The HDAC7-TET2 epigenetic axis is essential during early B lymphocyte development.

Correct B cell identity at each stage of cellular differentiation during B lymphocyte development is critically dependent on a tightly controlled epigenomic landscape. We previously identified HDAC7 as an essential regulator of early B cell development and its absence leads to a drastic block at the pro-B to pre-B cell transition. More recently, we demonstrated that HDAC7 loss in pro-B-ALL in infants associates with a worse prognosis. Here we delineate the molecular mechanisms by which HDAC7 modulates early B cell development. We find that HDAC7 deficiency drives global chromatin de-condensation, histone marks deposition and deregulates other epigenetic regulators and mobile elements. Specifically, the absence of HDAC7 induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. HDAC7 deficiency also results in the aberrant expression of microRNAs and LINE-1 transposable elements. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to B cell-based hematological malignancies.

Integrating differential expression, co-expression and gene network analysis for the identification of common genes associated with tumor angiogenesis deregulation.

Angiogenesis is essential for tumor growth and cancer metastasis. Identifying the molecular pathways involved in this process is the first step in the rational design of new therapeutic strategies to improve cancer treatment. In recent years, RNA-seq data analysis has helped to determine the genetic and molecular factors associated with different types of cancer. In this work we performed integrative analysis using RNA-seq data from human umbilical vein endothelial cells (HUVEC) and patients with angiogenesis-dependent diseases to find genes that serve as potential candidates to improve the prognosis of tumor angiogenesis deregulation and understand how this process is orchestrated at the genetic and molecular level. We downloaded four RNA-seq datasets (including cellular models of tumor angiogenesis and ischaemic heart disease) from the Sequence Read Archive. Our integrative analysis includes a first step to determine differentially and co-expressed genes. For this, we used the ExpHunter Suite, an R package that performs differential expression, co-expression and functional analysis of RNA-seq data. We used both differentially and co-expressed genes to explore the human gene interaction network and determine which genes were found in the different datasets that may be key for the angiogenesis deregulation. Finally, we performed drug repositioning analysis to find potential targets related to angiogenesis inhibition. We found that that among the transcriptional alterations identified, SEMA3D and IL33 genes are deregulated in all datasets. Microenvironment remodeling, cell cycle, lipid metabolism and vesicular transport are the main molecular pathways affected. In addition to this, interacting genes are involved in intracellular signaling pathways, especially in immune system and semaphorins, respiratory electron transport and fatty acid metabolism. The methodology presented here can be used for finding common transcriptional alterations in other genetically-based diseases.

Role of SWI/SNF chromatin remodeling genes in lung cancer development.

SWI/SNF family of chromatin remodeling complexes uses the energy of ATP to change the structure of DNA, playing key roles in DNA regulation and repair. It is estimated that up to 25% of all human cancers contain alterations in SWI/SNF, although the precise molecular mechanisms for their involvement in tumor progression are largely unknown. Despite the improvements achieved in the last decades on our knowledge of lung cancer molecular biology, it remains the major cause of cancer-related deaths worldwide and it is in urgent need for new therapeutic alternatives. We and others have described recurrent alterations in different SWI/SNF genes in nearly 20% of lung cancer patients, some of them with a significant association with worse prognosis, indicating an important role of SWI/SNF in this fatal disease. These alterations might be therapeutically exploited, as it has been shown in cellular and animal models with the use of EGFR inhibitors, DNA-damaging agents and several immunotherapy approaches. Therefore, a better knowledge of the molecular mechanisms regulated by SWI/SNF alterations in lung cancer might be translated into a therapeutic improvement of this frequently lethal disease. In this review, we summarize all the evidence of SWI/SNF alterations in lung cancer, the current knowledge about the potential mechanisms involved in their tumorigenic role, as well as the results that support a potential exploitation of these alterations to improve the treatment of lung cancer patients.

ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to chemotherapy in lung cancer.

The survival rate in lung cancer remains stubbornly low and there is an urgent need for the identification of new therapeutic targets. In the last decade, several members of the SWI/SNF chromatin remodeling complexes have been described altered in different tumor types. Nevertheless, the precise mechanisms of their impact on cancer progression, as well as the application of this knowledge to cancer patient management are largely unknown. In this study, we performed targeted sequencing of a cohort of lung cancer patients on genes involved in chromatin structure. In addition, we studied at the protein level the expression of these genes in cancer samples and performed functional experiments to identify the molecular mechanisms linking alterations of chromatin remodeling genes and tumor development. Remarkably, we found that 20% of lung cancer patients show ARID2 protein loss, partially explained by the presence of ARID2 mutations. In addition, we showed that ARID2 deficiency provokes profound chromatin structural changes altering cell transcriptional programs, which bolsters the proliferative and metastatic potential of the cells both in vitro and in vivo. Moreover, we demonstrated that ARID2 deficiency impairs DNA repair, enhancing the sensitivity of the cells to DNA-damaging agents. Our findings support that ARID2 is a bona fide tumor suppressor gene in lung cancer that may be exploited therapeutically.