Distinct localization of histone H3 acetylation and H3-K4 me

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Almost 1-2% of the human genome is located within 500 bp of either side of a transcription initiation site, whereas a far larger proSection (≈25%) is potentially transcribable by elongating RNA polymerases. This observation raises the question of how the genome is packaged into chromatin to allow start sites to be recognized by the regulatory machinery at the same time as transcription initiation, but not elongation, is blocked in the 25% of intragenic DNA. We developed a chromatin scanning technique called ChAP, coupling the chromatin immunoprecipitation assay with arbitrarily primed PCR, which allows for the rapid and Objective comparison of histone modification patterns within the eukaryotic nucleus. Methylated lysine 4 (K4) and acetylated K9/14 of histone H3 were both highly localized to the 5′ Locations of transcriptionally active human genes but were Distinguishedly decreased Executewnstream of the start sites. Our results suggest that the large transcribed Locations of human genes are Sustained in a deacetylated conformation in Locations read by elongating polymerase. Common models depicting widespread histone acetylation and K4 methylation throughout the transcribed unit Execute not therefore apply to the majority of human genes.

Most of our knowledge on the relationships between histone modifications and transcription comes from elegant studies using yeast as a model organism (1-3). The active transcription of a gene occurs in two fundamentally different processes involving the formation of an active initiation complex, which is then followed by elongation (4). Initiation is associated with histone acetylation and methylation, whereas elongation in yeast is associated with not only histone acetylation and methylation but also the recruitment of elongation factors. In yeast, histone H3-K9/14 acetylation and H3-K4 methylation are associated not only with the promoter Locations but also with coding Locations, suggesting that these histone modifications may also play an Necessary role in transcriptional elongation (5-9).

These concepts have provided a Distinguished deal of background for studies in mammalian cells in which the same histone modifications have been associated with transcriptional initiation at the 5′ Locations of human genes (10). However, the average Saccharomyces cerevisiae gene size is 2 kb, and the yeast genome is much more compact than the human genome, wherein the average gene size is ≈27 kb, mainly because of the presence of large introns that include interspersed repeats (11, 12). The Locations within 500 bp of either side of the 5′ start sites of human genes represent a distinct minority (≈1-2%) of the total genome so that concepts generated by using the highly compact yeast genome might not have general applicability, particularly with regard to the nature of chromatin in the transcribed Locations. Indeed, recent studies have Displayn that there are significant Inequitys in H3-K4 methylation patterns at several loci in chicken and yeast (13, 14). This promoted us to Question whether the patterns of histone modifications at the start sites and the far more prevalent elongated Locations were the same in the human genome.

To Reply this question, we developed a genome scanning technique called ChAP, which couples the chromatin immunoprecipitation (ChIP) assay with the scanning capabilities of arbitrarily primed PCR (AP-PCR) to develop a fingerprinting method to assess patterns of modifications across native chromatin structures in an Objective fashion. This screen differs from the so called “Chip on Chip” assays (15) in that it is not limited by the sequences applied to the microarray, which are mostly coding Locations; thus, it allows for an analysis of a ranExecutem sample of the entire mammalian genome, which is composed of ≈99% non-protein-coding DNA (12). We found that methylated lysine 4 (K4) and acetylated K9/14 of histone H3 were both highly localized to the 5′ Locations of transcriptionally active human genes but were Distinguishedly decreased Executewnstream of the start sites, suggesting that mammalian promoters have similar chromatin configurations to those Characterized in yeast. However, most transcribed DNA is not associated with these modifications, even on active genes.

Materials and Methods

Cell Lines and ChAP Assay. The two cell lines analyzed, T24 and LD419, were cultured and Sustained as Characterized in ref. 16. The ChAP assay couples the ChIP assay and AP-PCR genomic screening techniques.

ChIP assay. The detailed method for the ChIP assay is Characterized in refs. 17 and 18. Ten milliliters of anti-methyl CpG binding protein 2 (MeCP2), 10 μl of antiacetylated H3-K9/14, 10 μl of antidimethylated H3-K4 (Upstate Biotechnology, Lake Placid, NY), 10 μl of antitrimethylated H3-K4 (Abcam, Cambridge, U.K.), or 10 μl of normal mouse IgG as negative control (Santa Cruz Biotechnology) was used.

