RBFOX2 is critical for maintaining alternative polyadenylation patterns and mitochondrial health in rat myoblasts

Jun Cao; Sunil K. Verma; Elizabeth Jaworski; Stephanie Mohan; Chloe K. Nagasawa; Kempaiah Rayavara; Amanda Sooter; Sierra N. Miller; Richard J. Holcomb; Mason J. Powell; Ping Ji; Nathan D. Elrod; Eda Yildirim; Eric J. Wagner; Vsevolod Popov; Nisha J. Garg; Andrew L. Routh; Muge N. Kuyumcu-Martinez

doi:10.1016/j.celrep.2021.109910

RBFOX2 is critical for maintaining alternative polyadenylation patterns and mitochondrial health in rat myoblasts

Jun Cao, Sunil K. Verma, Elizabeth Jaworski, Stephanie Mohan, Chloe K. Nagasawa, Kempaiah Rayavara, Amanda Sooter, Sierra N. Miller, Richard J. Holcomb, Mason J. Powell, Ping Ji, Nathan D. Elrod, Eda Yildirim, Eric J. Wagner, Vsevolod Popov, Nisha J. Garg, Andrew L. Routh, Muge N. Kuyumcu-Martinez

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

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 3ʹ-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.

Original language	English (US)
Article number	109910
Journal	Cell Reports
Volume	37
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2021.109910
State	Published - Nov 2 2021

Keywords

RBFOX2
Slc25a4
Tropomyosin 1
alternative polyadenylation
mitochondria
nanopore sequencing
poly(A) sequencing

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2021.109910

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Cao, J., Verma, S. K., Jaworski, E., Mohan, S., Nagasawa, C. K., Rayavara, K., Sooter, A., Miller, S. N., Holcomb, R. J., Powell, M. J., Ji, P., Elrod, N. D., Yildirim, E., Wagner, E. J., Popov, V., Garg, N. J., Routh, A. L., & Kuyumcu-Martinez, M. N. (2021). RBFOX2 is critical for maintaining alternative polyadenylation patterns and mitochondrial health in rat myoblasts. Cell Reports, 37(5), Article 109910. https://doi.org/10.1016/j.celrep.2021.109910

Cao, J, Verma, SK, Jaworski, E, Mohan, S, Nagasawa, CK, Rayavara, K, Sooter, A, Miller, SN, Holcomb, RJ, Powell, MJ, Ji, P, Elrod, ND, Yildirim, E, Wagner, EJ, Popov, V , Garg, NJ, Routh, AL & Kuyumcu-Martinez, MN 2021, 'RBFOX2 is critical for maintaining alternative polyadenylation patterns and mitochondrial health in rat myoblasts', Cell Reports, vol. 37, no. 5, 109910. https://doi.org/10.1016/j.celrep.2021.109910

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title = "RBFOX2 is critical for maintaining alternative polyadenylation patterns and mitochondrial health in rat myoblasts",

abstract = "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 3ʹ-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.",

keywords = "RBFOX2, Slc25a4, Tropomyosin 1, alternative polyadenylation, mitochondria, nanopore sequencing, poly(A) sequencing",

author = "Jun Cao and Verma, {Sunil K.} and Elizabeth Jaworski and Stephanie Mohan and Nagasawa, {Chloe K.} and Kempaiah Rayavara and Amanda Sooter and Miller, {Sierra N.} and Holcomb, {Richard J.} and Powell, {Mason J.} and Ping Ji and Elrod, {Nathan D.} and Eda Yildirim and Wagner, {Eric J.} and Vsevolod Popov and Garg, {Nisha J.} and Routh, {Andrew L.} and Kuyumcu-Martinez, {Muge N.}",

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year = "2021",

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doi = "10.1016/j.celrep.2021.109910",

language = "English (US)",

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T1 - RBFOX2 is critical for maintaining alternative polyadenylation patterns and mitochondrial health in rat myoblasts

AU - Cao, Jun

AU - Verma, Sunil K.

AU - Jaworski, Elizabeth

AU - Mohan, Stephanie

AU - Nagasawa, Chloe K.

AU - Rayavara, Kempaiah

AU - Sooter, Amanda

AU - Miller, Sierra N.

AU - Holcomb, Richard J.

AU - Powell, Mason J.

AU - Ji, Ping

AU - Elrod, Nathan D.

AU - Yildirim, Eda

AU - Wagner, Eric J.

AU - Popov, Vsevolod

AU - Garg, Nisha J.

AU - Routh, Andrew L.

AU - Kuyumcu-Martinez, Muge N.

PY - 2021/11/2

Y1 - 2021/11/2

N2 - 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 3ʹ-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.

AB - 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 3ʹ-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.

KW - RBFOX2

KW - Slc25a4

KW - Tropomyosin 1

KW - alternative polyadenylation

KW - mitochondria

KW - nanopore sequencing

KW - poly(A) sequencing

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RBFOX2 is critical for maintaining alternative polyadenylation patterns and mitochondrial health in rat myoblasts

Abstract

Keywords

ASJC Scopus subject areas

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