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Publicaciones Nanomedicina

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26

Jul 2018

Epigenome-wide analysis reveals specific DNA hypermethylation of T cells during human hematopoietic differentiation

Posted by / in Publicaciones Nanomedicina, Publications 2018, Publications Nanomedicine 2018, Últimas Publicaciones CINN / No comments yet

Aim: Epigenetic regulation plays an important role in cellular development and differentiation. A detailed map of the DNA methylation dynamics that occur during cell differentiation would contribute to decipher the molecular networks governing cell fate commitment. Methods: Illumina MethylationEPIC BeadChip platform was used to describe the genome-wide DNA methylation changes observed throughout hematopoietic maturation by analyzing multiple myeloid and lymphoid hematopoietic cell types. Results: We identified a plethora of DNA methylation changes that occur during human hematopoietic differentiation. We observed that T lymphocytes display substantial enhancement of de novo CpG hypermethylation as compared with other hematopoietic cell populations. T-cell-specific hypermethylated regions were strongly associated with open chromatin marks and enhancer elements, as well as binding sites of specific key transcription factors involved in hematopoietic differentiation, such as PU.1 and TAL1. Conclusion: These results provide novel insights into the role of DNA methylation at enhancer elements in T-cell development.

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13

Jun 2018

Epigenetic dysregulation of TET2 in human glioblastoma

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Ten-eleven translocation (TET) enzymes are frequently deregulated in cancer, but the underlying molecular mechanisms are still poorly understood. Here we report that TET2 shows frequent epigenetic alterations in human glioblastoma including DNA hypermethylation and hypo-hydroxymethylation, as well as loss of histone acetylation. Ectopic overexpression of TET2 regulated neural differentiation in glioblastoma cell lines and impaired tumor growth. Our results suggest that epigenetic dysregulation of TET2 plays a role in human glioblastoma.

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14

May 2018

SDHC Promoter Methylation, a Novel Pathogenic Mechanism in Parasympathetic Paragangliomas

Posted by / in Publicaciones Nanomedicina, Publications 2018, Publications Nanomedicine 2018, Últimas Publicaciones CINN / No comments yet

Germline mutations in the succinate dehydrogenase A, B, C, and D genes (collectively, SDHx) predispose to the development of paragangliomas (PGLs) arising at the parasympathetic or sympathetic neuroendocrine systems. SDHxmutations cause absence of tumoral immunostaining for SDHB. However, negative SDHB immunostaining has also been found in a subset of PGLs that lack SDHx mutations.
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Here, we report the comprehensive molecular characterization of one such a tumor of parasympathetic origin compared with healthy paraganglia and other PGLs with or without SDHx mutations.

Results

Integration of multiplatform data revealed somatic SDHC methylation and loss of the 1q23.3 region containing the SDHC gene. This correlated with decreased SDHC messenger RNA (mRNA) and protein levels. Furthermore, another genetic event found affected the VHL gene, which showed a decreased DNA copy number, associated with low VHL mRNA levels, and an absence of VHL protein detected by immunohistochemistry. In addition, the tumor displayed a pseudohypoxic phenotype consisting in overexpression of the hypoxia-inducible factor (HIF)-1α and miR-210, as well as downregulation of the iron-sulfur cluster assembly enzyme (ISCU) involved in SDHB maturation. This profile resembles that of SDHx- or VHL-mutated PGLs but not of PGLs with decreased VHL copy number, pointing to SDHC rather than VHL as the pathogenic driver.

Conclusions

Collectively, these findings demonstrate the potential importance of both the SDHC epigenomic event and the activation of the HIF-1α/miR-210/ISCU axis in the pathogenesis of SDHx wild-type/SDHB-negative PGLs. To our knowledge, this is the first case of a sporadic parasympathetic PGL that carries silencing of SDHC, fulfilling the two-hit Knudson’s model for tumorigenesis.

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