Identification of a candidate alternative promoter region of the human Bcl2L11 (Bim) gene
© Gaviraghi et al; licensee BioMed Central Ltd. 2008
Received: 10 December 2007
Accepted: 12 June 2008
Published: 12 June 2008
Despite the importance of the BCL2L11 (BIM) protein in various apoptotic processes in development and disease, little is known of the promoter structure of the human BCL2L11 locus and of the cis-acting elements regulating expression of the human gene.
In the search for novel promoter sequences in the human BCL2L11 locus, we have identified previously unrecognized genomic sequences displaying promoter activity and E2F responsiveness, and driving the expression of BCL2L11 coding transcripts. In man, transcripts originating from this novel putative promoter contribute significantly to total BCL2L11 mRNA expression in testis, heart and liver. In HEK293 cells, this novel candidate promoter originates BCL2L11 transcripts whose expression can be modulated by a known modulator of BCL2L11 expression (Trichostatin A) and by E2F, a characterized transcriptional regulator of BCL2L11 expression.
The identification of a novel putative human BCL2L11 promoter provides new insights into the structure and regulation of the BCL2L11 locus.
The human BCL2L11 locus, located on chromosome 2q13, encodes a protein of 198 amino acids structurally and functionally related to the BH3-only group of pro-apoptotic BCL2 family members . The gene is frequently mutated in diverse human tumours leading to loss of BCL2L11 activity [14, 21]. Expression of BCL2L11 is induced by a diverse range of apoptotic stimuli such as deprivation of growth factors/cytokines, ionizing radiation, and cytotoxic peptides [2, 6, 14, 22]. Although the regulation of BCL2L11 activity is highly complex and is cell context-dependent, studies aimed at identifying the molecular mechanisms underlying BCL2L11 activation during apoptosis have revealed an important role for the transcriptional regulation of BCL2L11 gene expression [1, 6, 9, 12, 13, 22, 23]. A genomic region displaying promoter activity has been characterized for the human BCL2L11 locus , while in the rat the existence of three alternative promoter sequences has been postulated, the most upstream of which corresponds to the promoter described for the human BCL2L11 gene [2, 3]. Regulation of this conserved BCL2L11 promoter by FOXO and E2F has been described using rat BCL2L11 genomic constructs, thus providing a likely mechanism for the induction of BCL2L11 expression during programmed cell death [2, 9], through the involvement of these transcription factors whose activity is induced in apoptotic contexts. Whether regulation by E2F and FOXO factors is conserved in humans remains to be demonstrated; however, such studies are hampered by the relatively poor inter-specific sequence conservation in non-coding sequences and the paucity of information on the structure and regulation of the human BCL2L11 locus. We therefore set out to investigate the existence of as yet uncharacterized human BCL2L11 promoter regions, and to determine the conservation from rodents to man of E2F regulation of BCL2L11 expression.
Identification of a novel putative BCL2L11 promoter region and associated BCL2L11 exon
Exon 1 containing transcripts are widely expressed in human tissues
Exon 1 containing transcripts are coordinately and coherently regulated with other BCL2L11 transcripts by TSA in HEK293 cells
E2F regulates the activity of BCL2L11-P1
We have identified a novel putative promoter and associated exon of the human BCL2L11 locus in HEK293 cells and showed regulation of this promoter by the transcription factor E2F, which is known to modulate BCL2L11 transcription in other species. BCL2L11 transcripts derived from this promoter are widely expressed in human tissues, and contribute significantly to BCL2L11 expression in testis, heart and liver. The real-time PCR data presented here constitutes the first systematic, quantitative analysis of steady-state BCL2L11 transcript expression levels in different human tissues. Overall, the data obtained on the distribution of BCL2L11 mRNA levels in different human tissues correlate with published data on the distribution of BCL2L11 RNA and protein in human tissues, which indicates relatively higher expression in testis and spleen [23, 24], organs where BCL2L11 has recognized functions in spermatogenesis and hematopoiesis, respectively [25, 26]. Interestingly, the analysis presented in this manuscript indicates that the highest expression levels of BCL2L11 transcripts were detected in pancreas, placenta and thyroid tissue, suggesting an important role for BCL2L11 in the normal physiology of these tissues. With respect to P1-derived transcripts, up to 70% of total BCL2L11 transcripts are contributed from the newly