The long-term goal of this project is to develop a complete understanding of the spatial and temporal events involved in the regulation of RNA polymerase II transcription and pre-mRNA processing in living cells. An understanding of these parameters in the context of the living cell and organism will provide the basis to identify changes in these events that occur in cells or tissues associated with various disease states. The short-term goals will utilize a previously developed live cell gene expression system to address how a specific genetic locus is modulated at the G2/M and M/G1 transitions in living cells. The spatial and temporal dynamics of factors involved in gene expression will be examined as well as how the transcriptional status of a gene is transmitted to daughter cells during mitosis. In addition, this system will be used to study critical unanswered questions relating to where and when components of the mRNP export machinery associate with nascent mRNPs and how mRNPs are transported through the nuclear pore complex in human cells. Finally, a series of highly innovative experiments will be initiated to bring real-time gene expression studies into the context of a living animal in order to study tissue specific dynamics and changes in gene expression upon skin differentiation. This approach will provide significant insight into gene expression within a tissue and allow one to directly access nuclear dynamics in the context of differentiation and morphogenesis in vivo. Together, these studies will provide significant insight into our understanding of the functional organization of the nucleus with regard to gene expression. Aberrations in nuclear organization have the potential to result in alterations in gene expression, the end product of which may be one of the many pathologies associated with human disease. These studies will bring us a major step closer to studying and evaluating disease models by in vivo molecular imaging and dynamics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM042694-21
Application #
7796883
Study Section
Special Emphasis Panel (ZRG1-NDT-K (01))
Program Officer
Carter, Anthony D
Project Start
1990-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
21
Fiscal Year
2010
Total Cost
$676,357
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Zhang, Bin; Mao, Yuntao S; Diermeier, Sarah D et al. (2017) Identification and Characterization of a Class of MALAT1-like Genomic Loci. Cell Rep 19:1723-1738
Bergmann, Jan H; Li, Jingjing; Eckersley-Maslin, Mélanie A et al. (2015) Regulation of the ESC transcriptome by nuclear long noncoding RNAs. Genome Res 25:1336-46
Hogan, Megan S; Parfitt, David-Emlyn; Zepeda-Mendoza, Cinthya J et al. (2015) Transient pairing of homologous Oct4 alleles accompanies the onset of embryonic stem cell differentiation. Cell Stem Cell 16:275-88
Zepeda-Mendoza, Cinthya J; Mukhopadhyay, Swagatam; Wong, Emily S et al. (2015) Quantitative analysis of chromatin interaction changes upon a 4.3 Mb deletion at mouse 4E2. BMC Genomics 16:982
Bergmann, Jan H; Spector, David L (2014) Long non-coding RNAs: modulators of nuclear structure and function. Curr Opin Cell Biol 26:10-8
Eckersley-Maslin, Mélanie A; Spector, David L (2014) Random monoallelic expression: regulating gene expression one allele at a time. Trends Genet 30:237-44
Eckersley-Maslin, Mélanie A; Thybert, David; Bergmann, Jan H et al. (2014) Random monoallelic gene expression increases upon embryonic stem cell differentiation. Dev Cell 28:351-65
Hübner, Michael R; Eckersley-Maslin, Mélanie A; Spector, David L (2013) Chromatin organization and transcriptional regulation. Curr Opin Genet Dev 23:89-95
Dowen, Jill M; Bilodeau, Steve; Orlando, David A et al. (2013) Multiple structural maintenance of chromosome complexes at transcriptional regulatory elements. Stem Cell Reports 1:371-8
Eckersley-Maslin, Melanie A; Bergmann, Jan H; Lazar, Zsolt et al. (2013) Lamin A/C is expressed in pluripotent mouse embryonic stem cells. Nucleus 4:53-60

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