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Gene Promoter Region
European Molecular Biology Laboratory, D-69117 Heidelberg, Germany
Address all correspondence and requests for reprints to: Dr. Martin Kos, European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117, Heidelberg, Germany. E-mail: kos{at}embl-heidelberg.de
ABSTRACT
The ER
gene has been intensively studied for more than a decade.
During this long time, multiple promoters used in ER expression have
been discovered in several species. Although an already large body of
literature describing various aspects of the regulation of ER
expression and utilization of different promoters is constantly
growing, the inconsistent terminology used by individual authors makes
the interpretation and comparison of data very difficult. Furthermore,
completion of the human genome project now allows all known human ER
promoters to be placed on a physical map. This review describes
promoters used in the generation of ER transcripts in human and in
other species and suggests a consistent nomenclature. The possible role
of multiple promoters in the differential expression of ER in
tissues and during development is also discussed.
ESTROGENS PLAY A crucial role in sexual
development and reproduction as well as in many physiological processes
in various tissues. They are also known to be involved in many
pathological processes such as breast and endometrial cancer
(1) and osteoporosis (2). The effects of
estrogens are mediated by their intracellular receptors (3, 4). To date, two nuclear ERs have been described—ER (NR3A1)
(5) and ERß (NR3A2; Refs. 6 and
7). Both belong to the superfamily of nuclear receptors
and family of steroid receptors that act as ligand-inducible
transcription factors (8, 9). For a detailed overview of
the nuclear receptor superfamily, their structural features, and
interactions with cofactors, see Refs. 10, 11, 12, 13, 14 .
The human ER cDNA was cloned in 1986 (5, 15) and the
genomic organization was described 2 yr later (16).
Everything seemed to be clear—the gene consists of 8 exons spanning
140 kb of the chromosome 6q25.1 locus (17, 18). A
comparison of ER cDNA sequence from human with those of chicken
(19), rat (20), and mouse (21)
showed a high level of conservation between species with the exception
of the 5'- end. However, evidence from the analysis of other nuclear
receptor family members indicated that multiple promoters might be a
common feature of steroid hormone receptors (22, 23). To
date, several exons encoding 5'-untranslated regions (UTRs) of ER
mRNAs have been identified. Unfortunately, different terminology
has been used by individual researchers and has resulted in confusion
regarding the different promoters used in ER expression.
The aim of this review is to describe chronologically the discoveries
of all human ER exons upstream of the translational start site,
which is in exon 1 (16). Various names for each of these
exons are listed and a unified nomenclature is suggested. Furthermore,
the genomic organization of the promoter region of the human ER gene
is elucidated using sequences of two overlapping genomic contigs
sequenced and assembled by Sanger centre. Multiple promoters and
upstream exons of the human ER gene are compared with known exons
and promoters in ER genes from other species. Finally, some possible
functions of multiple promoters in regulation of ER expression are
discussed.
PROMOTER REGION OF THE HUMAN ER GENE
In the following paragraphs we will try to clearly describe the
discovery of human ER upstream exons, and we ask readers to refer to
Fig. 1
whenever they feel confused.
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gene. A region with high homology to the first exon of the mouse
ER gene (21) and the 5'-end of the rat ER cDNA
(20) was found approximately 2 kb upstream of the
transcription start site identified by Green et al.
(5). Moreover, a potential acceptor splice site located in
exon 1 of human ER at position +163 was found to be conserved
between species. It was proposed that the identified region, called at
that time "exon 1'," was spliced to this acceptor splice site +163.
This transcript was indeed isolated from human uterus
(24). Other laboratories subsequently confirmed this
finding (25, 26). Piva et al. (27)
then described an ER transcript containing the 1' exon found by
Keaveney et al. but extending approximately 1.1 kb upstream.
It was suggested that a putative promoter exists further upstream of
the one proposed by Keaveney et al. (based by then on the
homology with mouse ER gene) and that two major transcription start
sites are used to transcribe these two mRNAs (27).
However, the longer mRNA variant suggested by Piva et al.
(27) has not been detected in experiments designed to map
the 5'-ends of various ER mRNAs performed by others
(28, 29, 30). These results indicated that the human ER
gene is transcribed from at least two promoters and the resulting
transcripts differ in their 5'-UTR. The corresponding promoters were
referred to originally as proximal and distal or simply as P0 or P1.
