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Gene expression; Gene Expression Regulation; Genetic aspects; Genetics; Genome, Insect; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Medical research; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Physiological aspects; Promoter Regions, Genetic; Protein Binding; Proteins; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; Transcription Factor TFIIB - genetics; Transcription Factor TFIIB - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Vesicular Transport Proteins
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1002736

MOF is the major histone H4 lysine 16-specific (H4K16) acetyltransferase in mammals and Drosophila. In flies, it is involved in the regulation of X-chromosomal and autosomal genes as part of the MSL and the NSL complexes, respectively. While the function of the MSL complex as a dosage compensation regulator is fairly well understood, the role of the NSL complex in gene regulation is still poorly characterized. Here we report a comprehensive ChIP-seq analysis of four NSL complex members (NSL1, NSL3, MBD-R2, and MCRS2) throughout the Drosophila melanogaster genome. Strikingly, the majority (85.5%) of NSL-bound genes are constitutively expressed across different cell types. We find that an increased abundance of the histone modifications H4K16ac, H3K4me2, H3K4me3, and H3K9ac in gene promoter regions is characteristic of NSL-targeted genes. Furthermore, we show that these genes have a well-defined nucleosome free region and broad transcription initiation patterns. Finally, by performing ChIP-seq analyses of RNA polymerase II (Pol II) in NSL1- and NSL3-depleted cells, we demonstrate that both NSL proteins are required for efficient recruitment of Pol II to NSL target gene promoters. The observed Pol II reduction coincides with compromised binding of TBP and TFIIB to target promoters, indicating that the NSL complex is required for optimal recruitment of the pre-initiation complex on target genes. Moreover, genes that undergo the most dramatic loss of Pol II upon NSL knockdowns tend to be enriched in DNA Replication-related Element (DRE). Taken together, our findings show that the MOF-containing NSL complex acts as a major regulator of housekeeping genes in flies by modulating initiation of Pol II transcription.