Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants

Michelle L. Krishnan; Juliette Van Steenwinckel; Anne-laure Schang; Jun Yan; Johanna Arnadottir; Tifenn Le Charpentier; Zsolt Csaba; Pascal Dournaud; Sara Cipriani; Constance Auvynet; Luigi Titomanlio; Julien Pansiot; Gareth Ball; James P. Boardman; Andrew J. Walley; Alka Saxena; Ghazala Mirza; Bobbi Fleiss; A. David Edwards; Enrico Petretto; Pierre Gressens

doi:10.1038/s41467-017-00422-w

Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants

Michelle L. Krishnan, Juliette Van Steenwinckel, Anne-laure Schang, Jun Yan, Johanna Arnadottir, Tifenn Le Charpentier, Zsolt Csaba, Pascal Dournaud, Sara Cipriani, Constance Auvynet, Luigi Titomanlio, Julien Pansiot, Gareth Ball, James P. Boardman, Andrew J. Walley, Alka Saxena, Ghazala Mirza, Bobbi Fleiss, A. David Edwards, Enrico PetrettoPierre Gressens

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Abstract

Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1β administration, we undertake gene network analysis of the microglial transcriptomic response to injury, extend this by analysis of protein-protein interactions, transcription factors and human brain gene expression, and translate findings to living infants using imaging genomics. We show that DLG4 (PSD95) protein is synthesised by microglia in immature mouse and human, developmentally regulated, and modulated by inflammation; DLG4 is a hub protein in the microglial inflammatory response; and genetic variation in DLG4 is associated with structural differences in the preterm infant brain. DLG4 is thus apparently involved in brain development and impacts inter-individual susceptibility to injury after preterm birth.

Original language	English
Journal	Nature Communications
Volume	8
Issue number	1
Early online date	5 Sept 2017
DOIs	https://doi.org/10.1038/s41467-017-00422-w
Publication status	Published - 1 Dec 2017

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Integrative genomics of microglia_KRISHNAN_Publishedonline5September2017_GOLD VoR (CC BY)Final published version, 1.98 MBLicence: CC BY

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Krishnan, M. L., Van Steenwinckel, J., Schang, A., Yan, J., Arnadottir, J., Le Charpentier, T., Csaba, Z., Dournaud, P., Cipriani, S., Auvynet, C., Titomanlio, L., Pansiot, J., Ball, G., Boardman, J. P., Walley, A. J., Saxena, A., Mirza, G., Fleiss, B., Edwards, A. D., ... Gressens, P. (2017). Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants. Nature Communications, 8(1). https://doi.org/10.1038/s41467-017-00422-w

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title = "Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants",

abstract = "Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1β administration, we undertake gene network analysis of the microglial transcriptomic response to injury, extend this by analysis of protein-protein interactions, transcription factors and human brain gene expression, and translate findings to living infants using imaging genomics. We show that DLG4 (PSD95) protein is synthesised by microglia in immature mouse and human, developmentally regulated, and modulated by inflammation; DLG4 is a hub protein in the microglial inflammatory response; and genetic variation in DLG4 is associated with structural differences in the preterm infant brain. DLG4 is thus apparently involved in brain development and impacts inter-individual susceptibility to injury after preterm birth.",

author = "Krishnan, {Michelle L.} and {Van Steenwinckel}, Juliette and Anne-laure Schang and Jun Yan and Johanna Arnadottir and {Le Charpentier}, Tifenn and Zsolt Csaba and Pascal Dournaud and Sara Cipriani and Constance Auvynet and Luigi Titomanlio and Julien Pansiot and Gareth Ball and Boardman, {James P.} and Walley, {Andrew J.} and Alka Saxena and Ghazala Mirza and Bobbi Fleiss and Edwards, {A. David} and Enrico Petretto and Pierre Gressens",

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doi = "10.1038/s41467-017-00422-w",

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Krishnan, ML, Van Steenwinckel, J, Schang, A, Yan, J, Arnadottir, J, Le Charpentier, T, Csaba, Z, Dournaud, P, Cipriani, S, Auvynet, C, Titomanlio, L, Pansiot, J, Ball, G, Boardman, JP, Walley, AJ, Saxena, A, Mirza, G , Fleiss, B , Edwards, AD, Petretto, E & Gressens, P 2017, 'Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants', Nature Communications, vol. 8, no. 1. https://doi.org/10.1038/s41467-017-00422-w

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T1 - Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants

AU - Krishnan, Michelle L.

AU - Van Steenwinckel, Juliette

AU - Schang, Anne-laure

AU - Yan, Jun

AU - Arnadottir, Johanna

AU - Le Charpentier, Tifenn

AU - Csaba, Zsolt

AU - Dournaud, Pascal

AU - Cipriani, Sara

AU - Auvynet, Constance

AU - Titomanlio, Luigi

AU - Pansiot, Julien

AU - Ball, Gareth

AU - Boardman, James P.

AU - Walley, Andrew J.

AU - Saxena, Alka

AU - Mirza, Ghazala

AU - Fleiss, Bobbi

AU - Edwards, A. David

AU - Petretto, Enrico

AU - Gressens, Pierre

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1β administration, we undertake gene network analysis of the microglial transcriptomic response to injury, extend this by analysis of protein-protein interactions, transcription factors and human brain gene expression, and translate findings to living infants using imaging genomics. We show that DLG4 (PSD95) protein is synthesised by microglia in immature mouse and human, developmentally regulated, and modulated by inflammation; DLG4 is a hub protein in the microglial inflammatory response; and genetic variation in DLG4 is associated with structural differences in the preterm infant brain. DLG4 is thus apparently involved in brain development and impacts inter-individual susceptibility to injury after preterm birth.

AB - Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1β administration, we undertake gene network analysis of the microglial transcriptomic response to injury, extend this by analysis of protein-protein interactions, transcription factors and human brain gene expression, and translate findings to living infants using imaging genomics. We show that DLG4 (PSD95) protein is synthesised by microglia in immature mouse and human, developmentally regulated, and modulated by inflammation; DLG4 is a hub protein in the microglial inflammatory response; and genetic variation in DLG4 is associated with structural differences in the preterm infant brain. DLG4 is thus apparently involved in brain development and impacts inter-individual susceptibility to injury after preterm birth.

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DO - 10.1038/s41467-017-00422-w

M3 - Article

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants

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