Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders

Loredana Poeta; Agnese Padula; Benedetta Attianese; Mariaelena Valentino; Lucia Verrillo; Stefania Filosa; Cheryl Shoubridge; Adriano Barra; Charles E Schwartz; Jesper Christensen; Hans van Bokhoven; Kristian Helin; Maria Brigida Lioi; Patrick Collombat; Jozef Gecz; Lucia Altucci; Elia Di Schiavi; Maria Giuseppina Miano

doi:10.1093/hmg/ddz254

Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders

Loredana Poeta, Agnese Padula, Benedetta Attianese, Mariaelena Valentino, Lucia Verrillo, Stefania Filosa, Cheryl Shoubridge, Adriano Barra, Charles E Schwartz, Jesper Christensen, Hans van Bokhoven, Kristian Helin, Maria Brigida Lioi, Patrick Collombat, Jozef Gecz, Lucia Altucci, Elia Di Schiavi, Maria Giuseppina Miano

Abstract

A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling, and improve neuronal differentiation. Indeed, in ARX/alr-1 deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.

Original language	English
Journal	Human Molecular Genetics
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddz254
Publication status	Published - 15 Dec 2019

Access to Document

10.1093/hmg/ddz254

Cite this

Poeta, L., Padula, A., Attianese, B., Valentino, M., Verrillo, L., Filosa, S., Shoubridge, C., Barra, A., Schwartz, C. E., Christensen, J., van Bokhoven, H., Helin, K., Lioi, M. B., Collombat, P., Gecz, J., Altucci, L., Di Schiavi, E., & Miano, M. G. (2019). Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddz254

Poeta, L, Padula, A, Attianese, B, Valentino, M, Verrillo, L, Filosa, S, Shoubridge, C, Barra, A, Schwartz, CE, Christensen, J, van Bokhoven, H, Helin, K, Lioi, MB, Collombat, P, Gecz, J, Altucci, L, Di Schiavi, E & Miano, MG 2019, 'Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders', Human Molecular Genetics. https://doi.org/10.1093/hmg/ddz254

@article{25dc8e022f8f42148fd34d55322efd34,

title = "Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders",

abstract = "A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling, and improve neuronal differentiation. Indeed, in ARX/alr-1 deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.",

author = "Loredana Poeta and Agnese Padula and Benedetta Attianese and Mariaelena Valentino and Lucia Verrillo and Stefania Filosa and Cheryl Shoubridge and Adriano Barra and Schwartz, {Charles E} and Jesper Christensen and {van Bokhoven}, Hans and Kristian Helin and Lioi, {Maria Brigida} and Patrick Collombat and Jozef Gecz and Lucia Altucci and {Di Schiavi}, Elia and Miano, {Maria Giuseppina}",

year = "2019",

month = dec,

day = "15",

doi = "10.1093/hmg/ddz254",

language = "English",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

}

TY - JOUR

T1 - Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders

AU - Poeta, Loredana

AU - Padula, Agnese

AU - Attianese, Benedetta

AU - Valentino, Mariaelena

AU - Verrillo, Lucia

AU - Filosa, Stefania

AU - Shoubridge, Cheryl

AU - Barra, Adriano

AU - Schwartz, Charles E

AU - Christensen, Jesper

AU - van Bokhoven, Hans

AU - Helin, Kristian

AU - Lioi, Maria Brigida

AU - Collombat, Patrick

AU - Gecz, Jozef

AU - Altucci, Lucia

AU - Di Schiavi, Elia

AU - Miano, Maria Giuseppina

PY - 2019/12/15

Y1 - 2019/12/15

N2 - A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling, and improve neuronal differentiation. Indeed, in ARX/alr-1 deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.

AB - A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling, and improve neuronal differentiation. Indeed, in ARX/alr-1 deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.

U2 - 10.1093/hmg/ddz254

DO - 10.1093/hmg/ddz254

M3 - Journal article

C2 - 31691806

SN - 0964-6906

JO - Human Molecular Genetics

JF - Human Molecular Genetics

ER -

Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders

Abstract

Access to Document

Fingerprint

Cite this