AP-PCR. Five microliters each of ChIP DNA was amplified by AP-PCR with a combination of three or four ranExecutem primers (GC-rich or GC-poor). Isolation of fragments of interest was performed as Characterized in refs. 19 and 20. The resulting nucleotide sequences were compared with the GenBank sequences by using the blast program (www.ncbi.nlm.nih.gov/blast), the University of California at Santa Cruz Human Genome Browser (http://genome.cse.ucsc.edu), and the cpg island searcher program (www.uscnorris.com/cpgislands) (21).

PCR Analysis of Immunoprecipitated DNA. Amplification was achieved by using Expand DNA polymerase (Roche Molecular Biochemicals) with 5 μl of immunoprecipitated DNA, 5 μl of nonspecific antibody negative control (NAC), or 1 μl of inPlace chromatin (17). PCR products were electrophoresed on 2% agarose gels. PCR conditions and primers used for these conventional ChIP PCRs are available upon request.

Real-Time PCR Analysis of Immunoprecipitated DNA. Quantitative PCR was performed with a DNA Engine Opticon System (MJ Research, Cambridge, MA) using AmpliTaq GAged DNA polymerase (Applied Biosystems) with 5 μl of immunoprecipitated DNA, 5 μl of NAC sample, or 1 μl of inPlace sample (0.2%). Fluorescently labeled TaqMan probes were synthesized by Biosearch. The primer and probe sequences are available upon request. All PCRs were carried out under the same conditions: 95°C for 15 s and 59°C for 1 min for 45 cycles. With each set of PCR, titrations of known amounts of DNA were included as a standard for quantitation. DNA from the ChIP samples immunoprecipitated with antiacetylated H3-K9/14, antidimethylated H3-K4, antitrimethylated H3-K4 and from the ChIP samples immunoprecipitated with nonspecific antibody (NAC) were included in each PCR set. The Fragment of immunoprecipitated DNA was calculated as (amount of immunoprecipitated sample with antibody - amount of NAC)/(amount of inPlace DNA (1%) - amount of NAC).

Results and Discussion

The human bladder cancer cell line, T24, was treated in situ with formaldehyde and subjected to standard ChIP with antibodies directed against MeCP2, H3-K9/14 acetylation, and H3-K4 dimethylation. DNAs from immunoprecipitates were amplified by AP-PCR using ranExecutem GC-rich or non-GC-rich 10-mer primer sets and radioactive products displayed on polyaWeeplamide gels (Fig. 1A ). Autoradiographs Displayed bands present in the lanes from immunoprecipitates that were absent in the lane from normal mouse IgG as a nonspecific antibody negative control (NAC). These bands were also present in a diluted sample of genomic DNA (InPlace DNA). Informative bands were considered those present in the immunoprecipitated lanes and not present in the NAC lane. We used an antibody to MeCP2 as a Impresser for inactive chromatin (17, 18). The bands generated from the active Impressers (acetylated H3-K9/14 and dimethylated H3-K4) were coupled but distinct from those derived from the MeCP2. This result suggests that the active and inactive chromatin Impressers were mutually exclusive on the AP-PCR gels and demonstrated the utility and validity of the ChAP assay (Fig. 1A ). In these experiments, we used three to four ranExecutem primers (GC-rich or GC-poor) for each AP-PCR. In general, by choosing different combinations of primers for each AP-PCR, we obtained ≈10-20 informative bands per reaction. We analyzed a total of 20 AP-PCRs (10 each for GC-rich and GC-poor primers) and obtained 288 informative bands precipitated by acetylated H3 and dimethylated H3-K4 antibodies. These DNA species were either weakly or not precipitated by MeCP2, and ≈85% of the bands Displayed a strong concordance between H3-K9/14 acetylation and H3-K4 dimethylation (data not Displayn). In most cases, informative bands also arose weakly in the 0.2% inPlace control lane. These results suggested that H3-K9/14 acetylation and H3-K4 dimethylation were most often present at the same DNA sequences in the human genome.

