Dimethyl fumarate regulates histone deacetylase expression in astrocytes

Sergey Kalinin, Paul E. Polak, Shao Xia Lin, David Braun, Marina Guizzetti, Xiaolu Zhang, Israel Rubinstein, Douglas L. Feinstein

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

We previously showed that dimethyl fumarate (DMF) reduces inflammatory activation in astrocytes, involving activation of transcription factor Nrf2. However, the pathways causing Nrf2 activation were not examined. We now show that DMF modifies expression of histone deacetylases (HDACs) in primary rat astrocytes. After 4. h incubation, levels of HDAC1, 2, and 4 mRNAs were increased by DMF; however, after 24. h, levels returned to or were below control values. At that time, HDAC protein levels and overall activity were also reduced by DMF. Stimulation of astrocytes with pro-inflammatory cytokines significantly increased HDAC mRNA levels after 24. h, although protein levels were not increased at that time point. In the presence of cytokines, DMF reduced HDAC mRNAs, proteins, and activity. Proteomic analysis of DMF-treated astrocytes identified 8 proteins in which lysine acetylation was increased by DMF, including histones H2a.1 and H3.3. A role for HDACs in mediating DMF actions is suggested by findings that the selective HDAC inhibitor SAHA increased nuclear Nrf2:DNA binding activity, reduced inflammatory activation of astrocytes which was reversed by a selective inhibitor of the Nrf2 target gene heme-oxygenase 1. These data show that DMF regulates astrocyte HDAC expression, which could contribute to Nrf2 activation, suppression of inflammatory responses and cause long-lasting changes in gene expression.

Original languageEnglish (US)
Pages (from-to)13-19
Number of pages7
JournalJournal of Neuroimmunology
Volume263
Issue number1-2
DOIs
StatePublished - Oct 15 2013
Externally publishedYes

Fingerprint

Histone Deacetylases
Astrocytes
Messenger RNA
Proteins
Cytokines
Dimethyl Fumarate
Heme Oxygenase-1
Acetylation
Proteomics
Histones
Lysine
Transcription Factors
Gene Expression
DNA

Keywords

  • Astrocyte
  • Histone deacetylase
  • Multiple sclerosis
  • Nrf2

ASJC Scopus subject areas

  • Immunology
  • Clinical Neurology
  • Immunology and Allergy
  • Neurology

Cite this

Kalinin, S., Polak, P. E., Lin, S. X., Braun, D., Guizzetti, M., Zhang, X., ... Feinstein, D. L. (2013). Dimethyl fumarate regulates histone deacetylase expression in astrocytes. Journal of Neuroimmunology, 263(1-2), 13-19. https://doi.org/10.1016/j.jneuroim.2013.07.007

Dimethyl fumarate regulates histone deacetylase expression in astrocytes. / Kalinin, Sergey; Polak, Paul E.; Lin, Shao Xia; Braun, David; Guizzetti, Marina; Zhang, Xiaolu; Rubinstein, Israel; Feinstein, Douglas L.

In: Journal of Neuroimmunology, Vol. 263, No. 1-2, 15.10.2013, p. 13-19.

Research output: Contribution to journalArticle

Kalinin, S, Polak, PE, Lin, SX, Braun, D, Guizzetti, M, Zhang, X, Rubinstein, I & Feinstein, DL 2013, 'Dimethyl fumarate regulates histone deacetylase expression in astrocytes', Journal of Neuroimmunology, vol. 263, no. 1-2, pp. 13-19. https://doi.org/10.1016/j.jneuroim.2013.07.007
Kalinin, Sergey ; Polak, Paul E. ; Lin, Shao Xia ; Braun, David ; Guizzetti, Marina ; Zhang, Xiaolu ; Rubinstein, Israel ; Feinstein, Douglas L. / Dimethyl fumarate regulates histone deacetylase expression in astrocytes. In: Journal of Neuroimmunology. 2013 ; Vol. 263, No. 1-2. pp. 13-19.
@article{871a5a7fa6ab4d70b8e1e8e43d316dd0,
title = "Dimethyl fumarate regulates histone deacetylase expression in astrocytes",
abstract = "We previously showed that dimethyl fumarate (DMF) reduces inflammatory activation in astrocytes, involving activation of transcription factor Nrf2. However, the pathways causing Nrf2 activation were not examined. We now show that DMF modifies expression of histone deacetylases (HDACs) in primary rat astrocytes. After 4. h incubation, levels of HDAC1, 2, and 4 mRNAs were increased by DMF; however, after 24. h, levels returned to or were below control values. At that time, HDAC protein levels and overall activity were also reduced by DMF. Stimulation of astrocytes with pro-inflammatory cytokines significantly increased HDAC mRNA levels after 24. h, although protein levels were not increased at that time point. In the presence of cytokines, DMF reduced HDAC mRNAs, proteins, and activity. Proteomic analysis of DMF-treated astrocytes identified 8 proteins in which lysine acetylation was increased by DMF, including histones H2a.1 and H3.3. A role for HDACs in mediating DMF actions is suggested by findings that the selective HDAC inhibitor SAHA increased nuclear Nrf2:DNA binding activity, reduced inflammatory activation of astrocytes which was reversed by a selective inhibitor of the Nrf2 target gene heme-oxygenase 1. These data show that DMF regulates astrocyte HDAC expression, which could contribute to Nrf2 activation, suppression of inflammatory responses and cause long-lasting changes in gene expression.",
keywords = "Astrocyte, Histone deacetylase, Multiple sclerosis, Nrf2",
author = "Sergey Kalinin and Polak, {Paul E.} and Lin, {Shao Xia} and David Braun and Marina Guizzetti and Xiaolu Zhang and Israel Rubinstein and Feinstein, {Douglas L.}",
year = "2013",
month = "10",
day = "15",
doi = "10.1016/j.jneuroim.2013.07.007",
language = "English (US)",
volume = "263",
pages = "13--19",
journal = "Journal of Neuroimmunology",
issn = "0165-5728",
publisher = "Elsevier",
number = "1-2",