This was not the end of the story. Grandien (28) screened
various human cell lines and tissues and isolated from liver a new
ER mRNA variant that had a distinct 5'-UTR. This established that
another promoter and 5'-exon exist in the human ER gene. This exon
is also spliced to the acceptor splice site at position +163. As this
was the third exon to be identified, it was called "C" and the
previously identified exons were renamed "A" and "B." However,
1 yr later three new 5'-exons were isolated from a cDNA library
prepared from MCF7 cells (29). Screening of the cDNA
library yielded clones with two new transcripts that varied in their
5'-end from the previously described human ER mRNA variants. These
were named by Thompson et al. (29) as "E"
and "H." Sequence searches in databases that are now available show
that exon E is located in the intronic region between exons 1' and 1,
respectively, which had been sequenced previously (24, 25). Part of the H transcript turned out to be identical to the
3'-part of exon C described by Grandien (28), but both
sequences varied in their 5'-ends. Further analysis of a genomic
library revealed that the 5'-end of the H transcript is encoded by two
separate exons called "Ha" and "Hb" by Thompson et
al., and these were separated by an intronic sequence of more than
9 kb. Exon Hb is common to two separate transcripts that result from
the splicing of exon C (the 5'-unique part) or Ha to exon Hb, which is
then spliced to the splice acceptor site +163 in exon 1 of the human
ER gene (29). Only one year later another 5'-exon of
the human ER was reported (30). Using the rapid
amplification of cDNA ends technique, a new exon D was cloned
from MCF7 cells and localized to approximately 3.7 kb upstream of exon
1. The other previously identified mRNA variants were also isolated and
their 5'-ends mapped confirming the promoter and exon structure
reported previously. Authors tried to simplify the nomenclature and
renamed all the 5'-upstream exons using capital letters starting from
the originally identified exon as exon 1A and going upstream in
alphabetical order to 1F. This order has been recently again disrupted
by two new exons isolated from testis total RNA (Brand, H., M.
Ko, S. Denger, G. Flouriot, F. Gannon, and
G. Reid, manuscript submitted). Sequence search shows that
T1 and T2 exons are separated by 101-bp intron and are located
approximately 15 kb upstream of exon 1. Exon T1 can splice to exon T2
or directly to the acceptor splice site +163 (Brand et al.,
submitted).
In summary, the human ER gene is transcribed from at least seven
promoters into multiple transcripts that all vary in their 5'-UTRs. All
upstream exons are spliced to the acceptor splice site at position +163
in coding exon 1. The scheme of the genomic organization of the human
ER promoter region with all reported alternative splicing is shown
in Fig. 1
. This was constructed using the sequence of two genomic
contigs, available from the Sanger centre, that we found overlapped
with each other by 100 bp. We have confirmed this overlap by PCR using
primers that amplified a genomic region of 800 bp spanning the contig
junction (data not shown). A similar, but less complete, genomic
organization has been recently reported (31). The human
ER gene is a large genetic unit that spans approximately 300 kb of
chromosome 6 [including the 140 kb containing the 8 protein coding
exons (16)]. It is likely that other promoters and exons
exist that are perhaps used in only a selected range of cell types or
tissues and which have remained undiscovered to date. The description
of the testis transcript is perhaps a foretaste of such a
proliferation. Any nomenclature system will be inevitably affected by
future discoveries of new upstream exons. Although we are aware that an
"ideal" nomenclature is an impossible task, we would like to
suggest that the nomenclature shown in Fig. 1 is used in the future and
that any new exon is named using capital letters fitting into an
alphabetical order if possible, or a letter referring to the tissue to
which an expression of such exon is restricted (e.g. T1 and
T2 for testis). It is hoped that this will alleviate some of the
existing confusion.
ER GENE IN OTHER SPECIES
Are ER genes of other species as complex as the human gene?
Although ER cDNA from many species is known, only the genomic
structure of ER from chicken, mouse, rat, and rainbow trout has been
extensively studied. The genomic organization of the 5'-region of the
ER gene of these species compared with human is shown in Fig. 2.
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genomic
organization are the closely related rat and mouse. The first exon of
the mouse corresponds to exon C of the human and is also located
approximately 2 kb upstream of the second exon, which contains the
translation start site. Thus, exon 2 of the mouse is equal to exon 1 of
the human, etc. For simplicity we number the exons according to the
human gene: exon 1 is the exon that contains the translation start
site. The same applies to the rat ER gene. At least six upstream
exons (A, B, C, F1, F2, and H) exist in the ER gene of the mouse
(32) and four upstream exons (called 0 or B, 0S, 0N, and
liver-specific C) in the rat (33, 34, 35). Mouse promoters and
exons A and B are equivalent to human A and B; however, their
expression is very low in all tissues tested so far (32).
There is no functional A promoter in the rat (35). Human
and mouse exon C and rat exon 0/B share a high homology. Also the
sequences of the exons F of the human, F1 of the mouse, and part of
exon 0S of the rat are highly conserved between these species. Although
exons H of the mouse and C of the rat are more than 95% homologous and
they are both expressed specifically in liver, no known counterpart to
them has been identified in humans to date.
