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Published online before print
August 18, 2005, 10.1101/gr.3873705 Genome Res. 15:1189-1197, 2005 ©2005 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/05 $5.00
ATG deserts define a novel core promoter subclass1 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA 2 Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
The MHC class I gene, PD1, has neither functional TATAA nor Initiator (Inr) elements in its core promoter and initiates transcription at multiple, dispersed sites over an extended region in vitro. Here, we define a novel core promoter feature that supports regulated transcription through selective transcription start site (TSS) usage. We demonstrate that TSS selection is actively regulated and context dependent. Basal and activated transcriptions initiate from largely nonoverlapping TSS regions. Transcripts derived from multiple TSS encode a single protein, due to the absence of any ATG triplets within  430 bp upstream of the major transcription start site. Thus, the PD1 core promoter is embedded within an "ATG desert." Remarkably, extending this analysis genome-wide, we find that ATG deserts define a novel promoter subclass. They occur nonrandomly, are significantly associated with non-TATAA promoters that use multiple TSS, independent of the presence of CpG islands (CGI). We speculate that ATG deserts may provide a core promoter platform upon which complex upstream regulatory signals can be integrated, targeting multiple TSS whose products encode a single protein.
Regulation of gene expression is mediated by specific interactions of transcription factors with promoter DNA sequences, resulting in the assembly of the transcription machinery and onset of transcription (Chen et al. 1994  ; Roeder 1996; Berk 1999; Gill 2001; Kadonaga 2004). RNA pol II promoters are conceptually divided into two domains, upstream regulatory and core promoter regions. Although the diversity of transcription factor binding sites and the complexity of their organization in upstream regulatory regions has been long recognized (Struhl 2001), it is increasingly apparent that core promoter regions are also highly diverse and complex (Burke and Kadonaga 1997; Lagrange et al. 1998; Smale et al. 1998; Kutach and Kadonaga 2000; Willy et al. 2000; Smale 2001; Butler and Kadonaga 2002). Core promoters can be grouped according to the presence of specific DNA sequence elements such as TATAA box (Singer et al. 1990; Butler and Kadonaga 2002), Inr (Smale and Baltimore 1989; Zenzie-Gregory et al. 1993; Kaufmann and Smale 1994; Lo and Smale 1996; Smale et al. 1998), TFIIB response element (BRE) (Lagrange et al. 1998; Littlefield et al. 1999), the downstream promoter element (DPE) (Burke and Kadonaga 1997; Burke et al. 1998; Kutach and Kadonaga 2000; Butler and Kadonaga 2001; Kadonaga 2002), or the MED-1 element (Ince and Scotto 1995).
Another sequence feature common to many promoters is the presence of CpG islands (CGI) (Bird 1986
The sequence elements in the core promoter and its structure can both contribute to the regulation of gene expression. In yeast, it has been shown that these different classes of core promoters subserve different functions. While only about 20% of promoters in the yeast genome have TATAA elements, 50% of stress-responsive genes are TATAA promoters (Basehoar et al. 2004
Core promoter regions also differ in their patterns of transcription start sites (TSS). Recent genome-wide analyses have reported that the majority of genes initiate transcription at multiple sites distributed over the core promoter region (Suzuki et al. 2004
We have begun to address this challenge by characterizing the core promoter structure and patterns of expression of an MHC class I gene. The MHC class I gene family encodes cell-surface molecules that provide immune surveillance against intracellular pathogens. The classical class Ia genes HLA-A, B, and C in human and PD1 in miniature swine are ubiquitously expressed, however, their expression is actively regulated in a tissue-specific fashion (Singer and Maguire 1990
Here we report that differential transcription start site usage within the core promoter occurs in vivo in basal and activated transcription, demonstrating that transcription start-site selection is actively regulated. The regulation of class I transcription through the use of multiple TSS is made possible by the absence of any ATG codons within
Importantly, we identify a subclass of promoters in the human, mouse, and rat genomes that contain ATG deserts, thereby defining a novel core promoter feature. The ATG desert is a DNA segment that has a lower frequency of occurrence of the ATG trinucleotide than the surrounding sequences and spans a region of A consequence of the presence of ATG deserts is that they enable the use of multiple TSS whose products all encode a single protein, thereby permitting the core promoter to serve as a platform where complex upstream regulatory signals are integrated through selective transcription start site usage.
MHC class I gene transcription initiates at multiple start sites whose usage can be actively regulated In vitro transcription from a truncated promoter construct of the MHC class I gene, PD1, initiates at multiple start sites within a region of about 50 bp (Fig. 1A) (Howcroft et al. 2003 ), suggesting that transcription of native MHC class I genes in vivo also might initiate at multiple start sites.