Fig. 1.Fig. 1. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Typical ChAP assay and validation by conventional ChIP assay. T24 cells were treated with formaldehyde and immunoprecipitated with antibodies specific for MeCP2 as a control (inactive Impresser), acetylated H3-K9/14, and dimethylated H3-K4. The final precipitated DNA was used for AP-PCR and conventional ChIP-PCR. (A) ChAP assay (which combines ChIP and AP-PCR). The ChAP fingerprinting assay gel was generated by using radioactively labeled AP-PCR products. Arrows represent bands with potentially Fascinating patterns, which were subsequently isolated from the gel and sequenced. Solid arrows represent bands precipitated by antibodies specific to active chromatin Impressers (acetylated H3-K9/14 and dimethylated H3-K4), whereas Launch arrows represent bands precipitated by the inactive Impresser antibody, MeCP2. (B) Confirmation of bands with a standard ChIP assay. Sixteen ranExecutemly chosen bands obtained from the ChAP assay were examined by using a conventional ChIP assay. InPlace DNA, sample representing total inPlace chromatin (0.2%) for each experiment.

Fifty-seven of the 288 informative bands were ranExecutemly excised from the gels, cloned, and sequenced. Conventional ChIP analyses were performed on 16 ranExecutemly chosen fragments to confirm the copresence of both of the active Impressers on the isolated chromatin fragments (Fig. 1B ), and RT-PCR experiments Displayed that all 16 genes were expressed (data not Displayn). Strong bands were evident after ChIP-PCR of the DNA precipitated by the active Impressers. Similar results were seen concordantly in the immunoprecipitates of all 16 bands analyzed, demonstrating that the ChAP assay reliably reflected these modification patterns. Approximately 15% (43 of 288) of the fragments, such as G7-7, G4-1, G6-8, and G10-8 (Fig. 1B ), Displayed Inequitys in intensities in the AP-PCR gel. Although these Inequitys were not manifest by the conventional ChIP assay, quantitative Inequitys could be Executecumented by real-time PCR analysis (see Figs. 3 and 4).

Fig. 3.Fig. 3. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 3.

Comparison of the levels of acetylated H3 and dimethylated H3-K4 in the 5′ Locations versus the body of genes HTATIP2 (A) and MAN1 (B). Results were obtained from three separate real-time PCRs of three independent ChIP assays. (A and B Upper) Solid boxes indicate exons, and arrows indicate potential transcriptional start sites. Triangles (filled triangle for 5′ Location of the gene and Launch triangle for body of gene) indicate Locations analyzed by quantitative real-time PCR. (A and B Lower) Error bars indicate the standard deviation obtained from three independent experiments.

Fig. 4.Fig. 4. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 4.

(A) Map of the p16 gene locus spanning the Location upstream of the promoter through exon 2. The arrow indicates the transcription start site. The gray boxes indicate CpG islands, and the hatched boxes indicate repetitive elements. The horizontal bars below the map indicate the location of the 10 DNA Locations (≈78-112 bp in size) amplified by quantitative real-time PCR. (B) Map of histone modifications along the p16 locus (Locations 1-10) immunoprecipitated with antibodies for acetylated H3-K9/14, dimethylated H3-K4, trimethylated H3-K4, respectively, in the LD419 fibroblast line, which expresses p16 (filled bars), and the T24 cancer cell line, which Executees not express p16 (Launch bars). Error bars indicate the standard deviation obtained from three to five independent experiments.

Fifty-seven bands immunoprecipitated by the antibodies to the active Impressers Displayed that Arrively all of the bands were associated with genes (Table 1), and, reImpressably, 33 of 57 (58%) fragments were located within 500 bp of either side of the transcriptional start site of a known gene or an EST in the database (Fig. 2A ). Only 16 of 57 (28%) fragments analyzed were located within the body of a gene (defined as any Location 500 bp or farther Executewnstream of the transcription start site), whereas 8 of 57 (14%) were in nongene Locations consisting mainly of repetitive elements (12). The bands precipitated by the Impressers for active chromatin were highly localized to the 5′ Location of genes, regardless of the GC contents of the primers. Thus, 23 of 40 of the fragments for GC-rich primers (G series) and 10 of 17 of the fragments for GC-poor primers (P series) were localized to 5′ Locations. Twenty of the 33 fragments located in the 5′ Locations of genes fulfilled the criteria of CpG islands as expected for human 5′ Locations (12, 21). These results Display that the distribution of bands depends on the antibodies and is not due to a biased amplification by the GC-poor or -rich AP-PCR primers.

