Ikaros tumor suppressor function includes induction of active enhancers and super-enhancers along with pioneering activity

Yali Ding, Bo Zhang, Jonathon L. Payne, Chunhua Song, Zheng Ge, Chandrika Gowda, Soumya Iyer, Pavan K. Dhanyamraju, Glenn Dorsam, Mark E. Reeves, Dhimant Desai, Suming Huang, Kimberly J. Payne, Feng Yue, Sinisa Dovat

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Ikaros encodes a transcription factor that functions as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). The mechanisms through which Ikaros regulates gene expression and cellular proliferation in T-ALL are unknown. Re-introduction of Ikaros into Ikaros-null T-ALL cells resulted in cessation of cellular proliferation and induction of T-cell differentiation. We performed dynamic, global, epigenomic, and gene expression analyses to determine the mechanisms of Ikaros tumor suppressor activity. Our results identified novel Ikaros functions in the epigenetic regulation of gene expression: Ikaros directly regulates de novo formation and depletion of enhancers, de novo formation of active enhancers and activation of poised enhancers; Ikaros directly induces the formation of super-enhancers; and Ikaros demonstrates pioneering activity by directly regulating chromatin accessibility. Dynamic analyses demonstrate the long-lasting effects of Ikaros DNA binding on enhancer activation, de novo formation of enhancers and super-enhancers, and chromatin accessibility. Our results establish that Ikaros’ tumor suppressor function occurs via global regulation of the enhancer and super-enhancer landscape and through pioneering activity. Expression analysis identified a large number of novel signaling pathways that are directly regulated by Ikaros and Ikaros-induced enhancers, and that are responsible for the cessation of proliferation and induction of T-cell differentiation in T-ALL cells.

Original languageEnglish (US)
Pages (from-to)2720-2731
Number of pages12
JournalLeukemia
Volume33
Issue number11
DOIs
StatePublished - Nov 1 2019

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
T-Lymphocytes
Epigenomics
Chromatin
Cell Differentiation
Cell Proliferation
Gene Expression
Null Lymphocytes
Neoplasms
Gene Expression Regulation
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Transcription Factors
DNA

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Ding, Yali ; Zhang, Bo ; Payne, Jonathon L. ; Song, Chunhua ; Ge, Zheng ; Gowda, Chandrika ; Iyer, Soumya ; Dhanyamraju, Pavan K. ; Dorsam, Glenn ; Reeves, Mark E. ; Desai, Dhimant ; Huang, Suming ; Payne, Kimberly J. ; Yue, Feng ; Dovat, Sinisa. / Ikaros tumor suppressor function includes induction of active enhancers and super-enhancers along with pioneering activity. In: Leukemia. 2019 ; Vol. 33, No. 11. pp. 2720-2731.
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title = "Ikaros tumor suppressor function includes induction of active enhancers and super-enhancers along with pioneering activity",
abstract = "Ikaros encodes a transcription factor that functions as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). The mechanisms through which Ikaros regulates gene expression and cellular proliferation in T-ALL are unknown. Re-introduction of Ikaros into Ikaros-null T-ALL cells resulted in cessation of cellular proliferation and induction of T-cell differentiation. We performed dynamic, global, epigenomic, and gene expression analyses to determine the mechanisms of Ikaros tumor suppressor activity. Our results identified novel Ikaros functions in the epigenetic regulation of gene expression: Ikaros directly regulates de novo formation and depletion of enhancers, de novo formation of active enhancers and activation of poised enhancers; Ikaros directly induces the formation of super-enhancers; and Ikaros demonstrates pioneering activity by directly regulating chromatin accessibility. Dynamic analyses demonstrate the long-lasting effects of Ikaros DNA binding on enhancer activation, de novo formation of enhancers and super-enhancers, and chromatin accessibility. Our results establish that Ikaros’ tumor suppressor function occurs via global regulation of the enhancer and super-enhancer landscape and through pioneering activity. Expression analysis identified a large number of novel signaling pathways that are directly regulated by Ikaros and Ikaros-induced enhancers, and that are responsible for the cessation of proliferation and induction of T-cell differentiation in T-ALL cells.",
author = "Yali Ding and Bo Zhang and Payne, {Jonathon L.} and Chunhua Song and Zheng Ge and Chandrika Gowda and Soumya Iyer and Dhanyamraju, {Pavan K.} and Glenn Dorsam and Reeves, {Mark E.} and Dhimant Desai and Suming Huang and Payne, {Kimberly J.} and Feng Yue and Sinisa Dovat",
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Ding, Y, Zhang, B, Payne, JL, Song, C, Ge, Z, Gowda, C, Iyer, S, Dhanyamraju, PK, Dorsam, G, Reeves, ME, Desai, D, Huang, S, Payne, KJ, Yue, F & Dovat, S 2019, 'Ikaros tumor suppressor function includes induction of active enhancers and super-enhancers along with pioneering activity', Leukemia, vol. 33, no. 11, pp. 2720-2731. https://doi.org/10.1038/s41375-019-0474-0

