Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome

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

Standard

Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome. / Utami, Kagistia Hana; Skotte, Niels H.; Colaço, Ana R; Yusof, Nur Amirah Binte Mohammad; Sim, Bernice; Yeo, Xin Yi; Bae, Han-Gyu; Garcia-Miralles, Marta; Radulescu, Carola I; Chen, Qiyu; Chaldaiopoulou, Georgia; Liany, Herty; Nama, Srikanth; Peteri, Ulla-Kaisa A; Sampath, Prabha; Castrén, Maija L; Jung, Sangyong; Mann, Matthias; Pouladi, Mahmoud A.

In: Biological Psychiatry, Vol. 88, No. 6, 2020, p. 500-511.

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

Harvard

Utami, KH, Skotte, NH, Colaço, AR, Yusof, NABM, Sim, B, Yeo, XY, Bae, H-G, Garcia-Miralles, M, Radulescu, CI, Chen, Q, Chaldaiopoulou, G, Liany, H, Nama, S, Peteri, U-KA, Sampath, P, Castrén, ML, Jung, S, Mann, M & Pouladi, MA 2020, 'Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome', Biological Psychiatry, vol. 88, no. 6, pp. 500-511. https://doi.org/10.1016/j.biopsych.2020.05.005

APA

Utami, K. H., Skotte, N. H., Colaço, A. R., Yusof, N. A. B. M., Sim, B., Yeo, X. Y., Bae, H-G., Garcia-Miralles, M., Radulescu, C. I., Chen, Q., Chaldaiopoulou, G., Liany, H., Nama, S., Peteri, U-K. A., Sampath, P., Castrén, M. L., Jung, S., Mann, M., & Pouladi, M. A. (2020). Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome. Biological Psychiatry, 88(6), 500-511. https://doi.org/10.1016/j.biopsych.2020.05.005

Vancouver

Utami KH, Skotte NH, Colaço AR, Yusof NABM, Sim B, Yeo XY et al. Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome. Biological Psychiatry. 2020;88(6):500-511. https://doi.org/10.1016/j.biopsych.2020.05.005

Author

Utami, Kagistia Hana ; Skotte, Niels H. ; Colaço, Ana R ; Yusof, Nur Amirah Binte Mohammad ; Sim, Bernice ; Yeo, Xin Yi ; Bae, Han-Gyu ; Garcia-Miralles, Marta ; Radulescu, Carola I ; Chen, Qiyu ; Chaldaiopoulou, Georgia ; Liany, Herty ; Nama, Srikanth ; Peteri, Ulla-Kaisa A ; Sampath, Prabha ; Castrén, Maija L ; Jung, Sangyong ; Mann, Matthias ; Pouladi, Mahmoud A. / Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome. In: Biological Psychiatry. 2020 ; Vol. 88, No. 6. pp. 500-511.

Bibtex

@article{7067ed8b62f8441d93cbb50330fe379d,
title = "Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome",
abstract = "BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Efforts to understand the molecular underpinnings of the disease have been largely performed in rodent or nonisogenic settings. A detailed examination of the impact of FMRP loss on cellular processes and neuronal properties in the context of isogenic human neurons remains lacking.METHODS: Using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to introduce indels in exon 3 of FMR1, we generated an isogenic human pluripotent stem cell model of FXS that shows complete loss of FMRP expression. We generated neuronal cultures and performed genome-wide transcriptome and proteome profiling followed by functional validation of key dysregulated processes. We further analyzed neurodevelopmental and neuronal properties, including neurite length and neuronal activity, using multielectrode arrays and patch clamp electrophysiology.RESULTS: We showed that the transcriptome and proteome profiles of isogenic FMRP-deficient neurons demonstrate perturbations in synaptic transmission, neuron differentiation, cell proliferation and ion transmembrane transporter activity pathways, and autism spectrum disorder-associated gene sets. We uncovered key deficits in FMRP-deficient cells demonstrating abnormal neural rosette formation and neural progenitor cell proliferation. We further showed that FMRP-deficient neurons exhibit a number of additional phenotypic abnormalities, including neurite outgrowth and branching deficits and impaired electrophysiological network activity. These FMRP-deficient related impairments have also been validated in additional FXS patient-derived human-induced pluripotent stem cell neural cells.CONCLUSIONS: Using isogenic human pluripotent stem cells as a model to investigate the pathophysiology of FXS in human neurons, we reveal key neural abnormalities arising from the loss of FMRP.",
author = "Utami, {Kagistia Hana} and Skotte, {Niels H.} and Cola{\c c}o, {Ana R} and Yusof, {Nur Amirah Binte Mohammad} and Bernice Sim and Yeo, {Xin Yi} and Han-Gyu Bae and Marta Garcia-Miralles and Radulescu, {Carola I} and Qiyu Chen and Georgia Chaldaiopoulou and Herty Liany and Srikanth Nama and Peteri, {Ulla-Kaisa A} and Prabha Sampath and Castr{\'e}n, {Maija L} and Sangyong Jung and Matthias Mann and Pouladi, {Mahmoud A}",
year = "2020",
doi = "10.1016/j.biopsych.2020.05.005",
language = "English",
volume = "88",
pages = "500--511",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier",
number = "6",

}

RIS

TY - JOUR

T1 - Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome

AU - Utami, Kagistia Hana

AU - Skotte, Niels H.