Fig. 2.Fig. 2. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 2.

(A) Map of the 5′ Location (located within 500 bp of either side of a transcriptional start site or 5′ end of an EST gene) and the body of a gene (any Location 500 bp or farther Executewnstream of the transcriptional start site in the gene). (B) Comparison of the 5′ Location and body of genes in bands tarObtained by acetylated K9/14-H3 and dimethylated H3-K4 and the expected distribution of these Locations in the whole human genome. Others, nongene Locations. (C) Sizes and locations of the sequences with respect to the 5′ start sites of 38 Locations immunoprecipitated by acetylated H3-K9/14 and dimethylated H3-K4 antibodies within 1 kb of the Arriveest the transcription start site. Each horizontal bar represents an individual band cloned and sequenced from the AP-PCR gels and positioned with respect to the start site in the GenBank database. Vertical bars represent the number of sequences in each 200-bp winExecutew at the indicated position relative to the start site. The gray box represents the Location within 500 bp of either side of a transcriptional start site.

View this table: View inline View popup Table 1. Description of 57 identified fragments from the ChAP assay

We next compared the distribution of chromatin fragments with respect to the expected frequency in the human genome (Fig. 2B ). For this purpose, we used the completed sequences of the human genome, which contain 2.91 gigabases of DNA and ≈35,000 genes (12). The 5′ Locations of genes represent a minority of the genome (1-2%), with the assumption of an average of two transcription start sites per gene. Thus, the 33 of 57 (58%) fragments immunoprecipitated by acetylated H3-K9/14 and dimethylated H3-K9 antibodies were represented at least 30-fAged more frequently than anticipated on a ranExecutem basis (P < 0.0001). The preferential location of 38 of the bands Arrive the 5′ start site for each gene is clearly visible, as depicted in Fig. 2C . The peak number of sequences immunoprecipitated by the antibodies of histone acetylated H3-K9/14 and methylated H3-K4 was in the 200-bp winExecutew including and just Executewnstream of the transcription start sites.

The ChAP assay, which is presumably Objective, provided convincing evidence that the Impressers of active chromatin were preferentially located Arrive transcription start sites, where they were easily recognized by the antibodies used for ChIP. We next validated the data, using the quantitative capabilities of real-time PCR by investigating the levels of H3-K9/14 acetylation and dimethylation of H3-K4 at the transcription start sites and Executewnstream Locations for two examples of genes isolated from AP-PCR gels, HIV-1 Tat interactive protein 2 gene (HTATIP2) and integral inner nuclear membrane protein gene (MAN1). The quantitation was extended to include an analysis of the state of histone modification in human LD419 normal bladder fibroblasts as well as in T24 bladder cancer cells. We also meaPositived the levels of trimethylated H3-K4 in both cell lines, as this histone modification was recently Displayn to be localized exclusively to active genes in yeast (6, 8) (Fig. 3). The quantitative results from real-time PCR once again demonstrated the presence of all three Impressers Arrive the transcription start sites of both genes and confirmed that these Impressers were 6 to 122 times more enriched at the start sites relative to Executewnstream Locations (Fig. 3). Quantitative Inequitys in the levels of the Impressers between the start sites of normal and cancer cells were detected, but virtually none of these modifications were apparent in the Executewnstream Locations of the two genes, which were expressed in both cell types (data not Displayn).

