Genetic and Epigenetic Regulation of Gene Expression
While genetic information encoded by DNA provides a framework for gene expression, epigenetic regulation is equally critical for physiological responsiveness to extracellular cues. Traditionally, our laboratory has examined the chromatin structure of several key gene loci (e.g., histone H4, osteocalcin, Runx2) to understand how architectural and topological constraints on promoters in chromatin contribute to gene regulation. These studies have evolved into detailed molecular analyses of histone modifications (e.g., H4 acetylation, H3 methylation), SWI/SNF related chromatin remodeling and genome-wide transcription factor binding analyses using ChIP-on-chip and ChIP-Seq approaches (see Nuclear Structure and Function).
Beyond the conventional epigenetic mechanisms that include post-transcriptional modifications of histones, and methylation of CpG moieties in gene promoters, we have identified a unique epigenetic mechanism, where phenotypic transcription factors remain associated with target genes during mitosis. This association, termed architectural epigenetics (‘Bookmarking’) ensures that the progeny cells maintain the cell growth and proliferative potential, as well as remain committed to lineage of the parent cells. We are actively exploring mechanisms that ensure sustained architectural epigenetics during symmetrical division of committed cells and during asymmetrical mitosis of stem cells.
Another epigenetic mechanism that has become a focus of our research group is the involvement of microRNA in regulating osteoblast- and hematopoiesis-related gene expression. We have carried out genome-wide screens for the expression of miRs under various physiological conditions and have identified miR signatures that have the potential to predict a biological response or a pathological outcome. Our group is further dissecting roles of these miR signatures in osteoblastogenesis (see Musculoskeletal Biology and Pathology) and hematopoeisis, as well as in human leukemia.
- Zaidi SK, Young DW, Montecino MA, Lian JB, van Wijnen AJ, Stein JL, Stein GS. Mitotic bookmarking of genes: a novel dimension to epigenetic control.Nat Rev Genet. 2010 Aug;11(8):583-9.
- Gordon JA, Hassan MQ, Saini S, Montecino M, van Wijnen AJ, Stein GS, Stein JL, Lian JB. Pbx1 represses osteoblastogenesis by blocking Hoxa10-mediated recruitment of chromatin remodeling factors. Mol Cell Biol. 2010 Jul;30(14):3531-41.
- Ali SA, Zaidi SK, Dacwag CS, Salma N, Young DW, Shakoori AR, Montecino MA, Lian JB, van Wijnen AJ, Imbalzano AN, Stein GS, Stein JL. Phenotypic transcription factors epigenetically mediate cell growth control. Proc Natl Acad Sci U S A. 2008 May 6;105(18):6632-7.
- Gutierrez J, Paredes R, Cruzat F, Hill DA, van Wijnen AJ, Lian JB, Stein GS, Stein JL, Imbalzano AN, Montecino M. Chromatin remodeling by SWI/SNF results in nucleosome mobilization to preferential positions in the rat osteocalcin gene promoter. J Biol Chem. 2007 Mar 30;282(13):9445-57.
- Young DW, Hassan MQ, Yang XQ, Galindo M, Javed A, Zaidi SK, Furcinitti P, Lapointe D, Montecino M, Lian JB, Stein JL, van Wijnen AJ, Stein GS. Mitotic retention of gene expression patterns by the cell fate-determining transcription factor Runx2. Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3189-94. Epub 2007 Feb 20.
- Young DW, Hassan MQ, Pratap J, Galindo M, Zaidi SK, Lee SH, Yang X, Xie R, Javed A, Underwood JM, Furcinitti P, Imbalzano AN, Penman S, Nickerson JA, Montecino MA, Lian JB, Stein JL, van Wijnen AJ, Stein GS. Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2. Nature. 2007 Jan 25;445(7126):442-6.
- Zaidi SK, Young DW, Pockwinse SM, Javed A, Lian JB, Stein JL, van Wijnen AJ, Stein GS. Mitotic partitioning and selective reorganization of tissue-specific transcription factors in progeny cells. Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14852-7.
- Javed A, Gutierrez S, Montecino M, van Wijnen AJ, Stein JL, Stein GS, Lian JB. Multiple Cbfa/AML sites in the rat osteocalcin promoter are required for basal and vitamin D-responsive transcription and contribute to chromatin organization. Mol Cell Biol. 1999 Nov;19(11):7491-500.
- Montecino M, Frenkel B, van Wijnen AJ, Lian JB, Stein GS, Stein JL. Chromatin hyperacetylation abrogates vitamin D-mediated transcriptional upregulation of the tissue-specific osteocalcin gene in vivo. Biochemistry. 1999 Jan 26;38(4):1338-45.