To examine this possibility, the in vivo TSS of a genomic MHC class I transgene (PD1), as well as an endogenous MHC class I gene (H-2Kb) were determined in splenocytes by 5'RACE. As shown in Figure 1B, basal transcription in vivo of the PD1 transgene initiates over a 49-bp region at four predominant start sites at +12, +1, -14, and -37 and at a multiplicity of additional minor sites further upstream that are observed reproducibly. (The +1 assignment was arbitrarily chosen, as a reference point. Translation initiates at +32.) The usage of multiple start sites is also observed at the endogenous H-2Kb promoter that displays a similar pattern of start-site usage, the predominance of a few sites with a multiplicity of minor sites further upstream (Fig. 1C). Thus, the use of multiple transcription initiation sites is a naturally occurring in vivo phenomenon, which is likely to be common among MHC class I genes. To determine the functional 5' boundary of transcription initiation, we utilized a translational knock-out approach in which out-of-frame ATG codons (relative to a downstream reporter) were introduced at various upstream sites in the class I promoter, ligated to a CAT reporter gene (see schematic in Fig. 2A). Any transcription that initiates upstream of the out-of-frame ATG in these constructs would be translated into a nonsense product. The extent of the resulting decreased CAT reporter activity provides an assessment of the relative contribution of each TSS region to basal core promoter activity. Promoter constructs with an out-of-frame ATG codon inserted upstream of one of the three principle start sites were analyzed. Surprisingly, insertion of an out-of-frame ATG at position -6 bp dramatically reduced reporter activity, while a control TAG mutation (Cont-6) at the same position had no effect (Fig. 2A). The steady-state levels of CAT reporter RNA generated by the out-of-frame ATG-6 mutation and wild-type constructs were indistinguishable (Fig. 2B), demonstrating that altering the sequence at this position does not affect overall levels of transcription. Therefore, the majority of TSS occur upstream of -6 bp in basal transcription. To further map the functional 5' boundary of transcription initiation, we examined the effect of additional out-of-frame ATG's inserted at either -24 bp or -42 bp (Fig. 2A). The construct with an out-of-frame ATG at position -24 generated modest reporter activity (relative to the wild-type control), while the construct with an out-of-frame ATG at -42 was indistinguishable from the wild-type control. Thus, basal transcription in HeLa epithelial cells initiates from multiple, distinct start sites located largely between -42 and -6 bp.
Although many promoters are known to use multiple TSS (Suzuki et al. 2001
The MHC class I core promoter resides in an "ATG desert" The PD1 core promoter region contains no ATG codons within 42 bp of the major TSS, which enabled the use of the translation knock-out strategy. Indeed, there is a remarkable distribution of ATG codons in the extended promoter. There are no ATG codons, in any reading frame, within the first 459 bp upstream of the initiator ATG, in striking contrast to the occurrence of 17 ATG codons in the next 631 bp of DNA (extending 5' from -459) (Supplemental Fig. 1A). Thus, there is a sharp discontinuity in the ATG codon frequency between the promoter proximal and distal segments. Similarly, in the mouse class I H-2Kb gene, no ATG sequence occurs within 500 bp of its promoter, which also uses multiple transcription start sites. The absence of an ATG sequence within the extended promoter is not limited to the PD1 and H-2Kb genes, but is also a common feature of the human MHC class I genes, which reveal a relative paucity of ATG sequences in the 200-400 bp of the core promoter (Supplemental Figure 1B). Since the first ATG sequence to occur in any MHC class I transcript is the correct translation initiation codon, all transcripts from multiple TSS generate a common product. We propose that the absence of ATG sequences enables the extended core promoter to support multiple TSS, whose usage can be regulated. We have termed the absence of ATG codons in the extended promoter an "ATG desert."
The ATG desert defines a novel promoter class To determine whether TATAA boxes correlated with the ATG deserts, promoters were sorted based on their classification as either TATAA or non-TATAA (TATAA box was defined as the sequence TATAAT occurring within 200 bp of transcription initiation); each group was analyzed for the presence of ATG deserts. Remarkably, we found ATG deserts are a common feature of promoters, in particular, promoters that do not contain a TATAAT element (Fig. 3, cf. C and D with A and B). Among non-TATAA promoters, the ATG deserts are uniform V-shaped curves, symmetrically placed around the major TSS, such that the frequency of ATG codons within 1-2 Kb of transcription initiation plummets relative to the surrounding sequences, reaching a minimum within 100 bp of the TSS. (The same results are obtained if the definition of a TATAA box is expanded to include sequences TATA(A/T)(A/T) located within 40 bp of transcription initiation [Supplemental Fig. 2]). To control for possible distortions due to the differences in sample size between TATAA and non-TATAA promoter sets, we performed a permutation analysis. One thousand sets of randomly sampled genes, at a pool size equivalent to the TATAA group, were analyzed for the presence of ATG deserts. Even with the smaller pool size, ATG deserts were observed, indicating that the absence of ATG deserts in the TATAA-containing gene set is not due to the small sample size (data not shown). We conclude that ATG deserts are a novel structural feature of a subclass of promoters that is strongly correlated with non-TATAA promoters in the human genome.