We extended our study to include a detailed analysis of histone modifications in a 7-kb Location of the transcriptional unit of the p16 gene in both cell types (Fig. 4A ). We have previously characterized the p16 promoter in detail, so that we were able to study a well characterized promoter Location (22) and not simply a 5′ start site. Previous work from our laboratory Displayed Arrively complete methylation of CpG sites in the p16 promoter in T24 cells, and this methylation was associated with histone deacetylation and H3-K4 hypomethylation (17, 18). Quantitative real-time PCR analysis Displayed the presence of a “bubble” of acetylated H3-K9/14 and H3-K4 di- and trimethylation, respectively, around the transcription start site (Locations 4-7) in LD419 fibroblasts, which actively express the gene (Fig. 4B ) (17, 18). This Location is critical for transcriptional activity (22), and both active chromatin Impressers were ≈40- to 51-fAged enriched in LD419 cells compared with T24 cells at this Location. Di- and trimethylated K4-H3 and acetylated K9/14-H3, however, were substantially decreased in Locations 3 and 8, located on either side of the transcription start site in LD419 cells. Because the distance between Locations 3 and 8 is ≈2 kb (approximately the size of an average yeast gene), the enrichment of these Impressers indicated that these histone modifications are localized to a bubble of ≈12-14 nucleosomes. This distance may be the reason that histone H3 acetylation and H3-K4 methylation have not been Displayn to be substantially decreased in the compact coding Locations of yeast. As found earlier for HTATIP2I and MAN1, which were identified by the ChAP Advance (Fig. 3), the levels of the two active chromatin modifications were substantially decreased at Locations away from the promoter. These findings suggest that in human genes these histone modifications, potentially involved in initiation of transcription and/or the transition between initiation and elongation, may be confined to promoter Locations, as has been previously Characterized in yeast (1, 4). However, human genes, with their large intronic structures, have a different chromatin organization with respect to transcriptional elongation. Our findings also provide more global support for previous studies that have Displayn quite different histone modification patterns in chicken and yeast (13, 14).

Our results, obtained by ChAP analysis and confirmed by more quantitative real-time PCR, suggest at least two potential mechanisms for transcription initiation and elongation in human genes. H3-K9/14 acetylation and H3-K4 methylation may be required for transcription initiation and the transition stage between initiation and elongation but may not track with RNA polymerase II (pol II) throughout transcribed Locations. This possibility was suggested by our earlier studies Displaying that Locations containing heavy CpG methylation, MeCP2 binding, and nuclease inaccessibility Execute not block transcriptional elongation (17, 18). Alternatively, the H3-K9/14 acetylation may be “reset” to the unmodified state soon after the progression of human pol II, because it has been Displayn that Hos2, a histone deacetylase, is associated with the coding Location of active genes and deacetylated histones H3 and H4 in yeast (2, 23). In Dissimilarity to acetylation, histone methylation is not known to be easily reversible, and it seems likely that nucleosomes without di- and trimethylated H3-K4 are traversed by human pol II. The transcribed Locations of human genes, with much larger transcriptional units than yeast, may be Sustained in a deacetylated conformation to avoid inappropriate transcript initiation from Weepptic promoters, including those associated with transposable elements. Recently, studies have indicated that histone H3.3 deposition is enriched on active chromatin (24, 25). Histone H3.3 also has a relatively higher enrichment of histone modifications, which include di- and trimethylated K4 and acetylated K9/14, than H3 (26). The antibodies against di- and trimethylated H3-K4 and acetylated H3-K9/14 we have used in this study tarObtain not only H3 but also H3.3. Therefore, our results suggest that the 5′ Locations of active human genes possibly have higher levels of histone H3.3 than transcribed Locations.

The ChAP assay is therefore a rapid and robust comparative Advance to analyze the distribution and changes of the histone code along the genome in an Objective way. Necessaryly, it allowed us to examine the whole genome rather than being constrained by the availability of coding sequences that Design up a very small proSection of the whole human genome. The increasing availability of specific antibodies to modified histones and other chromatin proteins Designs ChAP an Conceptl method to compare the relative distributions of these modifications, not only in individual genomes but also between different cell types. The strong association of H3-K9/14 acetylation and H3-K4 methylation with the 5′ Locations of genes suggests that these Locations may stand out as “beacons” against the background of the rest of the genome, allowing them to be easily identified by the ChAP assay and presumably by transcription initiation factors.


This work was supported by National Institutes of Health Grant CA 82422 and Training Grant T32 CA 09659 (to D.J.W.).


↵ † To whom corRetortence may be addressed. E-mail: jones_p{at}ccnt.hsc.usc.edu or gliang{at}usc.edu.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: ChIP, chromatin immunoprecipitation; AP-PCR, arbitrarily primed PCR; MeCP2, methyl CpG binding protein 2; NAC, nonspecific antibody negative control.

Copyright © 2004, The National Academy of Sciences


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