Critical role of the BAF chromatin remodeling complex during murine neural crest development.

The BAF complex plays an important role in the development of a wide range of tissues by modulating gene expression programs at the chromatin level. However, its role in neural crest development has remained unclear. To determine the role of the BAF complex, we deleted BAF155/BAF170, the core subunits required for the assembly, stability, and functions of the BAF complex in neural crest cells (NCCs). Neural crest-specific deletion of BAF155/BAF170 leads to embryonic lethality due to a wide range of developmental defects including craniofacial, pharyngeal arch artery, and OFT defects. RNAseq and transcription factor enrichment analysis revealed that the BAF complex modulates the expression of multiple signaling pathway genes including Hippo and Notch, essential for the migration, proliferation, and differentiation of the NCCs. Furthermore, we demonstrated that the BAF complex is essential for the Brg1-Yap-Tead-dependent transcription of target genes in NCCs. Together, our results demonstrate an important role of the BAF complex in modulating the gene regulatory network essential for neural crest development.

Relevance of a TCGA-derived Glioblastoma Subtype Gene-Classifier among Patient Populations.

Glioblastoma multiforme (GBM), a deadly cancer, is the most lethal and common malignant brain tumor, and the leading cause of death in adult brain tumors. While genomic data continues to rocket, clinical application and translation to patient care are lagging behind. Big data now deposited in the TCGA network offers a window to generate novel clinical hypotheses. We hypothesized that a TCGA-derived gene-classifier can be applied across different gene profiling platforms and population groups. This gene-classifier validated three robust GBM-subtypes across six different platforms, among Caucasian, Korean and Chinese populations: Three Caucasian-predominant TCGA-cohorts (Affymetrix U133A = 548, Agilent Custom-Array = 588, RNA-seq = 168), and three Asian-cohorts (Affymetrix Human Gene 1.0ST-Array = 61, Illumina = 52, Agilent 4 × 44 K = 60). To understand subtype-relevance in patient therapy, we investigated retrospective TCGA patient clinical sets. Subtype-specific patient survival outcome was similarly poor and reflected the net result of a mixture of treatment regimens with/without surgical resection. As a proof-of-concept, in subtype-specific patient-derived orthotopic xenograft (PDOX) mice, Classical-subtype demonstrated no survival difference comparing radiation-therapy versus temozolomide monotherapies. Though preliminary, a PDOX model of Proneural/Neural-subtype demonstrated significantly improved survival with temozolomide compared to radiation-therapy. A larger scale study using this gene-classifier may be useful in clinical outcome prediction and patient selection for trials based on subtyping.