Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy

Christopher J. Terranova; Ming Tang; Mayinuer Maitituoheti; Ayush T. Raman; Archit K. Ghosh; Jonathan Schulz; Samir B. Amin; Elias Orouji; Katarzyna Tomczak; Sharmistha Sarkar; Junna Oba; Caitlin Creasy; Chang Jiun Wu; Samia Khan; Rossana Lazcano; Khalida Wani; Anand Singh; Praveen Barrodia; Dongyu Zhao; Kaifu Chen; Lauren E. Haydu; Wei Lien Wang; Alexander J. Lazar; Scott E. Woodman; Chantale Bernatchez; Kunal Rai

doi:10.1016/j.celrep.2021.109410

Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy

Christopher J. Terranova, Ming Tang, Mayinuer Maitituoheti, Ayush T. Raman, Archit K. Ghosh, Jonathan Schulz, Samir B. Amin, Elias Orouji, Katarzyna Tomczak, Sharmistha Sarkar, Junna Oba, Caitlin Creasy, Chang Jiun Wu, Samia Khan, Rossana Lazcano, Khalida Wani, Anand Singh, Praveen Barrodia, Dongyu Zhao, Kaifu ChenLauren E. Haydu, Wei Lien Wang, Alexander J. Lazar, Scott E. Woodman, Chantale Bernatchez, Kunal Rai

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients.

Original language	English (US)
Article number	109410
Journal	Cell Reports
Volume	36
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2021.109410
State	Published - Jul 20 2021

Keywords

Polycomb repressive complex 2
bivalent
broad domains
chromatin
epigenetics
melanoma
melanoma therapeutics
metastasis

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Cytogenetics and Cell Authentication Core
Research Animal Support Facility
Tissue Biospecimen and Pathology Resource

Access to Document

10.1016/j.celrep.2021.109410

Cite this

Terranova, C. J., Tang, M., Maitituoheti, M., Raman, A. T., Ghosh, A. K., Schulz, J., Amin, S. B., Orouji, E., Tomczak, K., Sarkar, S., Oba, J., Creasy, C., Wu, C. J., Khan, S., Lazcano, R., Wani, K., Singh, A., Barrodia, P., Zhao, D., ... Rai, K. (2021). Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy. Cell Reports, 36(3), Article 109410. https://doi.org/10.1016/j.celrep.2021.109410

Terranova, CJ, Tang, M, Maitituoheti, M, Raman, AT, Ghosh, AK, Schulz, J, Amin, SB, Orouji, E, Tomczak, K, Sarkar, S, Oba, J, Creasy, C, Wu, CJ, Khan, S, Lazcano, R, Wani, K, Singh, A, Barrodia, P, Zhao, D, Chen, K, Haydu, LE, Wang, WL , Lazar, AJ , Woodman, SE, Bernatchez, C & Rai, K 2021, 'Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy', Cell Reports, vol. 36, no. 3, 109410. https://doi.org/10.1016/j.celrep.2021.109410

@article{b39d52b5342b4cff90aa50b9c981c59c,

title = "Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy",

abstract = "The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients.",

keywords = "Polycomb repressive complex 2, bivalent, broad domains, chromatin, epigenetics, melanoma, melanoma therapeutics, metastasis",

author = "Terranova, {Christopher J.} and Ming Tang and Mayinuer Maitituoheti and Raman, {Ayush T.} and Ghosh, {Archit K.} and Jonathan Schulz and Amin, {Samir B.} and Elias Orouji and Katarzyna Tomczak and Sharmistha Sarkar and Junna Oba and Caitlin Creasy and Wu, {Chang Jiun} and Samia Khan and Rossana Lazcano and Khalida Wani and Anand Singh and Praveen Barrodia and Dongyu Zhao and Kaifu Chen and Haydu, {Lauren E.} and Wang, {Wei Lien} and Lazar, {Alexander J.} and Woodman, {Scott E.} and Chantale Bernatchez and Kunal Rai",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = jul,

day = "20",

doi = "10.1016/j.celrep.2021.109410",

language = "English (US)",

volume = "36",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy

AU - Terranova, Christopher J.

AU - Tang, Ming

AU - Maitituoheti, Mayinuer

AU - Raman, Ayush T.

AU - Ghosh, Archit K.

AU - Schulz, Jonathan

AU - Amin, Samir B.

AU - Orouji, Elias

AU - Tomczak, Katarzyna

AU - Sarkar, Sharmistha

AU - Oba, Junna

AU - Creasy, Caitlin

AU - Wu, Chang Jiun

AU - Khan, Samia

AU - Lazcano, Rossana

AU - Wani, Khalida

AU - Singh, Anand

AU - Barrodia, Praveen

AU - Zhao, Dongyu

AU - Chen, Kaifu

AU - Haydu, Lauren E.

AU - Wang, Wei Lien

AU - Lazar, Alexander J.

AU - Woodman, Scott E.

AU - Bernatchez, Chantale

AU - Rai, Kunal

PY - 2021/7/20

Y1 - 2021/7/20

N2 - The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients.

AB - The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients.

KW - Polycomb repressive complex 2

KW - bivalent

KW - broad domains

KW - chromatin

KW - epigenetics

KW - melanoma

KW - melanoma therapeutics

KW - metastasis

UR - http://www.scopus.com/inward/record.url?scp=85110708581&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85110708581&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.109410

DO - 10.1016/j.celrep.2021.109410

M3 - Article

C2 - 34289358

AN - SCOPUS:85110708581

SN - 2211-1247

VL - 36

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 109410

ER -

Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Cite this