Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Feedback Loop Regulation of SCAP/SREBP-1 by miR-29 Modulates EGFR Signaling-Driven Glioblastoma Growth

SummaryDysregulated lipid metabolism is a characteristic of malignancies. Sterol regulatory element binding protein 1 (SREBP-1), a transcription factor playing a central role in lipid metabolism, is highly activated in malignancies. Here, we unraveled a link between miR-29 and the SCAP (SREBP cleavage-activating protein)/SREBP-1 pathway in glioblastoma (GBM) growth. Epidermal growth factor receptor (EGFR) signaling enhances miR-29 expression in GBM cells via upregulation of SCAP/SREBP-1, and SREBP-1 activates miR-29 expression via binding to specific sites in its promoter. In turn, miR-29 inhibits SCAP and SREBP-1 expression by interacting with their 3′ UTRs. miR-29 transfection suppressed lipid synthesis and GBM cell growth, which were rescued by the addition of fatty acids or N-terminal SREBP-1 expression. Xenograft studies showed that miR-29 mimics significantly inhibit GBM growth and prolong the survival of GBM-bearing mice. Our study reveals a previously unrecognized negative feedback loop in SCAP/SREBP-1 signaling mediated by miR-29 and suggests that miR-29 treatment may represent an effective means to target GBM

Inhibition of SOAT1 suppresses glioblastoma growth via blocking SREBP-1-mediated lipogenesis

Purpose: Elevated lipogenesis regulated by sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor playing a central role in lipid metabolism, is a novel characteristic of glioblastoma (GBM). The aim of this study was to identify effective approaches to suppress GBM growth by inhibition of SREBP-1. As SREBP activation is negatively regulated by endoplasmic reticulum (ER) cholesterol, we sought to determine whether suppression of sterol O-acyltransferase (SOAT), a key enzyme converting ER cholesterol to cholesterol esters (CE) to store in lipid droplets (LDs), effectively suppressed SREBP-1 and blocked GBM growth. Experimental Design: The presence of LDs in glioma patient tumor tissues was analyzed using immunofluorescence, immunohistochemistry, and electronic microscopy. Western blotting and real-time PCR were performed to analyze protein levels and gene expression of GBM cells, respectively. Intracranial GBM xenografts were used to determine the effects of genetically silencing SOAT1 and SREBP-1 on tumor growth. Results: Our study unraveled that cholesterol esterification and LD formation are signature of GBM, and human patients with glioma possess elevated LDs that correlate with GBM progression and poor survival. We revealed that SOAT1 is highly expressed in GBM and functions as a key player in controlling the cholesterol esterification and storage in GBM. Targeting SOAT1 suppresses GBM growth and prolongs survival in xenograft models via inhibition of SREBP-1-regulated lipid synthesis. Conclusions: Cholesterol esterification and storage in LDs are novel characteristics of GBM, and inhibiting SOAT1 to block cholesterol esterification is a promising therapeutic strategy to treat GBM by suppressing SREBP-1