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^* (Corresponding Author), Kamil R Kranc^* (Corresponding Author)

^*Corresponding author for this work

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

88 Citations (Scopus)

Abstract

The mRNA N6-methyladenosine (m6A) 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	English
Article number	e20200829
Number of pages	15
Journal	Journal of Experimental Medicine
Volume	218
Issue number	3
Early online date	6 Nov 2020
DOIs	https://doi.org/10.1084/jem.20200829
Publication status	Published - 1 Mar 2021
Externally published	Yes

Bibliographical note

K.R. Kranc’s laboratory is funded by a Cancer Research UK program grant (C29967/A26787) and project grants from the Medical Research Council, Blood Cancer UK, Barts Charity, and the Kay Kendall Leukaemia Fund. This research was supported by Wellcome Trust funding to D. O’Carroll (106144) and the Wellcome Centre for Cell Biology (203149). Part of this work was carried out in the framework of the European Cooperation in Science and Technology EPITRAN CA16120. C. Mapperley is funded by a Wellcome Trust PhD studentship (108906/Z/15/Z).

Data Availability Statement

Online supplemental material

Keywords

Adenosine/analogs & derivatives
Animals
Cell Lineage
Cell Proliferation
Cellular Senescence
Gene Deletion
Hematopoiesis
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells/metabolism
Inflammation/genetics
Lymphocytes/metabolism
Mice, Inbred C57BL
Myeloid Cells/metabolism
RNA, Messenger/genetics
RNA-Binding Proteins/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1084/jem.20200829Licence: CC BY

Mapperley_etal_JEM_The_mRNA_m6A_VOR
© 2020 Mapperley et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/ by/4.0/).
Final published version, 4.7 MBLicence: CC BY

Cite this

Mapperley, C., van de Lagemaat, L. N., Lawson, H., Tavosanis, A., Paris, J., Campos, J., Wotherspoon, D., Durko, J., Sarapuu, A., Choe, J., Ivanova, I., Krause, D. S., von Kriegsheim, A., 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, 218(3), Article e20200829. https://doi.org/10.1084/jem.20200829

Mapperley, C, van de Lagemaat, LN, Lawson, H, Tavosanis, A, Paris, J, Campos, J, Wotherspoon, D, Durko, J, Sarapuu, A, Choe, J, Ivanova, I, Krause, DS, von Kriegsheim, A, 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, vol. 218, no. 3, e20200829. https://doi.org/10.1084/jem.20200829

@article{eea6eaf456944c1ba844a4793fdf4e1d,

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

abstract = "The mRNA N6-methyladenosine (m6A) 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.",

keywords = "Adenosine/analogs & derivatives, Animals, Cell Lineage, Cell Proliferation, Cellular Senescence, Gene Deletion, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells/metabolism, Inflammation/genetics, Lymphocytes/metabolism, Mice, Inbred C57BL, Myeloid Cells/metabolism, RNA, Messenger/genetics, RNA-Binding Proteins/metabolism",

author = "Christopher Mapperley and {van de Lagemaat}, {Louie N} 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 {von Kriegsheim}, Alex and Christian Much and Marcos Morgan and Gregory, {Richard I} and Mead, {Adam J} and D{\'o}nal O'Carroll and Kranc, {Kamil R}",

note = "K.R. Kranc{\textquoteright}s laboratory is funded by a Cancer Research UK program grant (C29967/A26787) and project grants from the Medical Research Council, Blood Cancer UK, Barts Charity, and the Kay Kendall Leukaemia Fund. This research was supported by Wellcome Trust funding to D. O{\textquoteright}Carroll (106144) and the Wellcome Centre for Cell Biology (203149). Part of this work was carried out in the framework of the European Cooperation in Science and Technology EPITRAN CA16120. C. Mapperley is funded by a Wellcome Trust PhD studentship (108906/Z/15/Z). ",

year = "2021",

month = mar,

day = "1",

doi = "10.1084/jem.20200829",

language = "English",

volume = "218",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "3",

}

TY - JOUR

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

AU - Mapperley, Christopher

AU - van de Lagemaat, Louie N

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 - von Kriegsheim, Alex

AU - Much, Christian

AU - Morgan, Marcos

AU - Gregory, Richard I

AU - Mead, Adam J

AU - O'Carroll, Dónal

AU - Kranc, Kamil R

N1 - K.R. Kranc’s laboratory is funded by a Cancer Research UK program grant (C29967/A26787) and project grants from the Medical Research Council, Blood Cancer UK, Barts Charity, and the Kay Kendall Leukaemia Fund. This research was supported by Wellcome Trust funding to D. O’Carroll (106144) and the Wellcome Centre for Cell Biology (203149). Part of this work was carried out in the framework of the European Cooperation in Science and Technology EPITRAN CA16120. C. Mapperley is funded by a Wellcome Trust PhD studentship (108906/Z/15/Z).

PY - 2021/3/1

Y1 - 2021/3/1

N2 - The mRNA N6-methyladenosine (m6A) 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 (m6A) 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.

KW - Adenosine/analogs & derivatives

KW - Animals

KW - Cell Lineage

KW - Cell Proliferation

KW - Cellular Senescence

KW - Gene Deletion

KW - Hematopoiesis

KW - Hematopoietic Stem Cell Transplantation

KW - Hematopoietic Stem Cells/metabolism

KW - Inflammation/genetics

KW - Lymphocytes/metabolism

KW - Mice, Inbred C57BL

KW - Myeloid Cells/metabolism

KW - RNA, Messenger/genetics

KW - RNA-Binding Proteins/metabolism

U2 - 10.1084/jem.20200829

DO - 10.1084/jem.20200829

M3 - Article

C2 - 33156926

SN - 0022-1007

VL - 218

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 3

M1 - e20200829

ER -

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

Abstract

Bibliographical note

Data Availability Statement

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this