The chicken ER gene is transcribed from at least five different
promoters known as A1, A2, B, C, and D (36, 37). Exons A1
and B are homologous to exons A and B of the human ER gene. Exon C
is not homologous directly to human C but to a region of human ER
located in the intron between exons B and C. The A2 promoter is located
in the region of the translational start site of the main open reading
frame, and the transcribed mRNA encodes a protein variant missing 41
amino acids at the N terminus. The smaller ER protein is
predominantly expressed in liver (37).
Finally, it has been known for several years that two ER protein
isoforms exist in rainbow trout (38). However, the origin
of these two isoforms has been elucidated only recently. The rainbow
trout ER gene is transcribed from two different promoters, and the
resulting mRNAs encode ER proteins of 65 kDa and 71 kDa; the latter
isoform possesses an additional 45 amino acids at its N terminus
(39).
We can conclude that chicken, mouse, rat, and rainbow trout ER
genes are also complex transcription units with multiple promoters and
upstream exons. All upstream exons are again spliced to an acceptor
splice site located in the first translated exon. This splice site is
highly conserved between species, although the sequences of upstream
exons are less homologous.
TISSUE-SPECIFIC PROMOTER UTILIZATION
The purpose and function of multiple promoters in the ER gene
has been questioned since the discovery of the first alternative
promoter. Probably one of the most obvious implications is a potential
for a tissue-specific regulation of particular promoters and thus
regulation of expression of mRNA variants in tissues. Indeed, Grandien
et al. (26) showed that both human ER
promoters A and C are used in MCF7 cells but only promoter A is used in
ZR-75-1 cells. Another report from the same laboratory describes an
increased utilization of the promoter A in comparison to decreased
transcription from the promoter B in tumor-derived cell lines as
opposed to normal breast and uterine tissue (40).
Differential use of promoter C in normal and cancerous breast tissue
was also demonstrated (41). Later, Grandien also described
the liver-specific mRNA variant "E2-E1" (28)
(originally called "C" by the author) showing the existence of the
promoter E, which is used predominantly in liver as confirmed by others
(30). However, as we have already mentioned, rat exon C
and mouse exon H are exclusively expressed in the liver of rat and
mouse and are highly conserved between both species (32, 35), and yet these are not homologous to the human
liver-specific exon E. Several other publications show tissue-
specific expression of ER mRNA variants in the human, mouse,
chicken, rat, rainbow trout, and even Japanese monkey (30, 32, 33, 34, 36, 37, 39, 42, 43, 44).
MULTIPLE PROMOTERS AND REGULATION OF ER EXPRESSION
Several attempts to characterize promoters of ER yielded a
handful of enhancer elements and transcription factors involved in
regulation of promoters in several cell lines (31, 45, 46, 47, 48, 49, 50, 51). Also auto-regulation of some ER promoters by
estrogen has been observed (36, 43, 52, 53, 54). Most ER
promoters have no TATA, CCAAT box, or GC box sequences or, if present,
these do not match consensus sequences very well. Consequently,
multiple transcription start sites have been identified for most
upstream exons. Furthermore, ER promoters are rather weak when
compared with other promoters, e.g. human A, F, and T
promoters are 100- to 1,000-fold weaker than the human
glyceraldehyde-3-phosphate dehydrogenase promoter in transient
transfection assays (our unpublished data). The low
transcriptional activity of the ER promoters ensures that only low
levels of protein are expressed in the cell. This raises the question
of why there are multiple promoters rather than one that would be
tightly regulated? Several explanations are possible: 1) different
tissues use different promoters and/or 2) different promoters are used
in different stages of development and/or 3) transcripts produced from
various promoters undergo different alternative splicing resulting in
transcripts encoding various protein isoforms. We should also note that
if we consider a hypothetical system with only one promoter, then the
levels of various transcription activators and/or repressors need to be
regulated in a tissue-specific or developmental stage-specific manner
to ensure appropriate spatiotemporal expression of the target protein.
This could be achieved, for example, by control of transcription by
other factor and/or by regulating differential stabilities of mRNAs
encoding these factors or by the various stabilities of the factors
themselves. Such a system is perhaps even more complicated than the
reality found in nature with multiple promoters for ER gene. An
increasing number of genes for which multiple promoters are being
described might support this view. Another interesting feature of the
ER gene is its size. Large distances between promoters might be
needed to allow epigenetic regulation of promoters, as gene silencing
usually involves large genomic regions (for review see e.g.
Ref. 55).
