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Understanding how the nuclear periphery and other subcompartments contribute to general nuclear architecture and to specific gene regulation
Understanding the cell biology of genomes and how nuclear architecture controls gene expression is necessary to truly understand biological processes such as development and disease. Although sequencing of the genome and comparative genome analysis have yielded insights into the regulation and dis-regulation of genetic information, these efforts shed little light into how genomes actually work in vivo. The impact of architectural and cellular organization of genomes on gene activity is a next step to unlocking genetic and epigenetic mechanisms in development and disease. Recent evidence is emerging that the non-random organization in the nucleus is a contributing factor in regulating genes important to multiple developmental processes. Moreover, some studies suggest that the non-random organization in the nucleus is a contributing factor in initiating translocations. In mammalian nuclei, chromatin is organized into structural domains by association with distinct nuclear compartments. Such interactions are likely to bring together coordinately regulated genes and to focus proteins and enzymes that regulate DNA based activities such as transcription, recombination, replication and repression. While evidence mounts that genes are regulated by association with distinct nuclear compartments, relatively little is known about how specific loci are directed to different domains. I hypothesize that such “nuclear addressing” requires specific cis elements that interact with a set of sequestered proteins (trans factors) to establish and maintain nuclear architecture and functionality. Such self-reinforcing interactions likely lie at the heart of nuclear structure and function. My recent work has demonstrated that one such compartment that is important for both nuclear structure and gene regulation is the nuclear periphery. In addition to regulation of Immunoglobulin Heavy Chain loci, the nuclear envelope (NE) is also implicated in regulating, among other things, muscle specific genes. The focus of the research in my lab is to begin to understand how the nuclear periphery and other subcompartments contribute to general nuclear architecture and to specific gene regulation. These questions comprise three complementary areas of research: understanding how genes are regulated at the nuclear periphery, deciphering how genes are localized (or “addressed”) to specific nuclear compartments and, finally, how these processes are utilized in development and corrupted in disease.
Harr, J.C, Luperchio, T.R., Wong, X., Cohen, E., Sheelan, S.J. and Reddy, K.L. (2015) Directed targeting of chromatin to the nuclear lamina is mediated by chromatin state and A-type lamins, Journal of Cell Biology, vol 208(1), 33-52.
Wong, X., Luperchio, T. R., & Reddy KL. (2014). NET gains and losses: the role of changing nuclear envelope proteomes in genome regulation. Current Opinion in Cell Biology, 28C, 105–120.
Luperchio, T. R., Wong, X., & Reddy KL. (2014). Genome regulation at the peripheral zone: lamina associated domains in development and disease. Current Opinion in Genetics & Development, 25C, 50–61.
Mohammad H, Luperchio, T. R., Cutler , J, Mitchell, C. J., Kim, M-S, Pandey, A, Sollner-Webb, B.and Reddy KL (2014) Prediction of Gene Activity in Early B Cell Development Based on an Integrative Multi-Omics Analysis. Journal of Proteomics & Bioinformatics.
Harr J. and Reddy KL. (2013) Live Cell imaging of Nuclear Dynamics. Encyclopedia of Biological Chemistry, 2nd Ed., p. 749 Link Reddy KL, & Feinberg, A. P. (2013). Higher order chromatin organization in cancer. Semin Cancer Biol, 23(2), 109–115.
Zullo, J. M., Demarco, I. a, Piquй-Regi, R., Gaffney, D. J., Epstein, C. B., Spooner, C. J., Reddy KL and Singh, H. (2012). DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell, 149(7), 1474–87.
Mewborn, S. K., Puckelwartz, M. J., Abuisneineh, F., Fahrenbach, J. P., Zhang, Y., MacLeod, H., Dellefave L, Pytel P, Selig S, Labno CM, Reddy KL, Singh H, McNally E. (2010). Altered chromosomal positioning, compaction, and gene expression with a lamin A/C gene mutation. PloS One, 5(12), e14342.
Johnson, K., Reddy, KL, & Singh, H. (2009). Molecular pathways and mechanisms regulating the recombination of immunoglobulin genes during B-lymphocyte development. Adv Exp Med Biol, 650(Journal Article), 133–147.
Reddy KL, & Singh, H. (2008). Using molecular tethering to analyze the role of nuclear compartmentalization in the regulation of mammalian gene activity. Methods (San Diego, Calif.), 45(3), 242–251. Methods Reddy KL, Zullo, J. M., Bertolino, E., & Singh, H. (2008). Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature, 452(7184), 243–7. doi:10.1038/nature06727
Reynaud, D., A, Demarco, I., L Reddy KL, Schjerven, H., Bertolino, E., Chen, Z., Reddy, K. L. (2008). Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros. Nature Immunology, 9(8), 927–936.
Schlimgen, R. J., Reddy KL, Singh, H., & Krangel, M. S. (2008). Initiation of allelic exclusion by stochastic interaction of Tcrb alleles with repressive nuclear compartments. Nature Immunology, 9(7), 802–809.