N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis

Daniel A. Kuppers; Sonali Arora; Yiting Lim; Andrea R. Lim; Lucas M. Carter; Philip D. Corrin; Christopher L. Plaisier; Ryan Basom; Jeffrey J. Delrow; Shiyan Wang; Housheng Hansen He; Beverly Torok-Storb; Andrew C. Hsieh; Patrick J. Paddison

doi:10.1038/s41467-019-12518-6

N⁶-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis

Daniel A. Kuppers, Sonali Arora, Yiting Lim, Andrea R. Lim, Lucas M. Carter, Philip D. Corrin, Christopher L. Plaisier, Ryan Basom, Jeffrey J. Delrow, Shiyan Wang, Housheng Hansen He, Beverly Torok-Storb, Andrew C. Hsieh, Patrick J. Paddison

Engineering, Ira A. Fulton Schools of (IAFSE)

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

41 Scopus citations

Abstract

Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N⁶-methyladenosine (m⁶A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m⁶A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m⁶A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m⁶A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m⁶A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m⁶A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

Original language	English (US)
Article number	4596
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12518-6
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Kuppers, D. A., Arora, S., Lim, Y., Lim, A. R., Carter, L. M., Corrin, P. D., Plaisier, C. L., Basom, R., Delrow, J. J., Wang, S., Hansen He, H., Torok-Storb, B., Hsieh, A. C., & Paddison, P. J. (2019). N⁶-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis. Nature communications, 10(1), Article 4596. https://doi.org/10.1038/s41467-019-12518-6

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abstract = "Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m6A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m6A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.",

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AU - Carter, Lucas M.

AU - Corrin, Philip D.

AU - Plaisier, Christopher L.

AU - Basom, Ryan

AU - Delrow, Jeffrey J.

AU - Wang, Shiyan

AU - Hansen He, Housheng

AU - Torok-Storb, Beverly

AU - Hsieh, Andrew C.

AU - Paddison, Patrick J.

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N2 - Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m6A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m6A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

AB - Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m6A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m6A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

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N⁶-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis

Abstract

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