The tissue-specific utilization of ER promoters has been well
demonstrated as we have described. However, the relative quantification
of levels of ER mRNA variants (28, 30, 32, 36, 37)
shows that some promoters are used, albeit to different extents, in all
the tissues tested and perhaps, surprisingly, also in tissues for which
a specific promoter had been described. We can speculate that the
promoters that are active in all tissues result in basal levels of
ER mRNA and the tissue-specific promoters refine the level of ER
expression according to the requirements of the cell. This would
presume that ubiquitously active promoters might share the same
regulatory elements; however no data supporting or rejecting this
hypothesis are available today. Perhaps a genetic approach using
conditional and selective knockout technology might help to elucidate
the role of individual promoters in development and
differentiation.
A lack of data also accompanies the question of the developmental
regulation of ER promoters. Kato et al. (42)
reported that levels of mRNA variants in rat brain change during
embryonic development. However, no more data addressing the regulation
of different promoters during development have been published. The
recent characterization of multiple ER variants in the mouse
(32) renders this issue more amenable to
investigation.
As indicated above, another possible explanation for multiple promoters
is that it permits the variation of the alternative splicing of
transcripts produced from different promoters. Splicing of upstream
exons to the acceptor splice site in the first coding exon results in
multiple transcripts encoding the same full-length protein. These mRNA
variants differ only in their 5'-UTRs. It is known that regulatory
elements and short open reading frames in the 5'-UTR can control the
translation of mRNA (for review see Ref. 56). Most
upstream exons contain short open reading frames. Our data show that
these can significantly reduce translation of the mRNA (our
unpublished data). ER 5'-UTRs may further tighten the
regulation of ER expression achieved by selective promoter usage.
However, it has been recently demonstrated that human exon F can be
spliced directly to the second coding exon in approximately 10% of
transcripts from F promoter in MCF7 cells. The resulting mRNA encodes
an ER protein variant that lacks the N-terminal domain containing
the trans-activation function 1 (AF-1). This protein isoform
was detected in MCF7 cells (57). The same transcript is
also present in human osteoblasts; however, in this case it is
expressed to the same level as the full-length ER protein
(58). The different relative levels of the
F-exon1 and F-exon2 transcripts indicate that this
alternative splicing might be regulated in a
tissue-specific manner. It is thus possible that utilization of
some promoters can lead to the alternative splicing of upstream exons
to different coding exons downstream of translational start sites and
thereby lead to the expression of ER protein variants lacking
various amounts of the N terminus. We have also observed that most
upstream exons in mouse ER can be spliced to the second or even
third coding exon, but the putative shorter protein isoforms encoded by
these transcripts have not been detected (our unpublished data).
Also, many alternatively spliced mRNA transcripts with a deletion of
one or more coding exons or truncation in the coding region have been
observed, especially in breast cancer tissue (for review see Refs.
59 and 60). However, a correlation between
the particular promoter usage and splicing pattern has not been
clearly demonstrated (61). Further investigation
addressing the question of possible tissue-specific regulation of
this alternative splicing and its consequences on a protein level is
necessary.
We have shown in this review that ER is a large and complex
transcription unit. Although a significant amount of data on the
function and regulation of ER in various species has been generated,
many questions, especially regarding the function of multiple
promoters, remain unanswered. We hope that this review
will help to stimulate new thoughts and
ideas to clarify these issues.
Sources of used sequences are listed in Table 1.
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ACKNOWLEDGMENTS
We would like to thank members of our laboratory for helpful comments and discussions.
FOOTNOTES
This work was partially supported by European Community Grant QLK6-1999-02108.
Abbreviations: UTR, Untranslated region.
Received for publication July 9, 2001. Accepted for publication August 3, 2001.
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D. A. Schreihofer, D. F. Rowe, E. F. Rissman, E. M. Scordalakes, J.-a. Gustafsson, and M. A. Shupnik Estrogen Receptor-{alpha} (ER{alpha}), But Not ER{beta}, Modulates Estrogen Stimulation of the ER{alpha}-Truncated Variant, TERP-1 Endocrinology, November 1, 2002; 143(11): 4196 - 4202. [Abstract] [Full Text] [PDF]
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 W. N. Jefferson, J. F. Couse, E. Padilla-Banks, K. S. Korach, and R. R. Newbold Neonatal Exposure to Genistein Induces Estrogen Receptor (ER){alpha} Expression and Multioocyte Follicles in the Maturing Mouse Ovary: Evidence for ER{beta}-Mediated and Nonestrogenic Actions Biol Reprod, October 1, 2002; 67(4): 1285 - 1296. [Abstract] [Full Text] [PDF]
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 M. Kos, S. Denger, G. Reid, and F. Gannon Upstream Open Reading Frames Regulate the Translation of the Multiple mRNA Variants of the Estrogen Receptor alpha J. Biol. Chem., September 27, 2002; 277(40): 37131 - 37138. [Abstract] [Full Text] [PDF]
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