Nuclear Structure and Function
Regulatory machinery for vital cellular processes, including transcription, replication, repair and apoptosis, are organized in distinct nuclear microenvironments. Our group has identified molecular and epigenetic mechanisms that govern localization of lineage-determining regulatory proteins to subnuclear sites of transcription. Applying a combination of genetic, biochemical, and in situ cell biological techniques, we have identified unique trafficking signals in Runx proteins, master regulators of osteogenesis, hematopoeisis and neurogenesis/gastro-intestinal development. Disruption of physiological localization of proteins to distinct subnuclear sites (e.g., ‘Runx foci’) results in altered transcriptional programs ultimately leading to compromised cell growth and differentiation. Clinical relevance of these findings is emphasized by aberrant subnuclear targeting of these proteins under a variety of pathological conditions that include acute myelogenous leukemia, as well as breast and prostate cancers. Currently, we are using genomic (high-throughput DeepSeq) and proteomic (high resolution mass spec) approaches to define mechanisms that relate subnuclear organization of regulatory factors and gene loci with biological control of cell function and pathological disruption in cancer.
Apart from subnuclear domains that support the function of Runx proteins, we investigate a number of other subnuclear organelles including Histone Locus Bodies (see Genetic and Epigenetic Regulation of Gene Expression).
Furthermore, our laboratory examines the chromatin structure of genes that are involved in cell cycle control (e.g., histone genes) and osteoblast differentiation (e.g., osteocalcin and Runx2 genes)(see Musculoskeletal Biology and Pathology).
- Zaidi SK, Young DW, Javed A, Pratap J, Montecino M, van Wijnen A, Lian JB, Stein JL, Stein GS. Nuclear microenvironments in biological control and cancer. Nat Rev Cancer. 2007 Jun;7(6):454-63.
- Vradii D, Zaidi SK, Lian JB, van Wijnen AJ, Stein JL, Stein GS. Point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and effects a transformation-like phenotype. Proc Natl Acad Sci U S A. 2005 May 17;102(20):7174-9.
- Javed A, Barnes GL, Pratap J, Antkowiak T, Gerstenfeld LC, van Wijnen AJ, Stein JL, Lian JB, Stein GS. Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1454-9.
- Young DW, Zaidi SK, Furcinitti PS, Javed A, van Wijnen AJ, Stein JL, Lian JB, Stein GS. Quantitative signature for architectural organization of regulatory factors using intranuclear informatics. J Cell Sci. 2004 Oct 1;117(Pt 21):4889-96.
- McNeil S, Zeng C, Harrington KS, Hiebert S, Lian JB, Stein JL, van Wijnen AJ, Stein GS. The t(8;21) chromosomal translocation in acute myelogenous leukemia modifies intranuclear targeting of the AML1/CBFalpha2 transcription factor. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14882-7.
- Tang L, Guo B, Javed A, Choi JY, Hiebert S, Lian JB, van Wijnen AJ, Stein JL, Stein GS, Zhou GW. Crystal structure of the nuclear matrix targeting signal of the transcription factor acute myelogenous leukemia-1/polyoma enhancer-binding protein 2alphaB/core binding factor alpha2. J Biol Chem. 1999 Nov 19;274(47):33580-6.
- Zeng C, van Wijnen AJ, Stein JL, Meyers S, Sun W, Shopland L, Lawrence JB, Penman S, Lian JB, Stein GS, Hiebert SW. Identification of a nuclear matrix targeting signal in the leukemia and bone-related AML/CBF-alpha transcription factors. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6746-51.
- Bidwell JP, Fey EG, van Wijnen AJ, Penman S, Stein JL, Lian JB, Stein GS. Nuclear matrix proteins distinguish normal diploid osteoblasts from osteosarcoma cells. Cancer Res. 1994 Jan 1;54(1):28-32.
- Bidwell JP, Van Wijnen AJ, Fey EG, Dworetzky S, Penman S, Stein JL, Lian JB, Stein GS. Osteocalcin gene promoter-binding factors are tissue-specific nuclear matrix components. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3162-6.
- Dworetzky SI, Wright KL, Fey EG, Penman S, Lian JB, Stein JL, Stein GS. Sequence-specific DNA-binding proteins are components of a nuclear matrix-attachment site. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4178-82.
- Lawrence JB, Singer RH, Villnave CA, Stein JL, Stein GS. Intracellular distribution of histone mRNAs in human fibroblasts studied by in situ hybridization. Proc Natl Acad Sci U S A. 1988 Jan;85(2):463-7.
- Wojtkowiak Z, Duhl DM, Briggs RC, Hnilica LS, Stein JL, Stein GS. A nuclear matrix antigen HeLa and other human malignant cells. Cancer Res. 1982 Nov;42(11):4546-52.