CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Aurélie de Thonel; Johanna K Ahlskog; Kevin Daupin; Véronique Dubreuil; Jérémy Berthelet; Carole Chaput; Geoffrey Pires; Camille Leonetti; Ryma Abane; Lluís Cordón Barris; Isabelle Leray; Anna L Aalto; Sarah Naceri; Marine Cordonnier; Carène Benasolo; Matthieu Sanial; Agathe Duchateau; Anniina Vihervaara; Mikael C Puustinen; Federico Miozzo; Patricia Fergelot; Élise Lebigot; Alain Verloes; Pierre Gressens; Didier Lacombe; Jessica Gobbo; Carmen Garrido; Sandy D Westerheide; Laurent David; Michel Petitjean; Olivier Taboureau; Fernando Rodrigues-Lima; Sandrine Passemard; Délara Sabéran-Djoneidi; Laurent Nguyen; Madeline Lancaster; Lea Sistonen; Valérie Mezger

doi:10.1038/s41467-022-34476-2

CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Aurélie de Thonel, Johanna K Ahlskog, Kevin Daupin, Véronique Dubreuil, Jérémy Berthelet, Carole Chaput, Geoffrey Pires, Camille Leonetti, Ryma Abane, Lluís Cordón Barris, Isabelle Leray, Anna L Aalto, Sarah Naceri, Marine Cordonnier, Carène Benasolo, Matthieu Sanial, Agathe Duchateau, Anniina Vihervaara, Mikael C Puustinen, Federico MiozzoPatricia Fergelot, Élise Lebigot, Alain Verloes, Pierre Gressens, Didier Lacombe, Jessica Gobbo, Carmen Garrido, Sandy D Westerheide, Laurent David, Michel Petitjean, Olivier Taboureau, Fernando Rodrigues-Lima, Sandrine Passemard, Délara Sabéran-Djoneidi, Laurent Nguyen, Madeline Lancaster, Lea Sistonen, Valérie Mezger

Biochemistry and Cell Biology

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Abstract

Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.

Original language	English
Article number	7002
Number of pages	21
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34476-2
Publication status	Published - 16 Nov 2022
MoE publication type	A1 Journal article-refereed

Keywords

Humans
CREB-Binding Protein/genetics
Heat-Shock Proteins/genetics
Histones/genetics
Mutation
Neurodevelopmental Disorders/genetics
Rubinstein-Taybi Syndrome/genetics
Transcription Factors/genetics
E1A-Associated p300 Protein/genetics

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10.1038/s41467-022-34476-2

s41467-022-34476-2Final published version, 9.28 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe202301235081

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de Thonel, A., Ahlskog, J. K., Daupin, K., Dubreuil, V., Berthelet, J., Chaput, C., Pires, G., Leonetti, C., Abane, R., Barris, L. C., Leray, I., Aalto, A. L., Naceri, S., Cordonnier, M., Benasolo, C., Sanial, M., Duchateau, A., Vihervaara, A., Puustinen, M. C., ... Mezger, V. (2022). CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder. Nature Communications, 13(1), Article 7002. https://doi.org/10.1038/s41467-022-34476-2

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title = "CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder",

abstract = "Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.",

keywords = "Humans, CREB-Binding Protein/genetics, Heat-Shock Proteins/genetics, Histones/genetics, Mutation, Neurodevelopmental Disorders/genetics, Rubinstein-Taybi Syndrome/genetics, Transcription Factors/genetics, E1A-Associated p300 Protein/genetics",

author = "{de Thonel}, Aur{\'e}lie and Ahlskog, {Johanna K} and Kevin Daupin and V{\'e}ronique Dubreuil and J{\'e}r{\'e}my Berthelet and Carole Chaput and Geoffrey Pires and Camille Leonetti and Ryma Abane and Barris, {Llu{\'i}s Cord{\'o}n} and Isabelle Leray and Aalto, {Anna L} and Sarah Naceri and Marine Cordonnier and Car{\`e}ne Benasolo and Matthieu Sanial and Agathe Duchateau and Anniina Vihervaara and Puustinen, {Mikael C} and Federico Miozzo and Patricia Fergelot and {\'E}lise Lebigot and Alain Verloes and Pierre Gressens and Didier Lacombe and Jessica Gobbo and Carmen Garrido and Westerheide, {Sandy D} and Laurent David and Michel Petitjean and Olivier Taboureau and Fernando Rodrigues-Lima and Sandrine Passemard and D{\'e}lara Sab{\'e}ran-Djoneidi and Laurent Nguyen and Madeline Lancaster and Lea Sistonen and Val{\'e}rie Mezger",

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year = "2022",

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doi = "10.1038/s41467-022-34476-2",

language = "English",

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journal = "Nature Communications",

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de Thonel, A, Ahlskog, JK, Daupin, K, Dubreuil, V, Berthelet, J, Chaput, C, Pires, G, Leonetti, C, Abane, R, Barris, LC, Leray, I, Aalto, AL, Naceri, S, Cordonnier, M, Benasolo, C, Sanial, M, Duchateau, A, Vihervaara, A, Puustinen, MC, Miozzo, F, Fergelot, P, Lebigot, É, Verloes, A, Gressens, P, Lacombe, D, Gobbo, J, Garrido, C, Westerheide, SD, David, L, Petitjean, M, Taboureau, O, Rodrigues-Lima, F, Passemard, S, Sabéran-Djoneidi, D, Nguyen, L, Lancaster, M, Sistonen, L & Mezger, V 2022, 'CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder', Nature Communications, vol. 13, no. 1, 7002. https://doi.org/10.1038/s41467-022-34476-2

TY - JOUR

T1 - CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

AU - de Thonel, Aurélie

AU - Ahlskog, Johanna K

AU - Daupin, Kevin

AU - Dubreuil, Véronique

AU - Berthelet, Jérémy

AU - Chaput, Carole

AU - Pires, Geoffrey

AU - Leonetti, Camille

AU - Abane, Ryma

AU - Barris, Lluís Cordón

AU - Leray, Isabelle

AU - Aalto, Anna L

AU - Naceri, Sarah

AU - Cordonnier, Marine

AU - Benasolo, Carène

AU - Sanial, Matthieu

AU - Duchateau, Agathe

AU - Vihervaara, Anniina

AU - Puustinen, Mikael C

AU - Miozzo, Federico

AU - Fergelot, Patricia

AU - Lebigot, Élise

AU - Verloes, Alain

AU - Gressens, Pierre

AU - Lacombe, Didier

AU - Gobbo, Jessica

AU - Garrido, Carmen

AU - Westerheide, Sandy D

AU - David, Laurent

AU - Petitjean, Michel

AU - Taboureau, Olivier

AU - Rodrigues-Lima, Fernando

AU - Passemard, Sandrine

AU - Sabéran-Djoneidi, Délara

AU - Nguyen, Laurent

AU - Lancaster, Madeline

AU - Sistonen, Lea

AU - Mezger, Valérie

PY - 2022/11/16

Y1 - 2022/11/16

N2 - Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.

AB - Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.

KW - Humans

KW - CREB-Binding Protein/genetics

KW - Heat-Shock Proteins/genetics

KW - Histones/genetics

KW - Mutation

KW - Neurodevelopmental Disorders/genetics

KW - Rubinstein-Taybi Syndrome/genetics

KW - Transcription Factors/genetics

KW - E1A-Associated p300 Protein/genetics

U2 - 10.1038/s41467-022-34476-2

DO - 10.1038/s41467-022-34476-2

M3 - Article

C2 - 36385105

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7002

ER -

CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Abstract

Keywords

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