Alternative splicing yields novel BMAL2 variants: tissue distribution and functional characterization.
The BMAL2 gene encodes a member of the basic helix-loop-helix PER-ARNT-SIM family of transcription factors, which control diverse physiological processes including circadian rhythms. We identified four novel human BMAL2 transcripts that differ by alternative splicing within their NH2-terminal regions. Divergent expression of these and previously reported transcripts was observed among human tissues. The functional consequences of alternative splicing for transcriptional activation by CLOCK:BMAL2 heterodimers were assessed using luciferase reporter gene constructs that contained one of three diurnally regulated promoters, namely, those of the mouse period1, mouse vasopressin, and human plasminogen activator inhibitor-1 genes. These studies revealed that alternative splicing generates BMAL2 isoforms possessing high, medium, low, or no transcriptional activity. Similar results were obtained with each promoter, suggesting that alternative splicing may influence the amplitudes of both central and peripheral oscillators. Indeed, alternative splicing of BMAL2 may provide tissues with a rheostat capable of regulating CLOCK:BMAL2 heterodimer function across a broad continuum of potential transcriptional activities to accommodate varied metabolic demands and physiological roles.
Schoenhard
John A
JA
Division of Cardiovascular Medicine, Departments of Medicine and Pharmacology, Vanderbilt University, Tennessee 37235, USA.
Eren
Mesut
M
Johnson
Carl H
CH
Vaughan
Douglas E
DE
D056930:ARNTL Transcription Factors; D017398:Alternative Splicing; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D002417:Cattle; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000502:physiology; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins / Q000494:pharmacology; D017353:Gene Deletion; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics; D056950:Period Circadian Proteins; D017956:Photoreceptor Cells, Invertebrate; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D015849:Plasminogen Inactivators / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D015533:Transcriptional Activation
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D056950:Period Circadian Proteins; D017395:Plasminogen Activator Inhibitor 1; D015849:Plasminogen Inactivators; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D014157:Transcription Factors; C486615:BMAL2 protein, human; C431792:Arntl2 protein, mouse; C539022:PER1 protein, human; C421902:PER2 protein, human; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; C119828:cry protein, Drosophila; C538943:CLOCK protein, human; C538944:Clock protein, mouse