title: The PTIP-Associated Histone Methyltransferase Complex Prevents Stress-Induced Maladaptive Cardiac Remodeling.
abstract: Pressure overload induces stress-induced signaling pathways and a coordinated transcriptional response that begets concentric cardiac hypertrophy. Although concentric hypertrophy initially attenuates wall stress and maintains cardiac function, continued stress can result in maladaptive cardiac remodeling. Cardiac remodeling is orchestrated by transcription factors that act within the context of an epigenetic landscape. Since the epigenetic landscape serves as a molecular link between environmental factors (stress) and cellular phenotype (disease), defining the role of the epigenome in the development and progression of cardiac remodeling could lead to new therapeutic approaches. In this study, we hypothesized that the epigenetic landscape is important in the development of cardiac hypertrophy and the progression to maladaptive remodeling. To demonstrate the importance of the epigenome in HF, we targeted the PTIP-associated histone methyltransferase complex in adult cardiac myocytes. This complex imparts histone H3 lysine 4 (H3K4) methylation marks at actively expressed genes. We subjected PTIP null (PTIP-) mice to 2 weeks of transverse aortic constriction, a stress that induces concentric hypertrophy in control mice (PTIP+). PTIP- mice have a maladaptive response to 2wk of transverse aortic constriction (TAC)-induced pressure overload characterized by cardiac dilatation, decreased LV function, cardiac fibrosis, and increased cell death. PTIP deletion resulted in altered stress-induced gene expression profiles including blunted expression of ADRA1A, ADRA1B, JUN, ATP2A2, ATP1A2, SCN4B, and CACNA1G. These results suggest that H3K4 methylation patterns and the complexes that regulate them, specifically the PTIP-associated HMT, are necessary for the adaptive response to TAC.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Stein
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: Sascha N
authors.initials: SN
authors.lastname: Goonewardena
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Jones
authors.affiliation: Central Michigan University College of Medicine, Mt. Pleasant, MI, 48859, United States of America.
authors.forename: Parker J
authors.initials: PJ
authors.lastname: Prusick
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Bazzi
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Belyavskaya
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: Makayla M
authors.initials: MM
authors.lastname: McCoskey
authors.affiliation: Department of Biology, Kalamazoo College, Kalamazoo, MI, 49006, United States of America.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Dandar
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; C412792:Paxip1 protein, mouse; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase