Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation

Isabella Y. Kong; Joel S. Rimes; Amanda Light; Izabela Todorovski; Sarah Jones; Eric Morand; Deborah A. Knight; Ylva E. Bergman; Simon J. Hogg; Hendrik Falk; Brendon J. Monahan; Paul A. Stupple; Ian P. Street; Susanne Heinzel; Philippe Bouillet; Ricky W. Johnstone; Philip D. Hodgkin; Stephin J. Vervoort; Edwin D. Hawkins

doi:10.1016/j.celrep.2020.108290

Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation

Isabella Y. Kong, Joel S. Rimes, Amanda Light, Izabela Todorovski, Sarah Jones, Eric Morand, Deborah A. Knight, Ylva E. Bergman, Simon J. Hogg, Hendrik Falk, Brendon J. Monahan, Paul A. Stupple, Ian P. Street, Susanne Heinzel, Philippe Bouillet, Ricky W. Johnstone, Philip D. Hodgkin, Stephin J. Vervoort, Edwin D. Hawkins

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7 Citations (Scopus)

Abstract

JQ1 is a BET-bromodomain inhibitor that has immunomodulatory effects. However, the precise molecular mechanism that JQ1 targets to elicit changes in antibody production is not understood. Our results show that JQ1 induces apoptosis, reduces cell proliferation, and as a consequence, inhibits antibody-secreting cell differentiation. ChIP-sequencing reveals a selective displacement of Brd4 in response to acute JQ1 treatment (<2 h), resulting in specific transcriptional repression. After 8 h, subsequent alterations in gene expression arise as a result of the global loss of Brd4 occupancy. We demonstrate that apoptosis induced by JQ1 is solely attributed to the pro-apoptotic protein Bim (Bcl2l11). Conversely, cell-cycle regulation by JQ1 is associated with multiple Myc-associated gene targets. Our results demonstrate that JQ1 drives temporal changes in Brd4 displacement that results in a specific transcriptional profile that directly affects B cell survival and proliferation to modulate the humoral immune response.

Original language	English
Article number	108290
Number of pages	22
Journal	Cell Reports
Volume	33
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2020.108290
Publication status	Published - 20 Oct 2020

Keywords

B cells
cellular immunology
epigenetics

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Kong, I. Y., Rimes, J. S., Light, A., Todorovski, I., Jones, S., Morand, E., Knight, D. A., Bergman, Y. E., Hogg, S. J., Falk, H., Monahan, B. J., Stupple, P. A., Street, I. P., Heinzel, S., Bouillet, P., Johnstone, R. W., Hodgkin, P. D., Vervoort, S. J., & Hawkins, E. D. (2020). Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation. Cell Reports, 33(3), Article 108290. https://doi.org/10.1016/j.celrep.2020.108290

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title = "Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation",

abstract = "JQ1 is a BET-bromodomain inhibitor that has immunomodulatory effects. However, the precise molecular mechanism that JQ1 targets to elicit changes in antibody production is not understood. Our results show that JQ1 induces apoptosis, reduces cell proliferation, and as a consequence, inhibits antibody-secreting cell differentiation. ChIP-sequencing reveals a selective displacement of Brd4 in response to acute JQ1 treatment (<2 h), resulting in specific transcriptional repression. After 8 h, subsequent alterations in gene expression arise as a result of the global loss of Brd4 occupancy. We demonstrate that apoptosis induced by JQ1 is solely attributed to the pro-apoptotic protein Bim (Bcl2l11). Conversely, cell-cycle regulation by JQ1 is associated with multiple Myc-associated gene targets. Our results demonstrate that JQ1 drives temporal changes in Brd4 displacement that results in a specific transcriptional profile that directly affects B cell survival and proliferation to modulate the humoral immune response.",

keywords = "B cells, cellular immunology, epigenetics",

author = "Kong, {Isabella Y.} and Rimes, {Joel S.} and Amanda Light and Izabela Todorovski and Sarah Jones and Eric Morand and Knight, {Deborah A.} and Bergman, {Ylva E.} and Hogg, {Simon J.} and Hendrik Falk and Monahan, {Brendon J.} and Stupple, {Paul A.} and Street, {Ian P.} and Susanne Heinzel and Philippe Bouillet and Johnstone, {Ricky W.} and Hodgkin, {Philip D.} and Vervoort, {Stephin J.} and Hawkins, {Edwin D.}",

year = "2020",

month = oct,

day = "20",

doi = "10.1016/j.celrep.2020.108290",

language = "English",

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journal = "Cell Reports",

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Kong, IY, Rimes, JS, Light, A, Todorovski, I, Jones, S , Morand, E, Knight, DA, Bergman, YE, Hogg, SJ, Falk, H, Monahan, BJ , Stupple, PA, Street, IP, Heinzel, S, Bouillet, P, Johnstone, RW, Hodgkin, PD, Vervoort, SJ & Hawkins, ED 2020, 'Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation', Cell Reports, vol. 33, no. 3, 108290. https://doi.org/10.1016/j.celrep.2020.108290

TY - JOUR

T1 - Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation

AU - Kong, Isabella Y.

AU - Rimes, Joel S.

AU - Light, Amanda

AU - Todorovski, Izabela

AU - Jones, Sarah

AU - Morand, Eric

AU - Knight, Deborah A.

AU - Bergman, Ylva E.

AU - Hogg, Simon J.

AU - Falk, Hendrik

AU - Monahan, Brendon J.

AU - Stupple, Paul A.

AU - Street, Ian P.

AU - Heinzel, Susanne

AU - Bouillet, Philippe

AU - Johnstone, Ricky W.

AU - Hodgkin, Philip D.

AU - Vervoort, Stephin J.

AU - Hawkins, Edwin D.

PY - 2020/10/20

Y1 - 2020/10/20

N2 - JQ1 is a BET-bromodomain inhibitor that has immunomodulatory effects. However, the precise molecular mechanism that JQ1 targets to elicit changes in antibody production is not understood. Our results show that JQ1 induces apoptosis, reduces cell proliferation, and as a consequence, inhibits antibody-secreting cell differentiation. ChIP-sequencing reveals a selective displacement of Brd4 in response to acute JQ1 treatment (<2 h), resulting in specific transcriptional repression. After 8 h, subsequent alterations in gene expression arise as a result of the global loss of Brd4 occupancy. We demonstrate that apoptosis induced by JQ1 is solely attributed to the pro-apoptotic protein Bim (Bcl2l11). Conversely, cell-cycle regulation by JQ1 is associated with multiple Myc-associated gene targets. Our results demonstrate that JQ1 drives temporal changes in Brd4 displacement that results in a specific transcriptional profile that directly affects B cell survival and proliferation to modulate the humoral immune response.

AB - JQ1 is a BET-bromodomain inhibitor that has immunomodulatory effects. However, the precise molecular mechanism that JQ1 targets to elicit changes in antibody production is not understood. Our results show that JQ1 induces apoptosis, reduces cell proliferation, and as a consequence, inhibits antibody-secreting cell differentiation. ChIP-sequencing reveals a selective displacement of Brd4 in response to acute JQ1 treatment (<2 h), resulting in specific transcriptional repression. After 8 h, subsequent alterations in gene expression arise as a result of the global loss of Brd4 occupancy. We demonstrate that apoptosis induced by JQ1 is solely attributed to the pro-apoptotic protein Bim (Bcl2l11). Conversely, cell-cycle regulation by JQ1 is associated with multiple Myc-associated gene targets. Our results demonstrate that JQ1 drives temporal changes in Brd4 displacement that results in a specific transcriptional profile that directly affects B cell survival and proliferation to modulate the humoral immune response.

KW - B cells

KW - cellular immunology

KW - epigenetics

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DO - 10.1016/j.celrep.2020.108290

M3 - Article

C2 - 33086063

AN - SCOPUS:85092913480

SN - 2211-1247

VL - 33

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 108290

ER -

Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation

Abstract

Keywords

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