Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis

Qing Jun Zhang, Tram Anh T. Tran, Ming Wang, Mark Ranek, Kristen M. Kokkonen-Simon, Jason Gao, Xiang Luo, Wei Tan, Viktoriia Kyrychenko, Lan Liao, Jianming Xu, Joseph A. Hill, Eric N. Olson, David A Kass, Elisabeth D. Martinez, Zhi Ping Liu

Research output: Contribution to journalArticle

Abstract

Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators of transcriptional reprogramming in cancer, though their potential role in abnormal heart growth and fibrosis remains little understood. Here, we investigate gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, and show it promotes LVH and fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates Timp1 transcription with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses pressure overload-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.

Original languageEnglish (US)
Article number5230
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Histone Demethylases
fibrosis
lysine
Cardiomegaly
Left Ventricular Hypertrophy
Histones
Lysine
Fibrosis
Genes
Transcription
genes
Pressure
Cardiac Myocytes
mortality
regulators
Molecular Biology
Down-Regulation
inhibitors
mice
Pharmacology

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis. / Zhang, Qing Jun; Tran, Tram Anh T.; Wang, Ming; Ranek, Mark; Kokkonen-Simon, Kristen M.; Gao, Jason; Luo, Xiang; Tan, Wei; Kyrychenko, Viktoriia; Liao, Lan; Xu, Jianming; Hill, Joseph A.; Olson, Eric N.; Kass, David A; Martinez, Elisabeth D.; Liu, Zhi Ping.

In: Nature Communications, Vol. 9, No. 1, 5230, 01.12.2018.

Research output: Contribution to journalArticle

Zhang, QJ, Tran, TAT, Wang, M, Ranek, M, Kokkonen-Simon, KM, Gao, J, Luo, X, Tan, W, Kyrychenko, V, Liao, L, Xu, J, Hill, JA, Olson, EN, Kass, DA, Martinez, ED & Liu, ZP 2018, 'Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis', Nature Communications, vol. 9, no. 1, 5230. https://doi.org/10.1038/s41467-018-07173-2
Zhang, Qing Jun ; Tran, Tram Anh T. ; Wang, Ming ; Ranek, Mark ; Kokkonen-Simon, Kristen M. ; Gao, Jason ; Luo, Xiang ; Tan, Wei ; Kyrychenko, Viktoriia ; Liao, Lan ; Xu, Jianming ; Hill, Joseph A. ; Olson, Eric N. ; Kass, David A ; Martinez, Elisabeth D. ; Liu, Zhi Ping. / Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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