The immense amount of DNA, RNA and proteins that contribute to our genetic programs are precisely organized inside the cell¹s nucleus. My group studies how nuclear organization impacts gene regulation, and how misregulation of non-coding RNAs contributes to human diseases such as cancer.
David L. Spector’s laboratory is focused on characterizing long non-coding RNAs (lncRNAs) that exhibit altered levels of expression in breast cancer progression and during embryonic stem cell differentiation. A major focus of their efforts has been on Malat1 lncRNA, which is one of the most abundant lncRNAs. The Spector lab previously identified a novel mechanism of 3′-end processing of this RNA. More recent studies have revealed that increased levels of Malat1 lncRNA impact breast cancer progression and metastasis. Knockout or antisense oligonucleotide knockdown of Malat1 results in the differentiation of mammary tumors and a significant reduction in metastasis. Studies are currently under way to elucidate the mechanism of action of this abundant nuclear retained lncRNA and to implement innovative therapeutic approaches that can impact its function in vivo. In addition, they have identified additional lncRNAs, termed Mammary Tumor Associated RNAs, that are upregulated in breast tumors, and they are currently assessing the function of these lncRNAs using 3D tumor organoids as well as mouse models.
A second area of study in the Spector lab is based on their earlier discovery of an increase in random autosomal monoallelic gene expression upon the differentiation of mouse embryonic stem cells to neural progenitor cells. These data support a model where stochastic gene regulation during differentiation results in monoallelic gene expression, and for some genes, the cell is able to compensate transcriptionally to maintain the required transcriptional output of these genes. Therefore, random monoallelic gene expression exemplifies the stochastic and plastic nature of gene expression in single cells. Ongoing studies are examining the relationship of monoallelic gene expression to lineage commitment.
Diermeier, Sarah D and Chang, Kung-Chi and Freier, Susan M and Song, Junyan and El Demerdash, Osama and Krasnitz, Alexander and Rigo, Frank and Bennett, C. Frank and Spector, David L (2016) Mammary Tumor-Associated RNAs Impact Tumor Cell Proliferation, Invasion, and Migration. Cell Reports, 17(1) pp. 261-274.
Arun, G. and Diermeier, S. and Akerman, M. and Chang, K. C. and Wilkinson, J. E. and Hearn, S. and Kim, Y. and MacLeod, A. R. and Krainer, A. R. and Norton, L. and Brogi, E. and Egeblad, M. and Spector, D. L. (2016) Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev, 30(1) pp. 34-51.
Bergmann, J. H. and Li, J. and Eckersley-Maslin, M. A. and Rigo, F. and Freier, S. M. and Spector, D. L. (2015) Regulation of the ESC transcriptome by nuclear long non-coding RNAs. Genome Res, 25(9) pp. 1336-1346.
Eckersley-Maslin, M. A. and Thybert, D. and Bergmann, J. H. and Marioni, J. C. and Flicek, P. and Spector, D. L. (2014) Random Monoallelic Gene Expression Increases upon Embryonic Stem Cell Differentiation. Developmental Cell, 28(4) pp. 351-65.
Zhang, B. and Arun, G. and Mao, Y. S. and Lazar, Z. and Hung, G. and Bhattacharjee, G. and Xiao, X. and Booth, C. J. and Wu, J. and Zhang, C. and Spector, D. L. (2012) The lncRNA Malat1 is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult. Cell Reports, 2(1) pp. 111-123.Additional materials of the author at
CSHL Institutional Repository