Deciphering the Transcriptional Histone Acetylation Code for a Human Gene

Agalioti, Theodora; Chen, Guoying; Thanos, Dimitris

doi:10.1016/s0092-8674(02)01077-2

Cited by 588 publications

(532 citation statements)

References 37 publications

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“…H3K9,14ac has been shown to be important in recruiting the general transcription factor complex TFIID to promoters. 48 In addition, the observation downstream of the promoter of histone PTMs associated with active transcription suggested the presence of intronic enhancers, which we confirmed using reporter assays.…”

Section: Discussionsupporting

confidence: 74%

The miR-17-92 MicroRNA Cluster Is Regulated by Multiple Mechanisms in B-Cell Malignancies

Rao

Ramachandrareddy

et al. 2011

The American Journal of Pathology

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A cluster of six microRNAs (miRNAs), miR-17-92, is processed from the transcript of C13orf25, a gene amplified in some lymphomas and solid tumors. We find that levels of the miRNAs in the cluster do not vary entirely in parallel with each other or with the primary RNA in B-cell lines or normal cells, suggesting that processing or stability of the miRNAs is differentially regulated. Using luciferase reporter assays, we identified the region required for maximum promoter activity. Additional deletions and mutations indicated that the promoter is regulated by the collaborative activity of several transcription factors, most of which individually have only a moderate effect; mutation of a cluster of putative SP1-binding sites, however, reduces promoter activity by 70%. MYC is known to regulate C13orf25; surprisingly, mutation of a putative promoter MYCbinding site enhanced promoter activity. We found that the inhibitory MYC family member MXI1 bound to this region. The chromatin structure of a >22.5-kb region encompassing the gene contains peaks of activating histone marks, suggesting the presence of enhancers, and we confirmed that at least two regions have enhancer activity. Because MicroRNAs (miRNAs) are single-stranded RNAs of ϳ22 nucleotides that negatively regulate expression of their target genes posttranscriptionally. 1-4 Various miRNAs are overexpressed or underexpressed in different types of cancer in humans and may function as either tumor suppressors or oncogenes. 5-13 A cluster of six miRNAs (miR-17-92, comprising miR-17, miR18a, miR-20a, miR-19a, miR-19b-1, and miR-92a-1) is processed from the transcript of C13orf25 (also known as MIR17HG or MIRHG1), a gene amplified in some lymphomas and solid tumors 5,14 -17 and overexpressed in a large fraction of lymphomas. 5 Overexpression of miR-17-92 accelerates lymphomagenesis in mouse models. 5,8 The miRNAs in the cluster can target transcripts of genes, such as E2F1, PTEN, and BIM, which are important in cell proliferation and apoptosis. 18 -22 The transcriptional regulation of the miR-17-92 cluster, however, is poorly understood.C13orf25 is activated by MYC and E2F transcription factors, and MYC was first shown to bind to a region containing a conserved CATGTG sequence in the first intron of the gene locus. 8 By chromatin immunoprecipitation (ChIP) in HeLa cells, endogenous E2F1, E2F2, and E2F3 were found to directly bind the promoter of the gene and regulate its transcription. 21 The primary transcript initiates from a consensus initiator sequence downstream of a nonconsensus TATA box. 23 This TATA box is flanked by a TP53 binding site that medi-

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Section: Discussionsupporting

confidence: 74%

The miR-17-92 MicroRNA Cluster Is Regulated by Multiple Mechanisms in B-Cell Malignancies

Rao

Ramachandrareddy

et al. 2011

The American Journal of Pathology

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“…S6C). Note that only a fraction of TAF1 colocalizes with H1.4K34ac, consistent with the fact that this protein has been also shown to bind to acetylated core histones (Jacobson et al 2000;Agalioti et al 2002), and another TFIID subunit interacts with H3K4me3 (Vermeulen et al 2007). Thus, the above data suggest that H1.4K34ac can help recruit a transcriptional activator to promoters.…”

Section: H14k34ac Can Recruit Taf1supporting

confidence: 72%

A dual role of linker histone H1.4 Lys 34 acetylation in transcriptional activation

Kamieniarz¹,

Izzo²,

Dundr³

et al. 2012

Genes Dev.

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The linker histone H1 is a key player in chromatin organization, yet our understanding of the regulation of H1 functions by post-translational modifications is very limited. We provide here the first functional characterization of H1 acetylation. We show that H1.4K34 acetylation (H1.4K34ac) is mediated by GCN5 and is preferentially enriched at promoters of active genes, where it stimulates transcription by increasing H1 mobility and recruiting a general transcription factor. H1.4K34ac is dynamic during spermatogenesis and marks undifferentiated cells such as induced pluripotent stem (iPS) cells and testicular germ cell tumors. We propose a model for H1.4K34ac as a novel regulator of chromatin function with a dual role in transcriptional activation.

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“…Acetylation of K9 can be catalyzed by the coactivator GCN5 and is ultimately thought to aid in the recruitment of the TATA-binding protein to promoters (37,38). In addition, this modification is associated with gene activation and was shown here to be most robust at DRA-X.…”

Section: Figurementioning

confidence: 68%

X Box-Like Sequences in the MHC Class II Region Maintain Regulatory Function

Gómez

Majumder

Nagarajan

et al. 2005

The Journal of Immunology

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Sequences homologous to the canonical MHC class II (MHC-II) gene X box regulatory elements were identified within the HLA-DR subregion of the human MHC and termed X box-like (XL) sequences. Several XL box sequences were found to bind the MHC class II-specific transcription factors regulatory factor X and CIITA and were transcriptionally active. The histone code associated with the XL boxes and that of the HLA-DRA X box was determined. Using CIITA-positive and -negative B cell lines, CIITA-specific histone modifications were identified and found to be consistent among the active XL boxes. Although a remarkable similarity was observed for most modifications, differences in magnitude between the HLA-DRA promoter for modifications associated with the assembly of the general transcription factors, such as histone H3 lysine 9 acetylation and H3 lysine 4 trimethylation, distinguished the very active HLA-DRA promoter from the XL box regions. In response to IFN-γ, XL box-containing histones displayed increased acetylation, coincident with CIITA expression and that observed in B cells, suggesting that the end point mechanisms of chromatin remodeling for cell type-specific MHC-II expression were similar. Lastly, an interaction between one XL box and the HLA-DRA promoter was observed in a chromatin-looping assay. Therefore, these data provide evidence that certain XL box sequences contribute to a global increase in chromatin accessibility of the HLA-DR region in B lymphocytes and in response to IFN-γ and supports the involvement of these XL sequences in the regulation of MHC-II genes.

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Deciphering the Transcriptional Histone Acetylation Code for a Human Gene

Cited by 588 publications

References 37 publications

The miR-17-92 MicroRNA Cluster Is Regulated by Multiple Mechanisms in B-Cell Malignancies

The miR-17-92 MicroRNA Cluster Is Regulated by Multiple Mechanisms in B-Cell Malignancies

A dual role of linker histone H1.4 Lys 34 acetylation in transcriptional activation

X Box-Like Sequences in the MHC Class II Region Maintain Regulatory Function

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