identified promoter in the testis, an organ where BCL2L11 activity was shown to contribute critically to spermatogenesis , suggestive for a prominent role for the putative BCL2L11 P1 in the expression of BCL2L11 in this tissue. Although the biological significance of BCL2L11 P1 remains to be determined, the expression of P1-derived transcripts in various human tissues of relevance to BCL2L11 biological function argues for a physiological significance of such transcripts. The biological significance of the newly identified putative BCL2L11 promoter was strengthened by the observation that transcripts derived from it could be shown to be co-regulated together with other BCL2L11 transcripts by a known pharmacological modulator of BCL2L11 expression (TSA), in the same cell line where such transcripts have been identified. Another piece of circumstantial evidence pointing to a physiological role for BCL2L11 P1 in BCL2L11 expression is its regulation by the transcription factor E2F. Studies performed on the rodent BIM promoters (the equivalents of BCL2L11 P2) have identified this transcriptional regulator as a modulator of BCL2L11 expression during apoptotic processes [2, 11]. Through a combination of reporter assays and DNA-protein interaction studies, we were able to demonstrate that E2F can upregulate BCL2L11 P1 activity in HEK293 cells through a cis-acting element identified through a bioinformatics analysis, which can bind E2F in EMSA assays and whose presence is required for responsiveness to overexpressed E2F. This is the first indication of direct transcriptional regulation of a BCL2L11 promoter by E2F, as previous reports of E2F involvement in the regulation of BCL2L11 expression have shown either an indirect regulation through other transcription factors  or have not investigated the underlying mechanism . The potential contribution of P1 activity during BCL2L11-mediated apoptotic processes induced by E2F may therefore be physiologically important and deserves further investigation. A number of further aspects are worthy of further analysis. First, further characterization of BCL2L11 P1 in different cellular contexts/backgrounds is required, in particular in contexts where BCL2L11 expression is higher than that observed in HEK293 cells where BCL2L11 expression is relatively low, in order to confirm that such new putative promoter is indeed generally active and drives BCL2L11 transcripts in most situations where the locus is transcribed. Second, the relative contribution of P1- and P2-derived transcripts to BCL2L11 protein expression may differ and needs to be investigated, as E1 and E2 are alternatively spliced and may contribute differently to mRNA stability and translation. Finally, it remains to be determined if a homologue of BCL2L11-P1 exists in rodents. Interestingly, a BLAST analysis using 13 kb of mouse genomic sequences upstream of the first coding exon of the murine BCL2L11 locus revealed a similar pattern of ESTs as that evidenced in this manuscript for the human locus, suggesting the potential existence of a BCL2L11-P1 homologue in mice (data not shown) and providing further indirect evidence of an important physiological role for P1 in BCL2L11 expression.
Through a combined bioinformatics and experimental approach we have identified a novel putative promoter and associated untranslated exon in the human BCL2L11 genomic locus, upstream of the previously characterized promoter. This candidate promoter generates transcripts which are widely expressed in human tissues, and which contribute significantly to overall BCL2L11 expression in tissues where BCL2L11 is known to play important physiological roles, such as the testis. Our data are suggestive of a complex pattern of transcriptional regulation of the human BCL2L11 locus, comprising alternative promoter usage and alternatively spliced 5' untranslated exons, and suggests the presence of additional, as yet unidentified promoter(s). Although, the general relevance and impact of BCL2L11-P1 and of its regulation by E2F in other human cell lines or in vivo remains to be determined, the present study offers novel insights into the structure and regulation of the human BCL2L11 locus.
DNA and RNA extraction, cDNA synthesis and PCR amplification
Genomic DNA was isolated from HEK293 cells as described . Total RNA was isolated using a commercial kit (RNeasy Kit, Quiagen, Hilden, Germany) as per manufacturer's instructions. RNAs from human tissues were obtained from a commercial source (Clontech Inc., CA). cDNA was synthesized from 2 μg total RNA using Superscript II Reverse Transcriptase (Invitrogen) as per manufacturer's instructions, using oligodT as a primer. Preparative PCR was performed using Phusion DNA polymerase from Finnzymes Inc (Espoo, Finland), as per manufacturer's instructions.
