Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma

Tara H.W. Dobson, Rong Hua Tao, Jyothishmathi Swaminathan, Shinji Maegawa, Shavali Shaik, Javiera Bravo-Alegria, Ajay Sharma, Bridget Kennis, Yanwen Yang, Keri Callegari, Amanda R. Haltom, Pete Taylor, Mari Kogiso, Lin Qi, Soumen Khatua, Stewart Goldman, Rishi R. Lulla, Jason Fangusaro, Tobey J. MacDonald, Xiaonan Li & 3 others Cynthia Hawkins, Veena Rajaram, Vidya Gopalakrishnan*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH- (children 3 to 16 years) and SHH- (infants) subgroups. Neuronal maturation is greater in SHH- than SHH- tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model (REST TG ) wherein conditional NeuroD2-controlled REST transgene expression in lineage-committed Ptch1 +/− cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease. This model revealed a neuronal maturation context-specific antagonistic interplay between the transcriptional repressor REST and the activator GLI1 at Ptch1. Expression of Arrb1, which encodes -arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committed REST TG cells compared with wild-type proliferating CGNPs. Lineage-committed REST TG cells also had decreased GLI1 activity and increased histone H3K9 methylation at the Ptch1 locus, which correlated with premature silencing of Ptch1. These cells also had decreased expression of Pten, which encodes a negative regulator of the kinase AKT. Expression of PTCH1 and GLI1 were less, and ARRB1 was somewhat greater, in patient SHH- than SHH- MBs, whereas that of PTEN was similarly lower in both subtypes than in others. Inhibition of histone modifiers or AKT reduced proliferation and induced apoptosis, respectively, in cultured REST-high MB cells. Our findings linking REST to differentiation-specific chromatin remodeling, PTCH1 silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.

Original languageEnglish (US)
Article numberaan8680
JournalScience Signaling
Volume12
Issue number565
DOIs
StatePublished - Jan 22 2019

Fingerprint

Medulloblastoma
Hedgehogs
Chromatin
Compaction
Chemical activation
Histones
Neurons
Tumors
RE1-silencing transcription factor
Methylation
Chromatin Assembly and Disassembly
Penetrance
Transgenes
Transgenic Mice
Neoplasms
Carcinogenesis
Phosphotransferases
Tissue
Apoptosis
Survival

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Dobson, T. H. W., Tao, R. H., Swaminathan, J., Maegawa, S., Shaik, S., Bravo-Alegria, J., ... Gopalakrishnan, V. (2019). Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma. Science Signaling, 12(565), [aan8680]. https://doi.org/10.1126/scisignal.aan8680
Dobson, Tara H.W. ; Tao, Rong Hua ; Swaminathan, Jyothishmathi ; Maegawa, Shinji ; Shaik, Shavali ; Bravo-Alegria, Javiera ; Sharma, Ajay ; Kennis, Bridget ; Yang, Yanwen ; Callegari, Keri ; Haltom, Amanda R. ; Taylor, Pete ; Kogiso, Mari ; Qi, Lin ; Khatua, Soumen ; Goldman, Stewart ; Lulla, Rishi R. ; Fangusaro, Jason ; MacDonald, Tobey J. ; Li, Xiaonan ; Hawkins, Cynthia ; Rajaram, Veena ; Gopalakrishnan, Vidya. / Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma. In: Science Signaling. 2019 ; Vol. 12, No. 565.
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abstract = "In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH- (children 3 to 16 years) and SHH- (infants) subgroups. Neuronal maturation is greater in SHH- than SHH- tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model (REST TG ) wherein conditional NeuroD2-controlled REST transgene expression in lineage-committed Ptch1 +/− cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease. This model revealed a neuronal maturation context-specific antagonistic interplay between the transcriptional repressor REST and the activator GLI1 at Ptch1. Expression of Arrb1, which encodes -arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committed REST TG cells compared with wild-type proliferating CGNPs. Lineage-committed REST TG cells also had decreased GLI1 activity and increased histone H3K9 methylation at the Ptch1 locus, which correlated with premature silencing of Ptch1. These cells also had decreased expression of Pten, which encodes a negative regulator of the kinase AKT. Expression of PTCH1 and GLI1 were less, and ARRB1 was somewhat greater, in patient SHH- than SHH- MBs, whereas that of PTEN was similarly lower in both subtypes than in others. Inhibition of histone modifiers or AKT reduced proliferation and induced apoptosis, respectively, in cultured REST-high MB cells. Our findings linking REST to differentiation-specific chromatin remodeling, PTCH1 silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.",
author = "Dobson, {Tara H.W.} and Tao, {Rong Hua} and Jyothishmathi Swaminathan and Shinji Maegawa and Shavali Shaik and Javiera Bravo-Alegria and Ajay Sharma and Bridget Kennis and Yanwen Yang and Keri Callegari and Haltom, {Amanda R.} and Pete Taylor and Mari Kogiso and Lin Qi and Soumen Khatua and Stewart Goldman and Lulla, {Rishi R.} and Jason Fangusaro and MacDonald, {Tobey J.} and Xiaonan Li and Cynthia Hawkins and Veena Rajaram and Vidya Gopalakrishnan",
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Dobson, THW, Tao, RH, Swaminathan, J, Maegawa, S, Shaik, S, Bravo-Alegria, J, Sharma, A, Kennis, B, Yang, Y, Callegari, K, Haltom, AR, Taylor, P, Kogiso, M, Qi, L, Khatua, S, Goldman, S, Lulla, RR, Fangusaro, J, MacDonald, TJ, Li, X, Hawkins, C, Rajaram, V & Gopalakrishnan, V 2019, 'Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma', Science Signaling, vol. 12, no. 565, aan8680. https://doi.org/10.1126/scisignal.aan8680

Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma. / Dobson, Tara H.W.; Tao, Rong Hua; Swaminathan, Jyothishmathi; Maegawa, Shinji; Shaik, Shavali; Bravo-Alegria, Javiera; Sharma, Ajay; Kennis, Bridget; Yang, Yanwen; Callegari, Keri; Haltom, Amanda R.; Taylor, Pete; Kogiso, Mari; Qi, Lin; Khatua, Soumen; Goldman, Stewart; Lulla, Rishi R.; Fangusaro, Jason; MacDonald, Tobey J.; Li, Xiaonan; Hawkins, Cynthia; Rajaram, Veena; Gopalakrishnan, Vidya.

In: Science Signaling, Vol. 12, No. 565, aan8680, 22.01.2019.

Research output: Contribution to journalArticle

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T1 - Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma

AU - Dobson, Tara H.W.

AU - Tao, Rong Hua

AU - Swaminathan, Jyothishmathi

AU - Maegawa, Shinji

AU - Shaik, Shavali

AU - Bravo-Alegria, Javiera

AU - Sharma, Ajay

AU - Kennis, Bridget

AU - Yang, Yanwen

AU - Callegari, Keri

AU - Haltom, Amanda R.

AU - Taylor, Pete

AU - Kogiso, Mari

AU - Qi, Lin

AU - Khatua, Soumen

AU - Goldman, Stewart

AU - Lulla, Rishi R.

AU - Fangusaro, Jason

AU - MacDonald, Tobey J.

AU - Li, Xiaonan

AU - Hawkins, Cynthia

AU - Rajaram, Veena

AU - Gopalakrishnan, Vidya

PY - 2019/1/22

Y1 - 2019/1/22

N2 - In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH- (children 3 to 16 years) and SHH- (infants) subgroups. Neuronal maturation is greater in SHH- than SHH- tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model (REST TG ) wherein conditional NeuroD2-controlled REST transgene expression in lineage-committed Ptch1 +/− cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease. This model revealed a neuronal maturation context-specific antagonistic interplay between the transcriptional repressor REST and the activator GLI1 at Ptch1. Expression of Arrb1, which encodes -arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committed REST TG cells compared with wild-type proliferating CGNPs. Lineage-committed REST TG cells also had decreased GLI1 activity and increased histone H3K9 methylation at the Ptch1 locus, which correlated with premature silencing of Ptch1. These cells also had decreased expression of Pten, which encodes a negative regulator of the kinase AKT. Expression of PTCH1 and GLI1 were less, and ARRB1 was somewhat greater, in patient SHH- than SHH- MBs, whereas that of PTEN was similarly lower in both subtypes than in others. Inhibition of histone modifiers or AKT reduced proliferation and induced apoptosis, respectively, in cultured REST-high MB cells. Our findings linking REST to differentiation-specific chromatin remodeling, PTCH1 silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.

AB - In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH- (children 3 to 16 years) and SHH- (infants) subgroups. Neuronal maturation is greater in SHH- than SHH- tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model (REST TG ) wherein conditional NeuroD2-controlled REST transgene expression in lineage-committed Ptch1 +/− cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease. This model revealed a neuronal maturation context-specific antagonistic interplay between the transcriptional repressor REST and the activator GLI1 at Ptch1. Expression of Arrb1, which encodes -arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committed REST TG cells compared with wild-type proliferating CGNPs. Lineage-committed REST TG cells also had decreased GLI1 activity and increased histone H3K9 methylation at the Ptch1 locus, which correlated with premature silencing of Ptch1. These cells also had decreased expression of Pten, which encodes a negative regulator of the kinase AKT. Expression of PTCH1 and GLI1 were less, and ARRB1 was somewhat greater, in patient SHH- than SHH- MBs, whereas that of PTEN was similarly lower in both subtypes than in others. Inhibition of histone modifiers or AKT reduced proliferation and induced apoptosis, respectively, in cultured REST-high MB cells. Our findings linking REST to differentiation-specific chromatin remodeling, PTCH1 silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.

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