The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

Christopher Mapperley; Louie N. van de Lagemaat; Hannah Lawson; Andrea Tavosanis; Jasmin Paris; Joana Campos; David Wotherspoon; Jozef Durko; Annika Sarapuu; Junho Choe; Ivayla Ivanova; Daniela S. Krause; Alex von Kriegsheim; Christian Much; Marcos Morgan; Richard I. Gregory; Adam J. Mead; Dónal O’Carroll; Kamil R. Kranc

doi:10.1084/jem.20200829

The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

Christopher Mapperley, Louie N. van de Lagemaat, Hannah Lawson, Andrea Tavosanis, Jasmin Paris, Joana Campos, David Wotherspoon, Jozef Durko, Annika Sarapuu, Junho Choe, Ivayla Ivanova, Daniela S. Krause, Alex von Kriegsheim, Christian Much, Marcos Morgan, Richard I. Gregory, Adam J. Mead, Dónal O’Carroll, Kamil R. Kranc

Research output: Contribution to journal › Review article › peer-review

Abstract

The mRNA N6 -methyladenosine (m6 A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis.
Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance.

Original language	Undefined/Unknown
Journal	Journal of Experimental Medicine
Early online date	6 Nov 2020
DOIs	https://doi.org/10.1084/jem.20200829
Publication status	Published - 1 Mar 2021

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10.1084/jem.20200829

jem_20200829Final published version, 4.72 MBLicence: Creative Commons: Attribution (CC-BY)

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Mapperley, C., Lagemaat, L. N. V. D., Lawson, H., Tavosanis, A., Paris, J., Campos, J., Wotherspoon, D., Durko, J., Sarapuu, A., Choe, J., Ivanova, I., Krause, D. S., Kriegsheim, A. V., Much, C., Morgan, M., Gregory, R. I., Mead, A. J., O’Carroll, D., & Kranc, K. R. (2021). The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20200829

@article{9b221e1f9c0f4559b6ec0705dd794f5c,

title = "The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function",

abstract = "The mRNA N6 -methyladenosine (m6 A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance.",

author = "Christopher Mapperley and Lagemaat, \{Louie N. van de\} and Hannah Lawson and Andrea Tavosanis and Jasmin Paris and Joana Campos and David Wotherspoon and Jozef Durko and Annika Sarapuu and Junho Choe and Ivayla Ivanova and Krause, \{Daniela S.\} and Kriegsheim, \{Alex von\} and Christian Much and Marcos Morgan and Gregory, \{Richard I.\} and Mead, \{Adam J.\} and D{\'o}nal O{\textquoteright}Carroll and Kranc, \{Kamil R.\}",

year = "2021",

month = mar,

day = "1",

doi = "10.1084/jem.20200829",

language = "Undefined/Unknown",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

}

Mapperley, C, Lagemaat, LNVD, Lawson, H, Tavosanis, A, Paris, J, Campos, J, Wotherspoon, D, Durko, J, Sarapuu, A, Choe, J, Ivanova, I, Krause, DS, Kriegsheim, AV, Much, C, Morgan, M, Gregory, RI, Mead, AJ, O’Carroll, D & Kranc, KR 2021, 'The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function', Journal of Experimental Medicine. https://doi.org/10.1084/jem.20200829

TY - JOUR

T1 - The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

AU - Mapperley, Christopher

AU - Lagemaat, Louie N. van de

AU - Lawson, Hannah

AU - Tavosanis, Andrea

AU - Paris, Jasmin

AU - Campos, Joana

AU - Wotherspoon, David

AU - Durko, Jozef

AU - Sarapuu, Annika

AU - Choe, Junho

AU - Ivanova, Ivayla

AU - Krause, Daniela S.

AU - Kriegsheim, Alex von

AU - Much, Christian

AU - Morgan, Marcos

AU - Gregory, Richard I.

AU - Mead, Adam J.

AU - O’Carroll, Dónal

AU - Kranc, Kamil R.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - The mRNA N6 -methyladenosine (m6 A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance.

AB - The mRNA N6 -methyladenosine (m6 A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance.

U2 - 10.1084/jem.20200829

DO - 10.1084/jem.20200829

M3 - Review article

SN - 0022-1007

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

ER -

The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

Abstract

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Equipment

Institute for Genetics and Cancer Mass Spectrometry Facility

IRR Flow Cytometry Facility

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