TY - JOUR
T1 - An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm
AU - Lino Cardenas, Christian L.
AU - Kessinger, Chase W.
AU - Cheng, Yisha
AU - MacDonald, Carolyn
AU - MacGillivray, Thomas
AU - Ghoshhajra, Brian
AU - Huleihel, Luai
AU - Nuri, Saifar
AU - Yeri, Ashish S.
AU - Jaffer, Farouc A.
AU - Kaminski, Naftali
AU - Ellinor, Patrick
AU - Weintraub, Neal L.
AU - Malhotra, Rajeev
AU - Isselbacher, Eric M.
AU - Lindsay, Mark E.
N1 - Funding Information:
M.E.L. is supported by the Fredman Fellowship, the Toomey Fund for Aortic Dissection Research, and the Hassenfeld Fellowship. M.E.L., C.L.L., and C.M. are supported by HL130113. N.L.W. is supported by grants HL126949, HL112640, HL134354, and AR070029. R.M. is supported by K08HL111210, the Hassenfeld Fellowship, and the Wild Family Foundation.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-β signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-β signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9-MALAT1-BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases.
AB - Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-β signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-β signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9-MALAT1-BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases.
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U2 - 10.1038/s41467-018-03394-7
DO - 10.1038/s41467-018-03394-7
M3 - Article
C2 - 29520069
AN - SCOPUS:85045071621
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1009
ER -