ATG deserts do not correlate with CGI To determine whether ATG deserts are restricted to those promoters residing within CGI, promoters were sorted into four classes, according to the presence or absence of a CGI and the presence or absence of a TATAAT sequence within 200 bp of transcription initiation (as defined by annotation in RefSeq NT_xxxxxx for the gene). No correlation was observed between the presence of an ATG desert and the location of the promoter within a CGI (Fig. 3, cf. C and D).
The only correlation found with CGI is that a more extreme ATG desert was observed in those non-TATAA promoters that resided within a CGI than those that did not (minimum count of 0.6 vs 1.0), presumably due to their location within a region with an overall high GC content. Furthermore, it is clear that the ATG desert is not simply the result of a nucleotide bias in CGI, since an ATG desert is also observed among non-TATAA promoter genes that lack CGI core promoter structures, but not in TATAA promoters in CGI. (We also considered the possibility that the ATG reflected a chance skewing of the GC content in the set of genes analyzed. However, the GC content in the 4-Kb region surrounding the non-TATAA promoters is 0.45, which is not different from the 0.44 value for the entire set; the GC content of the entire human genome is 0.41.) Among TATAA promoters, the frequency of ATG triplets more closely approximated that of the surrounding sequences, whether associated with a CGI or not. Thus, ATG deserts define a novel promoter region enriched in CpG dinucleotides relative to surrounding sequences, independent of the presence of a CGI.
ATG deserts do not occur around promoters of noncoding genes
Identification of ATG deserts in the genomes of other species
Surprisingly, yeast promoters also have associated ATG deserts, although these are shorter than those in mammalian genomes and are associated with non-TATAA promoters (Supplemental Fig. 3). The shorter deserts are consistent with the smaller genome of yeast. There is some association of ATG deserts with TATAA promoters in the yeast genome, perhaps a reflection of the observed regulated usage of tandem TATAA elements associated with a single gene (Iyer and Struhl 1995 ). Thus, not only are ATG deserts a common feature in human genes, but are conserved in other species.
Multiple TSS usage correlates with non-TATAA promoters and ATG deserts
A correlation between non-TATAA promoters and multiple TSS usage has been generally accepted but not exhaustively demonstrated, although Suzuki et al. (2001
To determine whether there is a direct correlation between the presence of an ATG desert around a promoter and the use of multiple TSS, human full-length transcripts (FLJ) from the DBTSS database (http://dbtss.hgc.jp/) were analyzed for the presence of ATG deserts. Of the set of human genes characterized by Suzuki et al. (2004 ), 383 could be aligned with mouse and rat genes. The predicted ATG deserts in this group correlated with non-TATAA promoters, as observed for the larger data set (Table 2B). Significantly, there is a correlation between ATG deserts and non-TATAA promoters that use multiple TSS (Table 3A; Supplemental Fig. 4). To extend this analysis, ATG desert predictions were determined by alignment of the human FLJ from the DBTSS database with the rat and mouse genomes and application of the algorithm. In this analysis, a gene was scored as having an ATG desert if the median frequency of ATG triplets in the interval between -1 and -1000 bp was  1.5 in at least one of three species. Of the 382 genes that could be analyzed, 360 were identified as being in ATG deserts (Table 3B). Consistent with the hypothesis that multiple TSS promoters are highly associated with ATG deserts, 293 of 360, or 81% of the predicted ATG deserts genes contain multiple TSS promoters. This is in contrast to 13 of 22, or 59%, of the predicted non-ATG desert promoters with multiple TSS. This is statistically significant with a P value of 0.023 and an odds ratio of 3. The presence of ATG deserts predicted to be associated with promoters with multiple TSS in the three species was verified by plotting ATG frequency as a function of TSS usage (Supplemental Fig. 5). Thus, there is a correlation between the presence of an ATG desert around a promoter and its use of multiple TSS, suggesting that among non-TATAA promoters that are located within an ATG desert, multiple TSS could be used as a regulatory mechanism.
