A new ternary molecular complex in Aortic thoracic aneurism cells dysfunction

da | Mag 28, 2018 | Biologia Molecolare

For the first time has been discovered the new HDAC9-BRG1-MALAT1 complex responsible for the smooth muscles cell dysfunction in Aortic thoracic aneurism, which would be a new target for epigenetic therapy of vascular diseases.

Figure 1. The assembly of the ternary molecular complex. (a) HDAC9-BRG1-MALAT1 complex formation in VSMCs, responsible of the loss of contractile property in the tissue. (b) Destruction of the HDAC9-BRG1-MALAT1 complex in VSMCs restores the contractile property.
Aneurism is a tricky disease for its fatal consequences. Because it is symptomless it is difficult to detect it in time and it can be solved only with surgery. Nowadays, there is not a pharmaceutical cure that could be employed for aneurysm treatment. For that reason, the study performed by Christian L. Lino Cardenas et al. Research group from the Harvard Medical School (Boston, USA), on samples cells collected from thoracic aortic aneurism tissue [1], could give new ideas for developing new therapeutic strategies against aneurysm and vasculopathies. In this paper, Christian L.Lino Cardenas et al. discovered the existence of a new molecular complex which is responsible for the silencing of contractile genes in vascular smooth muscle cells (VSMCs). This complex is composed by Histone Deacetylases 9 (HADC9), a protein which removes acetyl groups from histones tails and favours the formation of compact chromatin, Brahma Related Gene 1 (BRG1), a chromatin-remodelling enzyme and Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), a long non-coding RNA . These three together block the transcription of contractile genes in smooth muscle cells leading to the loss of contractile properties in the tissue and aneurism formation. The authors studied the aneurysm cells with genetic perturbation like altered TGFβ pathway and altered components and regulators of VSMC. They discovered an over-expression of HDAC9 in the nucleus. This result brought them to think that HDAC9 could bound another protein, forming a complex. This was confirmed by immunoprecipitation analysis, that showed HDAC9 binding to BRG1, a bond that has already been validated in cardiomyocytes[2], and they both are upregulated in nucleus. After that the team hypothesized that this complex may associate with nuclear RNA to modulate chromatin events. Indeed, after running a ChiRP assay, they found that HDAC9 and BRG1 bind only with one RNA, MALAT1. This new generation technique appears to be the most useful and designed to detect long non-coding RNA bindings with DNA sequences. Therefore, with the formation of the complex, Polycomb Repressive Complex 2 (PRC2), proteins responsible of silencing genes, is recruited and contractile genes are repressed. At the end, they ran experiments in vivo.
Their results show that in murine models modulating expression of one of the member of the complex, like MALAT1 or HDAC9, inhibits complex formation and improves the aneurism features. Interestingly, they discovered that HDAC9 expression is induced by cytoskeletal alteration and that MALAT1 is essential for HDAC9 accumulation, nuclear localization and complex formation; its depletion brings back to the healthy phenotype. It also reverses the expression of contractile proteins and lowers the level of Cofilin1, which inhibits actin polymerization. Otherwise, the target of interest seems to be HDAC9 since its human variants have been found in other vascular diseases such as stroke[3], myocardial infraction [4] intracranial aneurysm[5] and aortic calcification.

It remains obscure how the complex assemble and how it really works. To our knowledge, BRG1 is the element of the complex that binds to the nucleic acids on high conserved sequences [6]. HDAC9, that interacts with BRG1, is then the “recruiter” of PRC2 protein complex witch plays a role in epigenetic modifications, while MALAT1 with its triple helical motif at his 3’ end binds EZH2[7], the catalytic subunit of the PCR2 complex. This all bring to the trimethylation of the Lysine 27 on the H3 histone, epigenetic event well known to silence gene expression. It appears intriguing how this works but there is not a clear view on how all of this takes place, nor how to set in a temporal line all these events. We just know that MALAT1 is able to bind both BRG1 and HDAC9 and that it is the crucial link to the complex formation. It is easy to think MALAT1 as a target for therapy. However, besides the well known role of MALAT1 in cancer little is known about its role in aneurism.  It will be useful to study in detail other forms of aneurism and see whether it   forms the same or similar complexes to start thinking it as a new target for genetic therapy of aneurism. Until that we should focus our attention on HDAC9. It should be easier to ideate a new drug to interfere with the protein shuttling from the cytoplasm to the nucleus, sequestering HDAC9 in the cytoplasm  reducing its accumulation in the nucleus to   inhibit the complex formation

References

  1. Christian L. Lino Cardenas et al. An HDAC9-BRG1-MALAT1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. Nature communications, 2018.
  2. Hang, C. T. et al. Chromatin regulation by Brg1 underlies heart muscle development and disease. Nature 466, 62 –67.
  3. International Stroke Genetics, C. et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat. Genet. 44, 328–333.
  4. Consortium, C. A. D. et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat. Genet. 45, 25 –33.
  5. Foroud, T. et al. Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7. Stroke 45, 3194–3199.
  6. Filarsky, M. et al. The extended AT-hook is a novel RNA binding motif. RNA Biol. 12, 864–876.
  7. Wang, D. et al. LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer. Oncotarget 6, 41045–41055.

Claudia Grillo

Master Industrial Biotechnology student

Giulia Vassallo

Master Industrial Biotechnology student

 

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