Abstract

The objective of this program is to understand the regulation of the cell cycle dependent human histone genes. The histone genes are a multi-gene family of moderately repeated sequences with differences in the structure, organization and regulation of the various copies. The gene products, histone proteins, play a key role in the structural and functional properties of the eukaryotic genome. Histones package eukaryotic DNA into nucleosomes, and modifications in histone-DNA interactions are associated with changes in gene expression. The tight coupling of histone gene expression with DNA replication suggests a role for the histone genes in the control of cell growth and cell division. Studies carried out during the first two years of this program have clearly demonstrated that regulation of human histone gene expression includes both transcriptional and post-transcriptional components. These studies have also provided an initial indication of sequences involved in the regulation of two cell cycle dependent human histone genes. By deletion analysis and construction of chimeric genes that were assayed both in vitro and by transfection into mammalian cells, we have identified regions of these histone genes required for transcription, and shown that they undergo modifications in chromatin structure as a function of cell cycle dependent expression. Sequences within a histone mRNA that affect mRNA stability have been identified. We have also isolated from one of the histone gene clusters a fragment that can function as an origin of replication (ars element) in human cells. These results serve as the basis for our ongoing and proposed studies which are to: 1. Further define and characterize sequences that are required for 5' site specific initiation of transcription, that modulate levels of transcription, and that are responsible for cell cycle regulated expression of the human histone genes. 2. Characterize the modifications in histone gene chromatin structure that occur as a function of transcription during the cell cycle. 3. Isolate proteins that interact with specific regions of histone genes and examine their influence on chromatin structure and transcription. 4. Address the relationship between transcription and replication of human histone genes by further analysis of the structural and functional properties of the ars element we have isolated.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM032010-07
Application #
3280540
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1987-09-01
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
University of Massachusetts Medical School Worcester
Department
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655

  Publications

Stein, Gary S; Stein, Janet L; van J Wijnen, Andre et al. (2012) The architectural organization of human stem cell cycle regulatory machinery. Curr Pharm Des 18:1679-85
Zaidi, Sayyed K; Medina, Ricardo F; Pockwinse, Shirwin M et al. (2010) Subnuclear localization and intranuclear trafficking of transcription factors. Methods Mol Biol 647:77-93
Xie, Ronglin; Medina, Ricardo; Zhang, Ying et al. (2009) The histone gene activator HINFP is a nonredundant cyclin E/CDK2 effector during early embryonic cell cycles. Proc Natl Acad Sci U S A 106:12359-64
Mitra, Partha; Ghule, Prachi N; van der Deen, Margaretha et al. (2009) CDK inhibitors selectively diminish cell cycle controlled activation of the histone H4 gene promoter by p220NPAT and HiNF-P. J Cell Physiol 219:438-48
Ghule, Prachi N; Dominski, Zbigniew; Lian, Jane B et al. (2009) The subnuclear organization of histone gene regulatory proteins and 3' end processing factors of normal somatic and embryonic stem cells is compromised in selected human cancer cell types. J Cell Physiol 220:129-35
Filion, Tera M; Qiao, Meng; Ghule, Prachi N et al. (2009) Survival responses of human embryonic stem cells to DNA damage. J Cell Physiol 220:586-92
Medina, Ricardo; Buck, Timothy; Zaidi, Sayyed K et al. (2008) The histone gene cell cycle regulator HiNF-P is a unique zinc finger transcription factor with a novel conserved auxiliary DNA-binding motif. Biochemistry 47:11415-23
Pockwinse, Shirwin M; Zaidi, Sayyed K; Medina, Ricardo F et al. (2008) In situ nuclear organization of regulatory machinery. Methods Mol Biol 455:239-59
Medina, Ricardo; Zaidi, Sayyed K; Liu, Chang-Gong et al. (2008) MicroRNAs 221 and 222 bypass quiescence and compromise cell survival. Cancer Res 68:2773-80
Ghule, Prachi N; Dominski, Zbigniew; Yang, Xiao-Cui et al. (2008) Staged assembly of histone gene expression machinery at subnuclear foci in the abbreviated cell cycle of human embryonic stem cells. Proc Natl Acad Sci U S A 105:16964-9

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