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.

Loss of zebrafish Smyd1a interferes with myofibrillar integrity without triggering the misfolded myosin response

“…It might be possible that Smyd1a expression is controlled via different mechanisms, for example mechanical overload or hypoxia. In this context, it is already known that Smyd1, together with its interaction partner skNAC (muscle-restricted isoform of the DNA binding protein nascent polypeptide-associated complex) has a crucial role in the response to oxidative and ER stress in the developing mammalian heart [18]. Thus, in zebrafish it might be possible that Smyd1a exhibits the main PKMT activity whereas Smyd1b is mainly responsible for sarcomere organization.…”

Resetting the epigenome for heart regeneration.

“…Homozygous Smyd1 knockout mice are embryonic lethal at E10.5 and present with severe ventricular hypoplasia and defects in right ventricular formation and trabeculation, associated with transcriptional repression of right ventricular-specific TFs, including Hand2 [83]. Conditional deletion of Smyd1 using the Nkx2.5-Cre driver resulted in defective expansion of second heart field progentiors and reduced cardiomyocyte proliferation [84]. Smyd1 morpholino knockdown in zebrafish embryos also disrupts myofiber maturation [85], further suggesting SMYD1 is essential for cardiac muscle maturation.…”

Role of Muscle-Specific Histone Methyltransferase (Smyd1) in Exercise-Induced Cardioprotection against Pathological Remodeling after Myocardial Infarction

“…SET and MYND domain containing 1 (Smyd1) is a histone methyltransferase specifically expressed in skeletal muscle and myocardium [ 7 , 8 , 9 ]. Smyd1 has been reported to play a crucial regulatory role in differentiation and maturation of skeletal and cardiac muscle cells [ 10 , 11 , 12 ], especially in sarcomere formation and assembly, muscle fibers composition, and myogenesis during cardiogenesis and ventricular development [ 13 ]; however, its role in the adult heart remains poorly understood. It was recently demonstrated that Smyd1 was significantly upregulated in a mouse model of pressure overload-induced HF and that cardiac-specific Smyd1 knockout mice developed cardiomyocyte hypertrophy that led to significant structural remodeling and severe HF [ 14 ].…”

“…It was recently demonstrated that Smyd1 was significantly upregulated in a mouse model of pressure overload-induced HF and that cardiac-specific Smyd1 knockout mice developed cardiomyocyte hypertrophy that led to significant structural remodeling and severe HF [ 14 ]. On the other hand, Smyd1 was required for maintaining cardiomyocyte proliferation during the embryonic heart developmental stages and loss of Smyd1 led to lethal consequences [ 11 ]. Moreover, Franklin et al recently suggested a role of Smyd1 as a positive regulator of cardiac metabolism and that activation of Smyd1 can prevent pathological cell growth [ 14 ].…”