AU - Colaço, Ana R

AU - Yusof, Nur Amirah Binte Mohammad

AU - Sim, Bernice

AU - Yeo, Xin Yi

AU - Bae, Han-Gyu

AU - Garcia-Miralles, Marta

AU - Radulescu, Carola I

AU - Chen, Qiyu

AU - Chaldaiopoulou, Georgia

AU - Liany, Herty

AU - Nama, Srikanth

AU - Peteri, Ulla-Kaisa A

AU - Sampath, Prabha

AU - Castrén, Maija L

AU - Jung, Sangyong

AU - Mann, Matthias

AU - Pouladi, Mahmoud A

PY - 2020

Y1 - 2020

N2 - BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Efforts to understand the molecular underpinnings of the disease have been largely performed in rodent or nonisogenic settings. A detailed examination of the impact of FMRP loss on cellular processes and neuronal properties in the context of isogenic human neurons remains lacking.METHODS: Using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to introduce indels in exon 3 of FMR1, we generated an isogenic human pluripotent stem cell model of FXS that shows complete loss of FMRP expression. We generated neuronal cultures and performed genome-wide transcriptome and proteome profiling followed by functional validation of key dysregulated processes. We further analyzed neurodevelopmental and neuronal properties, including neurite length and neuronal activity, using multielectrode arrays and patch clamp electrophysiology.RESULTS: We showed that the transcriptome and proteome profiles of isogenic FMRP-deficient neurons demonstrate perturbations in synaptic transmission, neuron differentiation, cell proliferation and ion transmembrane transporter activity pathways, and autism spectrum disorder-associated gene sets. We uncovered key deficits in FMRP-deficient cells demonstrating abnormal neural rosette formation and neural progenitor cell proliferation. We further showed that FMRP-deficient neurons exhibit a number of additional phenotypic abnormalities, including neurite outgrowth and branching deficits and impaired electrophysiological network activity. These FMRP-deficient related impairments have also been validated in additional FXS patient-derived human-induced pluripotent stem cell neural cells.CONCLUSIONS: Using isogenic human pluripotent stem cells as a model to investigate the pathophysiology of FXS in human neurons, we reveal key neural abnormalities arising from the loss of FMRP.

AB - BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Efforts to understand the molecular underpinnings of the disease have been largely performed in rodent or nonisogenic settings. A detailed examination of the impact of FMRP loss on cellular processes and neuronal properties in the context of isogenic human neurons remains lacking.METHODS: Using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to introduce indels in exon 3 of FMR1, we generated an isogenic human pluripotent stem cell model of FXS that shows complete loss of FMRP expression. We generated neuronal cultures and performed genome-wide transcriptome and proteome profiling followed by functional validation of key dysregulated processes. We further analyzed neurodevelopmental and neuronal properties, including neurite length and neuronal activity, using multielectrode arrays and patch clamp electrophysiology.RESULTS: We showed that the transcriptome and proteome profiles of isogenic FMRP-deficient neurons demonstrate perturbations in synaptic transmission, neuron differentiation, cell proliferation and ion transmembrane transporter activity pathways, and autism spectrum disorder-associated gene sets. We uncovered key deficits in FMRP-deficient cells demonstrating abnormal neural rosette formation and neural progenitor cell proliferation. We further showed that FMRP-deficient neurons exhibit a number of additional phenotypic abnormalities, including neurite outgrowth and branching deficits and impaired electrophysiological network activity. These FMRP-deficient related impairments have also been validated in additional FXS patient-derived human-induced pluripotent stem cell neural cells.CONCLUSIONS: Using isogenic human pluripotent stem cells as a model to investigate the pathophysiology of FXS in human neurons, we reveal key neural abnormalities arising from the loss of FMRP.

U2 - 10.1016/j.biopsych.2020.05.005

DO - 10.1016/j.biopsych.2020.05.005

M3 - Journal article

C2 - 32653109

VL - 88

SP - 500

EP - 511

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 6

ER -

ID: 244959490