Cloning and generation of plasmid constructs
All cloning and subcloning was performed using PCR approaches as described in the text. For cloning and transformation, One Shot TOP10 Chemically Competent E. coli, Zero Blunt PCR Cloning Kit were from Invitrogen (San Diego, CA) and were used as per manufacturer's instructions. DNA manipulations were performed using techniques essentially as described . All PCR reactions were performed using a proofreading polymerase (Phusion polymerase, Finnzymes Inc.). Human genomic sequences associated with the BCL2L11 locus were amplified from HEK293 genomic DNA using a specific primer set and a nested PCR strategy (BCL2L11-P1-1918-FOR1 TAACAACATCAGTGCGGCTC and BCL2L11-P1-1918-REV1 AGAGAACGCAGTGTGAGAAG, followed by a second round using BCL2L11-P1-1918-FOR2 AAGAGCTCGGCTCAGACATCA and BCL2L11-P1-1918-REV2 AAAAGCTTCACCTCCTTCGCG). A 2235 bp fragment comprising the genomic region of interest was subcloned into pGL3Basic (Promega Inc.) as a transcriptional fusion (BCL2L11-P1-1918). Deletions construct of BCL2L11-P1-1918 were prepared using following primer set BCL2L11-P1-1566 FOR AAGAGCTCGGCATTGGCGTTAACAGC, BCL2L11-P1-1326 FOR AAGAGCTCGCTCTTCCTGTTCAGTTC, BCL2L11-P1-1284 FOR AAGAGCTCCCCAGGCACTCCAGAGGT, BCL2L11-P1-940 FOR AAGAGCTCAGCTGCTGTCACTAGATG and for all reactions BCL2L11-P1-2000 REV AAAAGCTTCTCCCCACCCTCT. RT-PCR to confirm the transcript originating from BCL2L11-P1 region was performed using the following primer set HsBCL2L11E1-FOR1 TTCAGCACAAGCCATCCTCC and HSBCL2L11-CDS-REV1 ACCTCCGTGATTGCCTTCAG. All constructs were confirmed by DNA sequencing.
RT-PCR and RACE cDNA cloning
RT-PCR and RACE-PCR was performed essentially as described previously . First strand synthesis was performed using Superscript II according to manufacturer's instructions, employing 2 μg total RNA. 5' Rapid amplification of cDNA ends (RACE) was carried out by reverse transcription of HEK 293 cells polyadenilated (poly A) RNA employing the primer, CCAGTGAGCAGAGTGACGAGGACTCGAGCTCAAGCTTTTTTTTTTTTTTTT, which contains an anchor region. For RT-PCR, a forward primer anchored to sequences present within Group 1, subgroup A ESTs (BCL2L11-RT-FOR AGCACAAGCCATCCTCCTTC) and a reverse primer anchored within the first BCL2L11 coding exon, 3' to the translational initiation codon (BCL2L11-RT-REV TTGCCTTCAGGATTACCTTG) were employed. For RACE-PCR, a nested amplification approach was used, employing the following primer BCL2L11-P1-RACE1 AGAGAACGCAGTGTGAGAAG and the 5' anchored externally primer RACEA CCAGTGAGCAGAGTGACG. Conditions were as follows: annealing 62°C for the first 10 cycles, then 40 cycles at 52°C (Dyad DNA Engine, Biorad, USA). For second round the following primer set was employed: BCL2L11-P1-RACE2 GGAGGATGGCTTGTGCTGAA and the primer anchored internally to RACEA, of sequence GAGGACTCGAGCTCAAGC using the same amplification program of the first round. The amplicon was loaded on a 1.5% gel, purified, and finally cloned. Purification was done using PCR purification kit (Quiagen, Hilden, Germany) and cloning in Zero Blunt cloning kit. Sequences were confirmed by sequencing both strands of more than one clone (MWG, Martinsried). All primer sets yielding PCR products from cDNA templates were tested for the absence of products resulting from amplification using the corresponding RNA as a template, to detect eventual problems due to genomic DNA contamination (data not shown).
Human Hembrional Kidney cells (HEK293) were provided from ATCC and were grown at 37°C, 5% CO2 in DMEM, medium (Gibco) supplemented with 10% fetal bovin serum (Biowhittaker, Cambrex), 1% streptomycin ampicillin (Cambrex) and 1% glutamax (Gibco). Trichostatin A was from Sigma Chemical Company. A 10 mM solution of TSA in dimethylsulphoxide was prepared and stored a -20°C until use. HEK293 plated in 6 wells were treated the day after with TSA 0.2 μM or 1 μM for 4, 8, 16, 24 hours. Control cells were treated with dimethylsulphoxide. At the end of incubation period cells were harvested. Total RNA extraction and cDNA synthesis were performed as described before.
