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The NSL complex regulates housekeeping genes in Drosophila.

Lam KC, Mühlpfordt F, Vaquerizas JM, Raja SJ, Holz H, Luscombe NM, Manke T, Akhtar A - PLoS Genet. (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck Institute of Immunobiology and Epigenetics, Freiburg im Breisgau, Germany.

ABSTRACT
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.

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Summary model: NSL-dependent Pol II recruitment to promoters of housekeeping genes.The majority of the NSL-bound targets are constitutively expressed or “housekeeping” genes. These genes are characterized by prominent enrichment of particular histone modifications (H4K16ac, H3K9ac, H3K4me2, H3K4me3) as well as specific core promoter elements (such as DRE, E-box and motif 1; indicated by colored squares). In contrast, tissue-specific or developmentally regulated genes (small inlay) usually contain the TATA-box as the most prominent core promoter element. We propose that the NSL complex acts as a regulator of constitutively expressed genes by facilitating stable recruitment of the pre-initiation complex (PIC) members such as Pol II, TBP and TFIIB on target genes. NSL complex may therefore serve as an important link between specific promoter architecture and PIC assembly.
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pgen-1002736-g007: Summary model: NSL-dependent Pol II recruitment to promoters of housekeeping genes.The majority of the NSL-bound targets are constitutively expressed or “housekeeping” genes. These genes are characterized by prominent enrichment of particular histone modifications (H4K16ac, H3K9ac, H3K4me2, H3K4me3) as well as specific core promoter elements (such as DRE, E-box and motif 1; indicated by colored squares). In contrast, tissue-specific or developmentally regulated genes (small inlay) usually contain the TATA-box as the most prominent core promoter element. We propose that the NSL complex acts as a regulator of constitutively expressed genes by facilitating stable recruitment of the pre-initiation complex (PIC) members such as Pol II, TBP and TFIIB on target genes. NSL complex may therefore serve as an important link between specific promoter architecture and PIC assembly.

Mentions: The promoters of NSL target genes exhibit prominent enrichment of certain histone modifications (H4K16ac, H3K9ac, H3K4me2, H3K4me3) as well as specific core promoter elements (such as DRE, E-box and motif 1). Furthermore, these genes display distinct nucleosome occupancy and dispersed promoter configuration characterized by multiple transcription start sites. The correlation between these promoter characteristics (well-defined chromatin marks, TATA-less DNA sequences and broad initiation patterns) was previously identified for housekeeping genes in mammals and flies [36], but how these promoter features are translated into gene transcription had remained elusive. We now conclusively demonstrate that the NSL complex modulates transcription at the level of transcription initiation by facilitating pre-initiation complex loading onto promoters. Therefore, we propose that the NSL complex is a key trans-acting factor that bridges the promoter architecture, defined by the DNA sequence, histone marks and higher chromatin structures with transcription regulation of constitutive genes in Drosophila (Figure 7).


The NSL complex regulates housekeeping genes in Drosophila.

Lam KC, Mühlpfordt F, Vaquerizas JM, Raja SJ, Holz H, Luscombe NM, Manke T, Akhtar A - PLoS Genet. (2012)

Summary model: NSL-dependent Pol II recruitment to promoters of housekeeping genes.The majority of the NSL-bound targets are constitutively expressed or “housekeeping” genes. These genes are characterized by prominent enrichment of particular histone modifications (H4K16ac, H3K9ac, H3K4me2, H3K4me3) as well as specific core promoter elements (such as DRE, E-box and motif 1; indicated by colored squares). In contrast, tissue-specific or developmentally regulated genes (small inlay) usually contain the TATA-box as the most prominent core promoter element. We propose that the NSL complex acts as a regulator of constitutively expressed genes by facilitating stable recruitment of the pre-initiation complex (PIC) members such as Pol II, TBP and TFIIB on target genes. NSL complex may therefore serve as an important link between specific promoter architecture and PIC assembly.
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Related In: Results  -  Collection

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pgen-1002736-g007: Summary model: NSL-dependent Pol II recruitment to promoters of housekeeping genes.The majority of the NSL-bound targets are constitutively expressed or “housekeeping” genes. These genes are characterized by prominent enrichment of particular histone modifications (H4K16ac, H3K9ac, H3K4me2, H3K4me3) as well as specific core promoter elements (such as DRE, E-box and motif 1; indicated by colored squares). In contrast, tissue-specific or developmentally regulated genes (small inlay) usually contain the TATA-box as the most prominent core promoter element. We propose that the NSL complex acts as a regulator of constitutively expressed genes by facilitating stable recruitment of the pre-initiation complex (PIC) members such as Pol II, TBP and TFIIB on target genes. NSL complex may therefore serve as an important link between specific promoter architecture and PIC assembly.
Mentions: The promoters of NSL target genes exhibit prominent enrichment of certain histone modifications (H4K16ac, H3K9ac, H3K4me2, H3K4me3) as well as specific core promoter elements (such as DRE, E-box and motif 1). Furthermore, these genes display distinct nucleosome occupancy and dispersed promoter configuration characterized by multiple transcription start sites. The correlation between these promoter characteristics (well-defined chromatin marks, TATA-less DNA sequences and broad initiation patterns) was previously identified for housekeeping genes in mammals and flies [36], but how these promoter features are translated into gene transcription had remained elusive. We now conclusively demonstrate that the NSL complex modulates transcription at the level of transcription initiation by facilitating pre-initiation complex loading onto promoters. Therefore, we propose that the NSL complex is a key trans-acting factor that bridges the promoter architecture, defined by the DNA sequence, histone marks and higher chromatin structures with transcription regulation of constitutive genes in Drosophila (Figure 7).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck Institute of Immunobiology and Epigenetics, Freiburg im Breisgau, Germany.

ABSTRACT
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.

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