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Ramos-Mejia V.,University of Granada | Ramos-Mejia V.,Center for Genomics and Oncological Research | Navarro-Montero O.,University of Granada | Ayllon V.,University of Granada | And 5 more authors.
Blood | Year: 2014

The molecular determinants regulating the specification of human embryonic stem cells (hESCs) into hematopoietic cells remain elusive. HOXA9 plays a relevant role in leukemogenesis and hematopoiesis. It is highly expressed in hematopoietic stem and progenitor cells (HSPCs) and isdownregulated upon differentiation. Hoxa9-deficient mice display impaired hematopoietic development, and deregulation of HOXA9 expression is frequently associated with acute leukemia. Analysis of the genes differentially expressed in cord blood HSPCs vs hESC-derived HSPCs identified HOXA9 as the most down-regulated gene in hESC-derived HSPCs, suggesting that expression levels of HOXA9 may be crucial for hematopoietic differentiation of hESC. Here we show that during hematopoietic differentiation of hESCs, HOXA9 expression parallels hematopoietic development, but is restricted to the hemogenic precursors (HEP) (CD31+CD34+CD452), and diminishes as HEPs differentiate into blood cells (CD45+). Different gain-of-function andloss-of-functionstudiesrevealthatHOXA9enhanceshematopoieticdifferentiationof hESCs by specifically promoting the commitment of HEPs into primitive and total CD45+ blood cells. Geneexpression analysis suggests that nuclearfactor-kB signaling could be collaborating with HOXA9toincrease hematopoietic commitment. However, HOXA9onits ownisnot sufficienttoconferinvivo longterm engraftment potential to hESC-hematopoietic derivatives, reinforcing the idea that additional molecular regulators are needed for the generation of definitive in vivo functional HSPCs from hESC. © 2014 by The American Society of Hematology. Source

Lessard C.J.,Oklahoma Medical Research Foundation | Lessard C.J.,The University of Oklahoma Health Sciences Center | Adrianto I.,Oklahoma Medical Research Foundation | Kelly J.A.,Oklahoma Medical Research Foundation | And 47 more authors.
American Journal of Human Genetics | Year: 2011

Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 × 10-8) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 × 10-8, OR = 0.83) and rs387619 (p = 7.7 × 10-7, OR = 0.83) in the European samples with pmeta = 1.82 × 10-9 for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 × 10-3, OR = 0.81 and p = 4.3 × 10-4, OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced pmeta = 2.36 × 10-13. This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex. © 2011 The American Society of Human Genetics. Source

Coira I.F.,University of Granada | Coira I.F.,Center for Genomics and Oncological Research | Rufino-Palomares E.E.,University of Granada | Rufino-Palomares E.E.,Center for Genomics and Oncological Research | And 17 more authors.
Human Molecular Genetics | Year: 2015

SMARCA4 is the catalytic subunit of the SWI/SNF chromatin-remodeling complex, which alters the interactions between DNA and histones and modifies the availability of the DNA for transcription. The latest deep sequencing of tumor genomes has reinforced the important and ubiquitous tumor suppressor role of the SWI/SNF complex in cancer. However, although SWI/SNF complex plays a key role in gene expression, the regulation of this complex itself is poorly understood. Significantly, an understanding of the regulation of SMARCA4 expression has gained in importance due to recent proposals incorporating it in therapeutic strategies that use synthetic lethal interactions between SMARCA4-MAX and SMARCA4-SMARCA2. In this report,we found that the loss of expression of SMARCA4 observed in some primary lung tumors, whose mechanismwas largely unknown, can be explained, at least partially by the activity of microRNAs (miRNAs). We reveal that SMARCA4 expression is regulated by miR-101, miR-199 and especially miR-155 through their binding to two alternative 30UTRs. Importantly, our experiments suggest that the oncogenic properties of miR-155 in lung cancer can be largely explained by its role inhibiting SMARCA4. This new discovered functional relationship could explain the poor prognosis displayed by patients that independently have high miR-155 and lowSMARCA4 expression levels. In addition, these results could lead to application of incipient miRNA technology to the aforementioned synthetic lethal therapeutic strategies. © The Author 2014. Source

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