Efficient Regulation of VEGF Expression by Promoter-Targeted Lentiviral shRNAs Based on Epigenetic Mechanism

Turunen, Mikko P.; Lehtola, Tiia; Heinonen, Suvi; Assefa, Genet S.; Korpisalo, Petra; Girnary, Roseanne; Glass, Christopher K.; Vaïsänen, Sami; Ylä‐Herttuala, Seppo

doi:10.1161/circresaha.109.200774

Cited by 99 publications

(136 citation statements)

References 25 publications

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“…TGS can be induced using siRNAs, antisense oligonucleotides [109], expressed antisense RNAs [110] or short hairpin RNAs [111,112]. And there are also examples of the successful implementation of this approach in vivo by local delivery in muscle [113], retina [112] and xenograft models [114]. The specificity of TGS is due to sequence complementarity between the small RNA effector and the target locus.…”

Section: Gene-specific Epigenetic Therapymentioning

confidence: 99%

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

2013

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The most fundamental roles of non-coding RNAs (ncRNAs) and epigenetic mechanisms are the guidance of cellular differentiation in development and the regulation of gene expression in adult tissues. In brain, both ncRNAs and the various epigenetic gene regulatory mechanisms play a fundamental role in neurogenesis and normal neuronal function. Thus, epigenetic chromatin remodelling can render coding sites transcriptionally inactive by DNA methylation, histone modifications or antisense RNA interactions. On the other hand, microRNAs (miRNAs) are ncRNA molecules that can regulate the expression of hundreds of genes post-transcriptionally, typically recognising binding sites in the 3′ untranslated region (UTR) of mRNA transcripts. Furthermore, there are a myriad of interactions in the interface of miRNAs and epigenetics. For example, epigenetic mechanisms can silence miRNA coding sites, and miRNAs can be the effectors of transcriptional gene silencing, targeting complementary promoters or silencing the expression of epigenetic modifier genes like MECP2 and EZH2 leading to global changes in the epigenome. Alterations in this regulatory machinery play a key role in the pathology of complex disorders including cancer and neurological diseases. For example, miRNA genes are frequently inactivated by epimutations in gliomas. Here we describe the interactions between epigenetic and ncRNA regulatory systems and discuss therapeutic potential, with an emphasis on tumors, cognitive disorders and neurodegenerative diseases.

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Section: Gene-specific Epigenetic Therapymentioning

confidence: 99%

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

2013

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“…The role of CREB2 in the regulation of VEGF-A is very interesting and warrants further studies. We have previously found H3K27 to be the most important histone residue for the epigenetic regulation of mouse VEGF-A expression [8,9]. Also, we have shown that CBP/CREB interaction inhibitor abolishes the shRNA-mediated upregulation of VEGF-A.…”

Section: Discussionmentioning

confidence: 77%

“…The construction of lentiviral (LV) shRNA expression vectors has been described [8]. The used target sequences were: CGTTCT-CAGTGCCACAAAT (-856) and GACGCGTGTTTCAATGTGA (-451).…”

Section: Vector Constructsmentioning

confidence: 99%

“…However, manipulation of VEGF-A expression, either upregulating the expression by delivering VEGF-A expression cassettes and recombinant proteins or inhibiting it by using RNAi or antibodies, is somewhat artificial in terms of endothelial biology. Recently it has become evident that small RNAs, such as miRNA, siRNA or shRNA, can regulate target gene expression via promoter targeted epigenetic modifications [6][7][8]. These processes have been studied in plants for a long time, but when Morris et al [6] found that small RNAs directed to the gene promoters induce transcriptional gene silencing (TGS) and a little later Li et al [7] showed that they can also induce transcriptional gene activation (TGA), their potential as therapeutics was quickly realized.…”

Section: Introductionmentioning

confidence: 99%

“…These molecules are complementary to the promoter of mouse VEGF-A gene, and they are known to either increase or decrease VEGF-A expression by causing epigenetic changes in the promoter region as described previously [8,9]. Epigenetic gene regulation is a natural mechanism for altering gene expression during development and adaptation to new situations.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of VEGF-A Expression in Endothelial Cells by Transcriptional Gene Activation or Transcriptional Gene Silencing: Analysis of Genome Wide Transcriptional Response

Husso¹,

Turunen²,

Ylä‐Herttuala³

2015

Gene Technol

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LINDA: the diabetes self-management training programme for people with type 1 or type 2 diabetes

Krakow¹,

Feulner-Krakow²

2007

European Diabetes Nursing

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Background: The LINDA education programme (LIP) is a new diabetes self-management tool for people with type 1 or type 2 diabetes mellitus (DM). Aim: To compare LIP with a standard education programme (control group, CG). Method: Clinical and behavioural data from 1109 DM patients, with mean diabetes duration of 12.6 years. A total of 374 type 2 non-insulin treated [T2]; 449 type 2 insulin-treated [T2I]; 286 type 1 [T1]) were evaluated over one year with the LIP in a randomised, controlled, three-arm study, or in a multicentre study. Results: T2 LIP patients achieved lower mean glycosylated haemoglobin (HbA 1c , 6.2%) and a reduction in body mass index (BMI) of 0.8 kg/m 2 . T2 CG patients reached a mean HbA 1c of 7% and showed an increase in BMI of 0.7 kg/m 2 . Mean blood pressure (BP) improved from 145/85 mmHg to 134/80 mmHg in T2 LIP patients, and from 145/84 mmHg to 141/80 mmHg in the CG. Triglyceride and cholesterol levels decreased in both groups. T2I patients reached a mean HbA 1c of 6.7% in the LIP group and 7.5% in the CG. BP fell to 136/79 mmHg in LIP patients and 138/79 mmHg in the CG. Triglyceride and cholesterol levels also decreased in both groups. For T1 patients, mean HbA 1c fell to 6.8% LIP; mean in CG patients reached 7.4%. A quality of life (QoL) questionnaire showed improvements from 20% to 80% in people who used the LIP. Conclusions: Patients who used the LIP achieved nearly normal values for HbA 1c and BP. Type 2 diabetes patients using LIP showed weight reduction and marked QoL improvement.

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Efficient Regulation of VEGF Expression by Promoter-Targeted Lentiviral shRNAs Based on Epigenetic Mechanism

Cited by 99 publications

References 25 publications

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

Regulation of VEGF-A Expression in Endothelial Cells by Transcriptional Gene Activation or Transcriptional Gene Silencing: Analysis of Genome Wide Transcriptional Response

LINDA: the diabetes self-management training programme for people with type 1 or type 2 diabetes

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