Ikaros tumor suppressor function includes induction of active enhancers and super-enhancers along with pioneering activity. / Ding, Yali; Zhang, Bo; Payne, Jonathon L.; Song, Chunhua; Ge, Zheng; Gowda, Chandrika; Iyer, Soumya; Dhanyamraju, Pavan K.; Dorsam, Glenn; Reeves, Mark E.; Desai, Dhimant; Huang, Suming; Payne, Kimberly J.; Yue, Feng; Dovat, Sinisa.

In: Leukemia, Vol. 33, No. 11, 01.11.2019, p. 2720-2731.

Research output: Contribution to journalArticle

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T1 - Ikaros tumor suppressor function includes induction of active enhancers and super-enhancers along with pioneering activity

AU - Ding, Yali

AU - Zhang, Bo

AU - Payne, Jonathon L.

AU - Song, Chunhua

AU - Ge, Zheng

AU - Gowda, Chandrika

AU - Iyer, Soumya

AU - Dhanyamraju, Pavan K.

AU - Dorsam, Glenn

AU - Reeves, Mark E.

AU - Desai, Dhimant

AU - Huang, Suming

AU - Payne, Kimberly J.

AU - Yue, Feng

AU - Dovat, Sinisa

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Ikaros encodes a transcription factor that functions as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). The mechanisms through which Ikaros regulates gene expression and cellular proliferation in T-ALL are unknown. Re-introduction of Ikaros into Ikaros-null T-ALL cells resulted in cessation of cellular proliferation and induction of T-cell differentiation. We performed dynamic, global, epigenomic, and gene expression analyses to determine the mechanisms of Ikaros tumor suppressor activity. Our results identified novel Ikaros functions in the epigenetic regulation of gene expression: Ikaros directly regulates de novo formation and depletion of enhancers, de novo formation of active enhancers and activation of poised enhancers; Ikaros directly induces the formation of super-enhancers; and Ikaros demonstrates pioneering activity by directly regulating chromatin accessibility. Dynamic analyses demonstrate the long-lasting effects of Ikaros DNA binding on enhancer activation, de novo formation of enhancers and super-enhancers, and chromatin accessibility. Our results establish that Ikaros’ tumor suppressor function occurs via global regulation of the enhancer and super-enhancer landscape and through pioneering activity. Expression analysis identified a large number of novel signaling pathways that are directly regulated by Ikaros and Ikaros-induced enhancers, and that are responsible for the cessation of proliferation and induction of T-cell differentiation in T-ALL cells.

AB - Ikaros encodes a transcription factor that functions as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). The mechanisms through which Ikaros regulates gene expression and cellular proliferation in T-ALL are unknown. Re-introduction of Ikaros into Ikaros-null T-ALL cells resulted in cessation of cellular proliferation and induction of T-cell differentiation. We performed dynamic, global, epigenomic, and gene expression analyses to determine the mechanisms of Ikaros tumor suppressor activity. Our results identified novel Ikaros functions in the epigenetic regulation of gene expression: Ikaros directly regulates de novo formation and depletion of enhancers, de novo formation of active enhancers and activation of poised enhancers; Ikaros directly induces the formation of super-enhancers; and Ikaros demonstrates pioneering activity by directly regulating chromatin accessibility. Dynamic analyses demonstrate the long-lasting effects of Ikaros DNA binding on enhancer activation, de novo formation of enhancers and super-enhancers, and chromatin accessibility. Our results establish that Ikaros’ tumor suppressor function occurs via global regulation of the enhancer and super-enhancer landscape and through pioneering activity. Expression analysis identified a large number of novel signaling pathways that are directly regulated by Ikaros and Ikaros-induced enhancers, and that are responsible for the cessation of proliferation and induction of T-cell differentiation in T-ALL cells.

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