Transient transfections and luciferase assays
The human E2F expression construct was purchased from a commercial source (Origene). DNA was prepared with Plasmid Maxi kits (Qiagen, Hilden, Germany). HEK293 cells were cotransfected with 0.05 μg of reporter plasmid, 0.01 μg of Renilla vector (pRL-TK, Promega), 0.01 μg of empty plasmid Bluescript (Stratagene, Inc.) or 0.1 or 0.05 μg Human E2F expression construct (Origene, Inc.) in 95 μl of serum-free medium per well in 96-well plate using Lipofectamine 2000 . Three hours later, medium with lipofectamine 2000 was replaced with fresh complete medium. Before use, 96 well plates were polylisinated with poly-D-lysine. Luciferase assays were performed using the Dual Reporter System (Promega Inc.). 24 hours post-transfection, cells were lysed in the buffer provided in the Promega Luciferase System. Dual luciferase assays were performed according to the manufacturer's instructions, using a Mithras LB 940 luminometer (Berthold). Relative luciferase activities were obtained by normalizing the luciferase activity against Renilla luciferase activity.
Real Time PCR
Quantitative real-time PCR (qPCR) primers specific for individual BCL2L11 exons and for total BCL2L11 transcripts used were BCL2L11E1-FOR CCATGATTTCCCATTTCTCA, BCL2L11E1-REV GGCTTGTGCTGAAAGAAACA, BCL2L11E2-FOR GCCACTACCACCACTTGATTCTT, BCL2L11E2-REV AACCGAATACCGCGATGATG, BCL2L11-1947F (5'-TGGATATTGTCAGGCCACTTG-3') and BCL2L11-2018R (5'-CATAAGGAGCAGGCACAGAGAA-3'). For normalization of Quantitative real-time PCR, β-actin levels were determined in each sample using the following primers: β-actin-FOR CCTGGCACCCAGCACAAT and β-actin-REV GCCGATCCACACGGAGTACT. Real time quantitative PCR analysis was carried out using an iQ5 cycler machine (Biorad). Reactions were prepared in triplicate using 2× SYBR Green Supermix (Biorad) according to manufacturer's instructions to a final volume sample of 30 μl. The program used was the following: 95°C 3' and 45 cycles at 95°C/30" and 55°C/30". For each experiment, at least 2 independent electrophoresis runs were performed.
Electrophoretic mobility shift assay (EMSA)
HEK293 were plated in 6 well plates and the day after were transfected as describe before using 2.5 μg of E2F plasmid or 2.5 μg of Bluescript plasmid. 24 hrs post-transfection, cells were washed twice with PBS and harvested for nuclear protein extraction according to the method of Osborn et al.  with minor modifications. The protease inhibitors leupeptin (10 μg/ml), antipain (5 μg/ml), and pepstatin (5 μg/ml) and phenylmethylsulfonyl fluoride (1 mM) were added. Protein concentration was measured by the Coomassie assay (Pierce), using BSA as standard protein. Binding reactions were carried out in a final volume of 20 μl using 8–10 μg nuclear extract according to the conditions already specifically described for E2F1 binding site . Radiolabelled probe was added last to each reaction mixture and samples were incubated at room temperature for 30 min. . In a competition assays a 50–100 × fold molar excess of unlabeled double-stranded oligonucleotide was added to the reaction mixture. Samples were then loaded onto a 5% (30:1:2) native polyacrylamide gel in 45 mM Tris Base, 45 mM Sodium borate, 10 mM EDTA ph 8 (0,5 × TBE) and run at 150 V, dried, and exposed to Storage Phosphor Screen (Amersham Biosciences). After overnight exposition, the image was visualized by PhosphorImager SF (Molecular Dynamics, Inc). Double stranded oligonucleotides were synthesized, annealed to complementary synthetic oligonucleotide in vitro and radiolabeled using T4 polynucleotide kinase (Boeheringer) and [γ-32P] labelled ATP (Perkin-Elmer, Inc.). Unincorporated nucleotides were removed by Sephadex G-50 column chromatography . The following pairs of oligonucleotides were employed (E2F sites underlined) E2F-1 P1 5'-AGTTCCCTCTGCGCGCCAGAGG GTG-3'. As cold competitor were used the following oligonucleotids: E2F-1 C+ 5'-ATT TAAGTTTCGCGCCCTTTCTCAA-3', E2F-1 P1 5'-AGTTCCCTCTGCGCGCCAGAGGGTG-3' and NF-κB 5'-AATGTGGGATTTTCCCATG-3'.
We thank, Elena Pecchioli and Raffaello Lorenzini for excellent experimental assistance.
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