UCL Cancer Institute

Transcriptional Regulation


Group Leader: Dr Barbara Jennings



Failure of correct gene regulation usually has catastrophic effects on the developing embryo, and in adult life leads to disease including cancer. We use a combination of Drosophila genetics, molecular biology, biochemistry and immunohistochemistry to study how gene expression is regulated during animal development.


Research

Our goal is to understand the molecular mechanisms regulating gene expression during cell fate determination and differentiation. Cells within a multicellular organism differ dramatically in their size, shape, function, longevity, and ability to keep dividing even though, with few exceptions, every cell contains the same set of genes. The great diversity of cells observed is a consequence of the different cell types expressing different profiles of genes. We are currently focussing on two examples of transcriptional repression observed in the early embryonic development of Drosophila.

Drosophila

Fig 1   Wild-type Drosophila



i) Repression by Groucho/TLE family proteins

Groucho/TLE family proteins are recruited to act as corepressors for many different families of transcription factors (including Hes, Runx, Nkx, LEF1/Tcf, Pax, Six and c-Myc) and are a key factor in many signalling pathways, including Notch and Wnt, which act during development, tissue regeneration, and stem cell specification/maintenance. Recent reports demonstrate that deregulated expression of human Gro family members is correlated with the pathogenesis of some cancers.


Drosophila Groucho


Fig 2  
Drosophila carrying the groucho¹ mutation (named after Groucho Marx - note the bushy "eyebrow")



ii) Repression via transcriptional pausing

Transcription is initiated by recruitment of a preinitiation complex containing RNA polymerase II (RNAP II) and assorted transcription factors at the promoter of a gene. After clearing the promoter, RNAP II transcribes 20-40 base pairs and pauses before transcribing the rest of the gene. This pausing is a checkpoint that can be regulated to repress or activate gene expression. Recent studies in human embryonic stem cells and Drosophila have revealed the large extent to which transcriptional pausing is used as a regulatory point in vivo.
The aim of our current research is to ascertain the molecular mechanisms by which contextual transcription factors regulate transcriptional pausing. Our central questions are: Which proteins are involved? How do these proteins interact with each other and RNA polymerase?

developmental gene regulation

Fig 3   Expression of the fushi tarazu pair-rule gene in the early Drosophila embryo - patterning of the Drosophila embryo is a paradigm for studying developmental gene regulation

 

Barbara Jennings

Dr Barbara Jennings


Group Members


•  Pedro Martinez
•  Dr Aamna Kaul

 



 

Selected Publications


Harvey R, Schuster E and Jennings BH. "Pleiohomeotic interacts with the core transcription elongation factor Spt5 to regulate gene expression in Drosophila", PLoS One. 2013 Jul 22;8(7):e70184. doi: 10.1371/journal.pone. 0070184. Print 2013. Online

Jennings BH. "Pausing for thought: disrupting the early transcription elongation checkpoint leads to developmental defects and tumourigenesis", Bioessays. 2013 Jun;35(6):553-60. doi: 10.1002/bies.201200179. Online

Jennings, BH. "Drosophila - A Versatile Model in Biology & Medicine", Materials Today, vol 14, 2011:190-195. Online

Vanrobays, E. Jennings, BH, and Ish-Horowicz D. "Identification and Mapping of Induced Chromosomal Deletions using Sequence Polymorphisms" Biotechniques, 2010; 48:53-60. Pubmed

Jennings, BH., and Ish-Horowicz D. “The Groucho/TLE/Grg Family of Transcriptional Corepressors” Genome Biol, 2008; 9(1):205. Pubmed

Jennings, BH., Wainwright, SM. and Ish-Horowicz D. "Differential in vivo requirements for oligomerisation during Groucho-mediated repression” EMBO Rep, 2008; 9:76-83. Pubmed

Jennings, BH., Pickles, LM., Wainwright SM., Roe SM., Pearl, LH. and Ish-Horowicz, D. "Molecular recognition of transcriptional repressor motifs by the WD domain of the Groucho/TLE corepressor" Mol Cell, 2006; 22:645-655. Pubmed

Jennings, BH., Shah, S., Yamaguchi, Y. Seki, M., Phillips, RG., Handa, H. and Ish-Horowicz D. "Locus-specific requirements for Spt5 in transcriptional activation and repression in Drosophila", Curr Biol, 2004; 14:1680-1684. Pubmed

Jennings, BH. "Stopping Transcription in its Tracks", Nat Genet, 2002; 32:87-88. Pubmed