The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers

Amalie C. Grenov; Lihee Moss; Sarit Edelheit; Ross Cordiner; Dominik Schmiedel; Adi Biram; Jacob H. Hanna; Torben Heick Jensen; Schraga Schwartz; Ziv Shulman

doi:10.1084/jem.20210360

The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers

Amalie C. Grenov, Lihee Moss, Sarit Edelheit, Ross Cordiner, Dominik Schmiedel, Adi Biram, Jacob H. Hanna, Torben Heick Jensen, Schraga Schwartz, Ziv Shulman^*

^*Corresponding author for this work

Department of Molecular Biology and Genetics - RNA Biology and Innovation

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

Long-lasting immunity depends on the generation of protective antibodies through the germinal center (GC) reaction. N6-methyladenosine (m6A) modification of mRNAs by METTL3 activity modulates transcript lifetime primarily through the function of m6A readers; however, the physiological role of this molecular machinery in the GC remains unknown. Here, we show that m6A modifications by METTL3 are required for GC maintenance through the differential functions of m6A readers. Mettl3-deficient GC B cells exhibited reduced cell-cycle progression and decreased expression of proliferation- and oxidative phosphorylation-related genes. The m6A binder, IGF2BP3, was required for stabilization of Myc mRNA and expression of its target genes, whereas the m6A reader, YTHDF2, indirectly regulated the expression of the oxidative phosphorylation gene program. Our findings demonstrate how two independent gene networks that support critical GC functions are modulated by m6A through distinct mRNA binders.

Original language	English
Article number	e20210360
Journal	The Journal of Experimental Medicine
Volume	218
Issue	10
Number of pages	26
ISSN	0022-1007
DOIs	https://doi.org/10.1084/jem.20210360
Publication status	Published - 17 Aug 2021

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title = "The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers",

abstract = "Long-lasting immunity depends on the generation of protective antibodies through the germinal center (GC) reaction. N6-methyladenosine (m6A) modification of mRNAs by METTL3 activity modulates transcript lifetime primarily through the function of m6A readers; however, the physiological role of this molecular machinery in the GC remains unknown. Here, we show that m6A modifications by METTL3 are required for GC maintenance through the differential functions of m6A readers. Mettl3-deficient GC B cells exhibited reduced cell-cycle progression and decreased expression of proliferation- and oxidative phosphorylation-related genes. The m6A binder, IGF2BP3, was required for stabilization of Myc mRNA and expression of its target genes, whereas the m6A reader, YTHDF2, indirectly regulated the expression of the oxidative phosphorylation gene program. Our findings demonstrate how two independent gene networks that support critical GC functions are modulated by m6A through distinct mRNA binders.",

author = "Grenov, {Amalie C.} and Lihee Moss and Sarit Edelheit and Ross Cordiner and Dominik Schmiedel and Adi Biram and Hanna, {Jacob H.} and Jensen, {Torben Heick} and Schraga Schwartz and Ziv Shulman",

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doi = "10.1084/jem.20210360",

language = "English",

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The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers. / Grenov, Amalie C.; Moss, Lihee; Edelheit, Sarit et al.
In: The Journal of Experimental Medicine, Vol. 218, No. 10, e20210360, 17.08.2021.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers

AU - Grenov, Amalie C.

AU - Moss, Lihee

AU - Edelheit, Sarit

AU - Cordiner, Ross

AU - Schmiedel, Dominik

AU - Biram, Adi

AU - Hanna, Jacob H.

AU - Jensen, Torben Heick

AU - Schwartz, Schraga

AU - Shulman, Ziv

PY - 2021/8/17

Y1 - 2021/8/17

N2 - Long-lasting immunity depends on the generation of protective antibodies through the germinal center (GC) reaction. N6-methyladenosine (m6A) modification of mRNAs by METTL3 activity modulates transcript lifetime primarily through the function of m6A readers; however, the physiological role of this molecular machinery in the GC remains unknown. Here, we show that m6A modifications by METTL3 are required for GC maintenance through the differential functions of m6A readers. Mettl3-deficient GC B cells exhibited reduced cell-cycle progression and decreased expression of proliferation- and oxidative phosphorylation-related genes. The m6A binder, IGF2BP3, was required for stabilization of Myc mRNA and expression of its target genes, whereas the m6A reader, YTHDF2, indirectly regulated the expression of the oxidative phosphorylation gene program. Our findings demonstrate how two independent gene networks that support critical GC functions are modulated by m6A through distinct mRNA binders.

AB - Long-lasting immunity depends on the generation of protective antibodies through the germinal center (GC) reaction. N6-methyladenosine (m6A) modification of mRNAs by METTL3 activity modulates transcript lifetime primarily through the function of m6A readers; however, the physiological role of this molecular machinery in the GC remains unknown. Here, we show that m6A modifications by METTL3 are required for GC maintenance through the differential functions of m6A readers. Mettl3-deficient GC B cells exhibited reduced cell-cycle progression and decreased expression of proliferation- and oxidative phosphorylation-related genes. The m6A binder, IGF2BP3, was required for stabilization of Myc mRNA and expression of its target genes, whereas the m6A reader, YTHDF2, indirectly regulated the expression of the oxidative phosphorylation gene program. Our findings demonstrate how two independent gene networks that support critical GC functions are modulated by m6A through distinct mRNA binders.

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JO - The Journal of Experimental Medicine

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The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers

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