}

TY - JOUR

T1 - Dimethyl fumarate regulates histone deacetylase expression in astrocytes

AU - Kalinin, Sergey

AU - Polak, Paul E.

AU - Lin, Shao Xia

AU - Braun, David

AU - Guizzetti, Marina

AU - Zhang, Xiaolu

AU - Rubinstein, Israel

AU - Feinstein, Douglas L.

PY - 2013/10/15

Y1 - 2013/10/15

N2 - We previously showed that dimethyl fumarate (DMF) reduces inflammatory activation in astrocytes, involving activation of transcription factor Nrf2. However, the pathways causing Nrf2 activation were not examined. We now show that DMF modifies expression of histone deacetylases (HDACs) in primary rat astrocytes. After 4. h incubation, levels of HDAC1, 2, and 4 mRNAs were increased by DMF; however, after 24. h, levels returned to or were below control values. At that time, HDAC protein levels and overall activity were also reduced by DMF. Stimulation of astrocytes with pro-inflammatory cytokines significantly increased HDAC mRNA levels after 24. h, although protein levels were not increased at that time point. In the presence of cytokines, DMF reduced HDAC mRNAs, proteins, and activity. Proteomic analysis of DMF-treated astrocytes identified 8 proteins in which lysine acetylation was increased by DMF, including histones H2a.1 and H3.3. A role for HDACs in mediating DMF actions is suggested by findings that the selective HDAC inhibitor SAHA increased nuclear Nrf2:DNA binding activity, reduced inflammatory activation of astrocytes which was reversed by a selective inhibitor of the Nrf2 target gene heme-oxygenase 1. These data show that DMF regulates astrocyte HDAC expression, which could contribute to Nrf2 activation, suppression of inflammatory responses and cause long-lasting changes in gene expression.

AB - We previously showed that dimethyl fumarate (DMF) reduces inflammatory activation in astrocytes, involving activation of transcription factor Nrf2. However, the pathways causing Nrf2 activation were not examined. We now show that DMF modifies expression of histone deacetylases (HDACs) in primary rat astrocytes. After 4. h incubation, levels of HDAC1, 2, and 4 mRNAs were increased by DMF; however, after 24. h, levels returned to or were below control values. At that time, HDAC protein levels and overall activity were also reduced by DMF. Stimulation of astrocytes with pro-inflammatory cytokines significantly increased HDAC mRNA levels after 24. h, although protein levels were not increased at that time point. In the presence of cytokines, DMF reduced HDAC mRNAs, proteins, and activity. Proteomic analysis of DMF-treated astrocytes identified 8 proteins in which lysine acetylation was increased by DMF, including histones H2a.1 and H3.3. A role for HDACs in mediating DMF actions is suggested by findings that the selective HDAC inhibitor SAHA increased nuclear Nrf2:DNA binding activity, reduced inflammatory activation of astrocytes which was reversed by a selective inhibitor of the Nrf2 target gene heme-oxygenase 1. These data show that DMF regulates astrocyte HDAC expression, which could contribute to Nrf2 activation, suppression of inflammatory responses and cause long-lasting changes in gene expression.

KW - Astrocyte

KW - Histone deacetylase

KW - Multiple sclerosis

KW - Nrf2

UR - http://www.scopus.com/inward/record.url?scp=84884819095&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884819095&partnerID=8YFLogxK

U2 - 10.1016/j.jneuroim.2013.07.007

DO - 10.1016/j.jneuroim.2013.07.007

M3 - Article

C2 - 23916696

AN - SCOPUS:84884819095

VL - 263

SP - 13

EP - 19

JO - Journal of Neuroimmunology

JF - Journal of Neuroimmunology

SN - 0165-5728

IS - 1-2

ER -