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

Qing-Jun Zhang, Tram Anh T. Tran, Ming Wang, Mark J. 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 () and Zhi-Ping Liu ()
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Qing-Jun Zhang: UT Southwestern Medical Center
Tram Anh T. Tran: UT Southwestern Medical Center
Ming Wang: UT Southwestern Medical Center
Mark J. Ranek: The Johns Hopkins Medical Institutions
Kristen M. Kokkonen-Simon: The Johns Hopkins Medical Institutions
Jason Gao: UT Southwestern Medical Center
Xiang Luo: UT Southwestern Medical Center
Wei Tan: UT Southwestern Medical Center
Viktoriia Kyrychenko: UT Southwestern Medical Center
Lan Liao: Baylor College of Medicine
Jianming Xu: Baylor College of Medicine
Joseph A. Hill: UT Southwestern Medical Center
Eric N. Olson: UT Southwestern Medical Center
David A. Kass: The Johns Hopkins Medical Institutions
Elisabeth D. Martinez: UT Southwestern Medical Center
Zhi-Ping Liu: UT Southwestern Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07173-2

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