The present studies identify a new class of promoters characterized by the presence of a novel core promoter feature, the ATG desert. ATG deserts are found in the genomes of human, mouse, and rat, extend symmetrically up to 1 kB upstream and downstream of the major regions of transcription initiation, and are largely associated with promoters that do not contain a canonical TATAA element. Although the function of the ATG desert remains to be clearly established, we speculate that two distinct properties are conferred on ATG desert promoters as follows: (1) the ATG deserts establish a platform for the integration of regulatory signals through alternative transcription start site usage, and (2) the ATG desert region acquires a structural feature that focuses the transcription initiation complex on the core promoter in the absence of the canonical TATAA box.
The class of ATG desert promoters is distinct from other characterized promoters that are defined by distinct DNA sequence motifs that are present in various combinations in a sub-population of core promoters and function to focus transcription initiation to one or a limited number of tightly clustered start sites (Chen et al. 1994
Another DNA structure that is highly correlated with core promoter regions is the CGI (Bird 1986
The presence of ATG deserts correlates with non-TATAA promoters that use multiple TSS, leading to a model in which the ATG deserts provide a platform for the integration of complex regulatory networks at multiple TSS within an extended promoter. The organization and regulation of the promoter of the MHC class I PD1 gene provides an example of regulated TSS usage. Like other class I genes, the PD1 gene is ubiquitously expressed, requiring that the promoter be continually operational. In addition, its level of transcription varies among the different cell types and is further activated or repressed by hormonal or cytokine signals (Singer and Maguire 1990
The regulated use of TSS has been previously reported only for the yeast his3 gene (Iyer and Struhl 1995
The presence of ATG deserts may also define structural boundaries of the core promoter, thus providing a recognition site for the transcription preinitiation complex (PIC). The TATAA sequence in those promoters that contain it nucleates the PIC by serving as a binding site for TBP; the Inr sequence serves to stabilize the interaction of TFIID with the promoter (Aso et al. 1994
The ATG deserts described in this report differ from the previously reported negative selection against ATG triplets near start codons, which examined only 5' regions' mRNAs and speculated a role in translation regulation (Saito and Tomita 1999
Plasmids and cloning strategies The MHC class I promoter used in these studies derived from the swine class I gene, PD1 (Singer et al. 1982 ; Frels et al. 1985). The PD1 promoter reporter construct -416WT, containing 416 bp of core promoter and promoter proximal upstream sequence ligated to the CAT reporter, was previously described (Howcroft et al. 1999). To generate the ATG mutants -416ATG-6, -416ATG-24, and -416ATG-42, -416WT was digested with NarI and HindIII, which cut at positions -50 and +14. Synthetic double-stranded oligonucleotides were inserted into the NarI/HindIII-digested -416WT to generate derivative ATG mutant and control TAG reporter constructs. The sense-strand sequences of the oligonucleotides synthesized (from -50 to +14) are provided in the Supplemental material.
Transfections
Isolation of RNA and 5'RACE analysis of transcription start sites
In vitro transcription/coupled primer extension
Genome-wide analysis for ATG deserts and for TSS
ATG desert predictor using multiple-species sequence alignments
The authors gratefully acknowledge Dr. Ying Hu's assistance in the analysis of TSS and regulatory RNAs. We also thank David Levens, Ranjan Sen, Alfred Singer, and Jocelyn Weissman for helpful discussions and critical reading of the manuscript and Eric Lander for helpful discussions and suggestions.
3 These two authors contributed equally to this work. 
4 Present address: Cancer Immunology and Hematology Branch, Division of Cancer Biology, Bethesda, MD 20892.
5 Corresponding author. [Supplemental material is available online at www.genome.org.] Article and publication are at http://www.genome.org/cgi/doi/10.1101/gr.3873705. Article published online before print in August 2005.
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ftp://ftp.ncbi.nih.gov/genomes/H_sapiens/; GenBank. http://dbtss.hgc.jp/; DBTSS database. http://hgdownload.cse.ucsc.edu/goldenPath/hg16/humor/; GoldenPath.
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ABSTRACT
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500 bp) and a higher G+C content (>0.55) and observed/expected CpG ratio (>0.65) (Takai and Jones 2002
-interferon (IFN
2 test). Among the non-TATAA promoters with multiple TSS, the average distribution of TSS was 15.4 bp SD, while that of the TATAA promoters with multiple TSS was 9 bp SD. Thus, even where TATAA promoters use multiple TSS, their distribution is significantly tighter than among the non-TATAA promoters (P < 0.001). These findings extend the earlier ones of Suzuki et al. (2001
-gal. 
