Broad Institute

About: Broad Institute is a nonprofit organization based out in Cambridge, Massachusetts, United States. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 6584 authors who have published 11618 publications receiving 1522743 citations. The organization is also known as: Eli and Edythe L. Broad Institute of MIT and Harvard.

Dicer1 functions as a haploinsufficient tumor suppressor

Abstract: MicroRNAs (miRNAs) are short, noncoding RNAs that function to suppress post-transcriptionally the expression of target mRNAs, predominately via inhibition of translation. Such translational inhibition relies on imperfect base-pairing between the miRNA and the target transcript, with the interaction at nucleotides 2–8 (or the “seed” region) of the miRNA being required for translational repression. Computational prediction of miRNA targets based on seed regions and sequence conservation has revealed a widespread potential for miRNA-mediated transcript regulation, with hundreds of putative mRNA targets for an individual miRNA (Bartel 2004). In line with their broad-based effects, miRNAs have been proposed to function as oncogenes or tumor suppressor genes based on their inhibition of a variety of tumor-suppressive and oncogenic mRNAs, respectively (Plasterk 2006; Ventura and Jacks 2009). In particular, three distinct mechanisms have been posited. First, oncogenic miRNAs can undergo gain of function in tumors. This has been most clearly demonstrated for the miR-17∼92 cluster, whose amplification in B-cell lymphomas promotes their development, potentially through its control of B-cell differentiation (He et al. 2005; Koralov et al. 2008; Ventura et al. 2008). Furthermore, tumor-suppressive miRNAs could undergo loss of function in tumors. This has been shown for several miRNAs, including the let-7 family, whose expression can limit lung tumorigenesis through inhibition of oncogenes like the Ras family and HMGA2 (Esquela-Kerscher et al. 2008; Kumar et al. 2008). In particular, let-7 family members are in sites of frequent deletion in human tumors, and their processing is inhibited by the oncogenic Lin-28 proteins (Heo et al. 2008; Newman et al. 2008; Viswanathan et al. 2008; Chang et al. 2009). Finally, oncogenes can acquire mutations to remove miRNA-binding sites in tumors. This has been described for HMGA2, whose translocation promotes lipoma development by releasing the transcript from let-7-mediated tumor suppression (Mayr et al. 2007). We reported a global down-regulation of miRNAs in several types of human and murine cancer (Lu et al. 2005). From this initial study, it was unclear whether this widespread loss of miRNAs was merely a consequence of tumor development or was functionally related to the disease process. We demonstrated previously that this global loss of miRNAs was functionally relevant to oncogenesis, as impairment of miRNA maturation enhanced transformation in both cancer cells and a K-Ras-driven model of lung cancer (Kumar et al. 2007). While these studies provide a framework to explain inhibition of miRNA biogenesis in cancer, the genetic basis of impaired miRNA processing in human cancer has been largely undefined. For a subset of miRNAs, widespread silencing occurs at the transcriptional level via the c-Myc oncogene (Chang et al. 2008). However, it has also been shown that such broad reductions in miRNAs can occur post-transcriptionally, since changes in miRNA levels frequently occur without changes in the levels of the primary miRNA transcript (Thomson et al. 2006). Recently, it was shown that mutations in the miRNA processing component TARBP2 occur frequently in mismatch repair-deficient colon cancer, and that these mutations promote tumorigenesis by impaired processing of miRNAs (Melo et al. 2009). While interesting, these limited cases do not resolve the common global reduction of miRNAs in human cancers. Moreover, the precise genetics of such changes in tumors is poorly defined, especially as no components of the miRNA processing pathway have been reported to be completely deleted in human tumors. This is not surprising, since it has been shown that germline deletion of miRNA processing components Dicer1 and Dgcr8 in mice fails to produce viable progeny (Bernstein et al. 2003; Wang et al. 2007). Thus, conditional deletion of miRNA processing components provides a powerful means of examining the role of miRNAs in tumorigenesis.

Distinct microRNA expression profiles in acute myeloid leukemia with common translocations

Abstract: MicroRNAs (miRNAs) are postulated to be important regulators in cancers. Here, we report a genome-wide miRNA expression analysis in 52 acute myeloid leukemia (AML) samples with common translocations, including t(8;21)/AML1(RUNX1)-ETO(RUNX1T1), inv(16)/CBFB-MYH11, t(15;17)/PML-RARA, and MLL rearrangements. Distinct miRNA expression patterns were observed for t(15;17), MLL rearrangements, and core-binding factor (CBF) AMLs including both t(8;21) and inv(16) samples. Expression signatures of a minimum of two (i.e., miR-126/126*), three (i.e., miR-224, miR-368, and miR-382), and seven (miR-17-5p and miR-20a, plus the aforementioned five) miRNAs could accurately discriminate CBF, t(15;17), and MLL-rearrangement AMLs, respectively, from each other. We further showed that the elevated expression of miR-126/126* in CBF AMLs was associated with promoter demethylation but not with amplification or mutation of the genomic locus. Our gain- and loss-of-function experiments showed that miR-126/126* inhibited apoptosis and increased the viability of AML cells and enhanced the colony-forming ability of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, likely through targeting Polo-like kinase 2 (PLK2), a tumor suppressor. Our results demonstrate that specific alterations in miRNA expression distinguish AMLs with common translocations and imply that the deregulation of specific miRNAs may play a role in the development of leukemia with these associated genetic rearrangements.

Sequencing of Culex quinquefasciatus Establishes a Platform for Mosquito Comparative Genomics

Abstract: Culex quinquefasciatus (the southern house mosquito) is an important mosquito vector of viruses such as West Nile virus and St. Louis encephalitis virus, as well as of nematodes that cause lymphatic filariasis. C. quinquefasciatus is one species within the Culex pipiens species complex and can be found throughout tropical and temperate climates of the world. The ability of C. quinquefasciatus to take blood meals from birds, livestock, and humans contributes to its ability to vector pathogens between species. Here, we describe the genomic sequence of C. quinquefasciatus: Its repertoire of 18,883 protein-coding genes is 22% larger than that of Aedes aegypti and 52% larger than that of Anopheles gambiae with multiple gene-family expansions, including olfactory and gustatory receptors, salivary gland genes, and genes associated with xenobiotic detoxification.