Atp2c2 Is Transcribed From a Unique Transcriptional Start Site in Mouse Pancreatic Acinar Cells

Abstract

Proper regulation of cytosolic Ca(2+) is critical for pancreatic acinar cell function. Disruptions in normal Ca(2+) concentrations affect numerous cellular functions and are associated with pancreatitis. Membrane pumps and channels regulate cytosolic Ca(2+) homeostasis by promoting rapid Ca(2+) movement. Determining how expression of Ca(2+) modulators is regulated and the cellular alterations that occur upon changes in expression can provide insight into initiating events of pancreatitis. The goal of this study was to delineate the gene structure and regulation of a novel pancreas-specific isoform for Secretory Pathway Ca(2+) ATPase 2 (termed SPCA2C), which is encoded from the Atp2c2 gene. Using Next Generation Sequencing of RNA (RNA-seq), chromatin immunoprecipitation for epigenetic modifications and promoter-reporter assays, a novel transcriptional start site was identified that promotes expression of a transcript containing the last four exons of the Atp2c2 gene (Atp2c2c). This region was enriched for epigenetic marks and pancreatic transcription factors that promote gene activation. Promoter activity for regions upstream of the ATG codon in Atp2c2's 24th exon was observed in vitro but not in in vivo. Translation from this ATG encodes a protein aligned with the carboxy terminal of SPCA2. Functional analysis in HEK 293A cells indicates a unique role for SPCA2C in increasing cytosolic Ca(2+) . RNA analysis indicates that the decreased Atp2c2c expression observed early in experimental pancreatitis reflects a global molecular response of acinar cells to reduce cytosolic Ca(2+) levels. Combined, these results suggest SPCA2C affects Ca(2+) homeostasis in pancreatic acinar cells in a unique fashion relative to other Ca(2+) ATPases. J. Cell. Physiol. 231: 2768-2778, 2016. © 2016 Wiley Periodicals, Inc.

Genome-wide DNA methylation analysis reveals loci that distinguish different types of adipose tissue in obese individuals

“…The CpG site (cg00838040) was located within a binding site for transcription factor CEBPB, which plays a role in adipogenesis and inflammatory responses (for a review, see [65]). A previously unreported transcript of ATP2C2 , termed ATP2C2c , was recently identified in mice [66]. Transcription of this isoform is initiated in intron 23 and under epigenetic (histone modification) and transcription factor (MIST1) control.…”

“…Transcription of this isoform is initiated in intron 23 and under epigenetic (histone modification) and transcription factor (MIST1) control. Expression of ATP2C2 appeared to be mostly restricted to pancreatic acinar cells in mice, which plays a crucial role in the regulation of Ca 2+ associated with the control of secretion of digestive enzymes [66]. While the intronic location of the transcription start site for ATP2C2c is some 30 kb away from cg00838040 and the CEBPB binding site, it raises the possibility that other, yet to be identified, isoforms of ATP2C2 exist, which may have important tissue-specific functions.…”

Subtype specific targeting of calcium signaling in breast cancer

“…In this context, an alternative transcription start site in the SPCA2 gene has been discovered that encodes a membrane-embedded C-terminal fragment of SPCA2 lacking ATPase-depending pumping activity [55]. This fragment is capable activating Ca 2+ influx although it has not been investigated in breast cancer cells [56]. These results could explain how inappropriate expression of SPCA2 or its splice variants in non-lactation conditions drives Ca 2+ -mediated oncogenesis in receptor positive breast cancers.…”

Integrative single-cell characterization of frugivory adaptations in the bat kidney and pancreas

“…Of note, while we observed some significant differences in gene expression between fasted and fed states in each species (Table S2-3), these were minimal compared to species gene expression differences (Fig. S2A-B) (longer treatments are likely needed for many transcriptional differences between fasted and fed ( 49 )), with the exception of acinar cells, which are known to dominate total mRNA population from the pancreas ( 50 ) and permit rapid exocytosis of enzymes for digestion ( 51 ). Given our small sample sizes for treatment (N=1-2/treatment), we focused on subsequent analyses on species differences (N=3-4/species).…”