PARP1 Regulates Circular RNA Biogenesis though Control of Transcriptional Dynamics

Author:

Eleazer Rebekah12,De Silva Kalpani34,Andreeva Kalina34,Jenkins Zoe1,Osmani Nour2,Rouchka Eric C.45ORCID,Fondufe-Mittendorf Yvonne2ORCID

Affiliation:

1. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA

2. Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA

3. Department of Neuroscience Training, University of Louisville, Louisville, KY 40292, USA

4. Kentucky IDeA Networks of Biomedical Research Excellence Bioinformatics Core, University of Louisville, Louisville, KY 40292, USA

5. Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA

Abstract

Circular RNAs (circRNAs) are a recently discovered class of RNAs derived from protein-coding genes that have important biological and pathological roles. They are formed through backsplicing during co-transcriptional alternative splicing; however, the unified mechanism that accounts for backsplicing decisions remains unclear. Factors that regulate the transcriptional timing and spatial organization of pre-mRNA, including RNAPII kinetics, the availability of splicing factors, and features of gene architecture, have been shown to influence backsplicing decisions. Poly (ADP-ribose) polymerase I (PARP1) regulates alternative splicing through both its presence on chromatin as well as its PARylation activity. However, no studies have investigated PARP1’s possible role in regulating circRNA biogenesis. Here, we hypothesized that PARP1’s role in splicing extends to circRNA biogenesis. Our results identify many unique circRNAs in PARP1 depletion and PARylation-inhibited conditions compared to the wild type. We found that while all genes producing circRNAs share gene architecture features common to circRNA host genes, genes producing circRNAs in PARP1 knockdown conditions had longer upstream introns than downstream introns, whereas flanking introns in wild type host genes were symmetrical. Interestingly, we found that the behavior of PARP1 in regulating RNAPII pausing is distinct between these two classes of host genes. We conclude that the PARP1 pausing of RNAPII works within the context of gene architecture to regulate transcriptional kinetics, and therefore circRNA biogenesis. Furthermore, this regulation of PARP1 within host genes acts to fine tune their transcriptional output with implications in gene function.

Funder

National Science Foundation

National Institutes of Health

Publisher

MDPI AG

Subject

General Medicine

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