Intrinsic function of the peptidylarginine deiminase PADI4 is dispensable for normal haematopoiesis

Christine Young; John R Russell; Louie N van de Lagemaat; Hannah Lawson; Christopher Mapperley; Kamil R Kranc; Maria A Christophorou

doi:10.1242/bio.059143

Intrinsic function of the peptidylarginine deiminase PADI4 is dispensable for normal haematopoiesis

Christine Young, John R Russell, Louie N van de Lagemaat, Hannah Lawson, Christopher Mapperley, Kamil R Kranc^* (Corresponding Author), Maria A Christophorou^* (Corresponding Author)

^*Corresponding author for this work

Applied Medicine

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

2 Citations (Scopus)

Abstract

Peptidylarginine deiminases (PADIs) are strongly associated with the development of autoimmunity, neurodegeneration and cancer but their physiological roles are ill-defined. The nuclear deiminase PADI4 regulates pluripotency in the mammalian pre-implantation embryo but its function in tissue development is unknown. PADI4 is primarily expressed in the bone marrow, as part of a self-renewal-associated gene signature. It has been shown to regulate the proliferation of multipotent haematopoietic progenitors and proposed to impact on the differentiation of haematopoietic stem cells (HSCs), suggesting that it controls haematopoietic development or regeneration. Using conditional in vivo models of steady state and acute Padi4 ablation, we examined the role of PADI4 in the development and function of the haematopoietic system. We found that PADI4 loss does not significantly affect HSC self-renewal or differentiation potential upon injury or serial transplantation, nor does it lead to HSC exhaustion or premature ageing. Thus PADI4 is dispensable for cell-autonomous HSC maintenance, differentiation and haematopoietic regeneration. This work represents the first study of PADI4 in tissue development and indicates that pharmacological PADI4 inhibition may be tolerated without adverse effects.

Original language	English
Article number	bio059143
Number of pages	18
Journal	Open Biology
Volume	11
Issue number	6
Early online date	13 Jun 2022
DOIs	https://doi.org/10.1242/bio.059143
Publication status	Published - 15 Jun 2022

Bibliographical note

We thank the flow cytometry and mouse facilities at the Scottish Centre for Regenerative Medicine. We thank M. Dawson for useful discussions at the conception stage of the project and members of the Christophorou and Kranc labs for critical discussions of the work.

Funding: This work was funded by a Wellcome Trust and Royal Society Sir Henry Dale Fellowship to M.A.C. (grant no. 105642/Z/14/Z). K.R.K.’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. Open Access funding provided by Wellcome Trust and Babraham Institute. Deposited in PMC for immediate release.

Data Availability Statement

Gene expression data were derived from multiple bulk-sequencing datasets from ArrayExpress and NCBI GEO. Each study, identified by accession number, contributed data to multiple populations as follows: E-MTAB-1963 (LSK, CMP); E-MTAB-3079 (LSK, CLP, CMP, GMP); E-MTAB-2262 (HSC, MPP1, MPP2, MPP3, MPP4); GSE116177 (LSK, CLP, CMP, GMP); GSE125846 (HSC, CMP, GMP, MEP).

Keywords

Peptidylarginine deiminase IV (PAD14)
Haemopoietic development
Bone marrow
Differentiation
Regeneration
Ageing

UN SDGs

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

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Cite this

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title = "Intrinsic function of the peptidylarginine deiminase PADI4 is dispensable for normal haematopoiesis",

abstract = "Peptidylarginine deiminases (PADIs) are strongly associated with the development of autoimmunity, neurodegeneration and cancer but their physiological roles are ill-defined. The nuclear deiminase PADI4 regulates pluripotency in the mammalian pre-implantation embryo but its function in tissue development is unknown. PADI4 is primarily expressed in the bone marrow, as part of a self-renewal-associated gene signature. It has been shown to regulate the proliferation of multipotent haematopoietic progenitors and proposed to impact on the differentiation of haematopoietic stem cells (HSCs), suggesting that it controls haematopoietic development or regeneration. Using conditional in vivo models of steady state and acute Padi4 ablation, we examined the role of PADI4 in the development and function of the haematopoietic system. We found that PADI4 loss does not significantly affect HSC self-renewal or differentiation potential upon injury or serial transplantation, nor does it lead to HSC exhaustion or premature ageing. Thus PADI4 is dispensable for cell-autonomous HSC maintenance, differentiation and haematopoietic regeneration. This work represents the first study of PADI4 in tissue development and indicates that pharmacological PADI4 inhibition may be tolerated without adverse effects.",

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author = "Christine Young and Russell, {John R} and {van de Lagemaat}, {Louie N} and Hannah Lawson and Christopher Mapperley and Kranc, {Kamil R} and Christophorou, {Maria A}",

note = "We thank the flow cytometry and mouse facilities at the Scottish Centre for Regenerative Medicine. We thank M. Dawson for useful discussions at the conception stage of the project and members of the Christophorou and Kranc labs for critical discussions of the work. Funding: This work was funded by a Wellcome Trust and Royal Society Sir Henry Dale Fellowship to M.A.C. (grant no. 105642/Z/14/Z). K.R.K.{\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. Open Access funding provided by Wellcome Trust and Babraham Institute. Deposited in PMC for immediate release.",

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AU - Lawson, Hannah

AU - Mapperley, Christopher

AU - Kranc, Kamil R

AU - Christophorou, Maria A

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AB - Peptidylarginine deiminases (PADIs) are strongly associated with the development of autoimmunity, neurodegeneration and cancer but their physiological roles are ill-defined. The nuclear deiminase PADI4 regulates pluripotency in the mammalian pre-implantation embryo but its function in tissue development is unknown. PADI4 is primarily expressed in the bone marrow, as part of a self-renewal-associated gene signature. It has been shown to regulate the proliferation of multipotent haematopoietic progenitors and proposed to impact on the differentiation of haematopoietic stem cells (HSCs), suggesting that it controls haematopoietic development or regeneration. Using conditional in vivo models of steady state and acute Padi4 ablation, we examined the role of PADI4 in the development and function of the haematopoietic system. We found that PADI4 loss does not significantly affect HSC self-renewal or differentiation potential upon injury or serial transplantation, nor does it lead to HSC exhaustion or premature ageing. Thus PADI4 is dispensable for cell-autonomous HSC maintenance, differentiation and haematopoietic regeneration. This work represents the first study of PADI4 in tissue development and indicates that pharmacological PADI4 inhibition may be tolerated without adverse effects.

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KW - Differentiation

KW - Regeneration

KW - Ageing

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M1 - bio059143

ER -

Intrinsic function of the peptidylarginine deiminase PADI4 is dispensable for normal haematopoiesis

Abstract

Bibliographical note

Data Availability Statement

Keywords

UN SDGs

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