title: Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses.
abstract: Smyd1/Bop is an evolutionary conserved histone methyltransferase previously shown by conventional knockout to be critical for embryonic heart development. To further explore the mechanism(s) in a cell autonomous context, we conditionally ablated Smyd1 in the first and second heart fields of mice using a knock-in (KI) Nkx2.5-cre driver. Robust deletion of floxed-Smyd1 in cardiomyocytes and the outflow tract (OFT) resulted in embryonic lethality at E9.5, truncation of the OFT and right ventricle, and additional defects consistent with impaired expansion and proliferation of the second heart field (SHF). Using a transgenic (Tg) Nkx2.5-cre driver previously shown to not delete in the SHF and OFT, early embryonic lethality was bypassed and both ventricular chambers were formed; however, reduced cardiomyocyte proliferation and other heart defects resulted in later embryonic death at E11.5-12.5. Proliferative impairment prior to both early and mid-gestational lethality was accompanied by dysregulation of transcripts critical for endoplasmic reticulum (ER) stress. Mid-gestational death was also associated with impairment of oxidative stress defense-a phenotype highly similar to the previously characterized knockout of the Smyd1-interacting transcription factor, skNAC. We describe a potential feedback mechanism in which the stress response factor Tribbles3/TRB3, when directly methylated by Smyd1, acts as a co-repressor of Smyd1-mediated transcription. Our findings suggest that Smyd1 is required for maintaining cardiomyocyte proliferation at minimally two different embryonic heart developmental stages, and its loss leads to linked stress responses that signal ensuing lethality.
authors: Molecular Biosciences and Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas, United States of America.
authors: Tara L
authors: TL
authors: Rasmussen
authors: Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Affiliated Hospital of Hainan Medical University, Haikou, Hainan, P.R. China; Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors: Yanlin
authors: Y
authors: Ma
authors: Gladstone Institute of Cardiovascular Disease and Departments of Pediatrics and Biochemistry and Biophysics, University of California, San Francisco, California, United States of America.
authors: Chong Yon
authors: CY
authors: Park
authors: Molecular Biosciences and Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas, United States of America.
authors: June
authors: J
authors: Harriss
authors: Gladstone Institute of Cardiovascular Disease and Departments of Pediatrics and Biochemistry and Biophysics, University of California, San Francisco, California, United States of America.
authors: Stephanie A
authors: SA
authors: Pierce
authors: Molecular Biosciences and Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas, United States of America.
authors: Joseph D
authors: JD
authors: Dekker
authors: Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors: Nicolas
authors: N
authors: Valenzuela
authors: Gladstone Institute of Cardiovascular Disease and Departments of Pediatrics and Biochemistry and Biophysics, University of California, San Francisco, California, United States of America.
authors: Deepak
authors: D
authors: Srivastava
authors: Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors: Robert J
authors: RJ
authors: Schwartz
authors: Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors: M David
authors: MD
authors: Stewart
authors: Molecular Biosciences and Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas, United States of America.
authors: Haley O
authors: HO
authors: Tucker
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000196:embryology; D059865:Endoplasmic Reticulum Stress; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006321:Heart / Q000254:growth & development*; D006801:Humans; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D018384:Oxidative Stress; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009124:Muscle Proteins; C096485:Smyd1 protein, mouse; C474830:TRB3 protein, mouse; D014157:Transcription Factors