期刊
CELL REPORTS
卷 37, 期 5, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109910
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资金
- UTMB Department of Biochemistry and Molecular Biology Bridging funds
- National Institutes of Health/National Heart Lung Blood Institute [1R01HL135031]
- UTMB John Sealy Memorial Endowment Pilot Award
- American Heart Association [18POST 3399018, 20TPA35490206, 2021AHA000DIVSUP0211476]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01AI136031]
- UTMB
- National Institutes of Health [R03CA223893]
The study uncovered a role for RBFOX2 in maintaining alternative polyadenylation signatures in myoblasts, influencing the mRNA levels and isoform expression of various genes, including those related to mitochondria and muscle contraction. Depletion of RBFOX2 negatively impacted mitochondrial health in myoblasts, particularly through disruption of APA in the Slc25a4 gene.
RBFOX2, which has a well-established role in alternative splicing, is linked to heart diseases. However, it is unclear whether RBFOX2 has other roles in RNA processing that can influence gene expression in muscle cells, contributing to heart disease. Here, we employ both 3MODIFIER LETTER PRIME-end and nanopore cDNA sequencing to reveal a previously unrecognized role for RBFOX2 in maintaining alternative polyadenylation (APA) signatures in myoblasts. RBFOX2-mediated APA modulates mRNA levels and/or isoform expression of a collection of genes, including contractile and mitochondrial genes. Depletion of RBFOX2 adversely affects mitochondrial health in myoblasts, correlating with disrupted APA of mitochondrial gene Slc25a4. Mechanistically, RBFOX2 regulation of Slc25a4 APA is mediated through consensus RBFOX2 binding motifs near the distal polyadenylation site, enforcing the use of the proximal polyadenylation site. In sum, our results unveil a role for RBFOX2 in fine-tuning expression of mitochondrial and contractile genes via APA in myoblasts relevant to heart diseases.
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