SMYD2 is induced during cell differentiation and participates in early development

Sesé, Borja; Barrero, María J.; Fabregat, Maria-Carme; Sander, Veronika; Belmonte, Juan Carlos Izpisúa

doi:10.1387/ijdb.130051ji

Cited by 29 publications

(21 citation statements)

References 51 publications

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“…While smyd1a and smyd2 showed higher expressions in developing somite region from 10 somite stage (ss) than smyd3 and setd7 , hinting their roles in somitogenesis (Figs. 1 and 2) (Sesé et al, 2013), the developmental expression regions of smyd3 and setd7 were highly expressed within the heart forming region at 36 h post-fertilization (hpf) and 48 hpf, respectively (red arrow heads in Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Proper Activity of Histone H3 Lysine 4 (H3K4) Methyltransferase Is Required for Morphogenesis during Zebrafish Cardiogenesis

Kim¹,

Kim²,

Koun³

et al. 2015

Molecules and Cells

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While increasing evidence indicates the important function of histone methylation during development, how this process influences cardiac development in vertebrates has not been explored. Here, we elucidate the functions of two histone H3 lysine 4 (H3K4) methylation enzymes, SMYD3 and SETD7, during zebrafish heart morphogenesis using gene expression profiling by whole mount in situ hybridization and antisense morpholino oligonucleotide (MO)-based gene knockdown. We find both smyd3 and setd7 are highly expressed within developing zebrafish heart and knock-down of these genes led to severe defects in cardiac morphogenesis without altering the expressions pattern of heart markers, including cmlc2, vmhc, and amhc. Furthermore, double knock-down by coinjection of smyd3 and setd7 MOs caused the synergistic defects in heart development. As similar to knock-down effect, overexpression of these genes also caused the heart morphogenesis defect in zebrafish. These results indicate that histone modifying enzymes, SMYD3 and SETD7, appear to function synergistically during heart development and their proper functioning is essential for normal heart morphogenesis during development.

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Section: Resultsmentioning

confidence: 99%

Proper Activity of Histone H3 Lysine 4 (H3K4) Methyltransferase Is Required for Morphogenesis during Zebrafish Cardiogenesis

Kim¹,

Kim²,

Koun³

et al. 2015

Molecules and Cells

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show abstract

“…SMYD2 regulates HSP90 methylation50 and the inhibition of HSP90 has been shown to reduce AAA formation in murine models51, suggesting this as a possible link between SMYD2 and AAA. SMYD2 also plays a role in the differentiation of embryonic stem cells52, again suggesting a possible role for aberrations of in utero aortic development influencing the risk of aortic disease later in life.…”

Section: Discussionmentioning

confidence: 99%

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Jones¹,

Tromp²,

Kuivaniemi³

et al. 2017

Circulation Research

174

195

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Rationale Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective To identify additional AAA risk loci using data from all available genome-wide association studies (GWAS). Methods and Results Through a meta-analysis of 6 GWAS datasets and a validation study totalling 10,204 cases and 107,766 controls we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches we observed no new associations between the lead AAA SNPs and coronary artery disease, blood pressure, lipids or diabetes. Network analyses identified ERG, IL6R and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions The 4 new risk loci for AAA appear to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

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“…The involvement of SMYD2 in regulation of cell proliferation was suggested previously. Indeed, overexpression of SMYD2 stimulated proliferation of esophageal squamous cancer cell lines, but inhibited growth of murine fibroblasts and Embryonic Stem Cells indicating strong cell type dependency [31, 32, 50]. Moreover, knockdown of SMYD2 attenuated growth of several epithelial and mesenchyme derived cancer lines [30, 31].…”

Section: Discussionmentioning

confidence: 99%

SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress

et al. 2017

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The molecular determinants governing escape of Acute Myeloid Leukemia (AML) cells from DNA damaging therapy remain poorly defined and account for therapy failures. To isolate genes responsible for leukemia cells regeneration following multiple challenges with irradiation we performed a genome-wide shRNA screen. Some of the isolated hits are known players in the DNA damage response (e.g. p53, CHK2), whereas other, e.g. SMYD2 lysine methyltransferase (KMT), remains uncharacterized in the AML context. Here we report that SMYD2 knockdown confers relative resistance to human AML cells against multiple classes of DNA damaging agents. Induction of the transient quiescence state upon SMYD2 downregulation correlated with the resistance. We revealed that diminished SMYD2 expression resulted in the upregulation of the related methyltransferase SET7/9, suggesting compensatory relationships. Indeed, pharmacological targeting of SET7/9 with (R)-PFI2 inhibitor preferentially inhibited the growth of cells expressing low levels of SMYD2.Finally, decreased expression of SMYD2 in AML patients correlated with the reduced sensitivity to therapy and lower probability to achieve complete remission. We propose that the interplay between SMYD2 and SET7/9 levels shifts leukemia cells from growth to quiescence state that is associated with the higher resistance to DNA damaging agents and rationalize SET7/9 pharmacological targeting in AML.

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SMYD2 is induced during cell differentiation and participates in early development

Cited by 29 publications

References 51 publications

Proper Activity of Histone H3 Lysine 4 (H3K4) Methyltransferase Is Required for Morphogenesis during Zebrafish Cardiogenesis

Proper Activity of Histone H3 Lysine 4 (H3K4) Methyltransferase Is Required for Morphogenesis during Zebrafish Cardiogenesis

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress

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