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  current news   Press   selected story    
     
  29th June 2009  
 

Congratulations to IMCB’s recent PhD graduates

 
 



(To view more about each student's thesis, please click on their name in the image above)

PhD Gradute: Liew Hoe Peng
Thesis Title: Genetic Control of Vertebrate Muscle Cell Identity

Abstract
The skeletal muscles of vertebrates are typically composed of slow and fast-twitch fibres that differ in morphology, gene expression profiles, contraction speeds, metabolic properties and patterns of innervation.  Slow-twitch muscle fibres are capable of repetitive low peak force contractions and are highly resistant to fatigue.  In contrast, fast-twitch muscle fibres produce high peak force contractions for short durations before they become fatigued.  During myogenesis, how muscle precursors are induced to mature into distinct slow or fast-twitch fibre types is inadequately understood. In the somites of the zebrafish embryo, the activity of the zinc finger and SET domain containing transcriptional regulator Blimp1 is essential for the specification of slow muscle fibres.

I have investigated the mechanism by which Blimp1 programs myoblasts to adopt the slow-twitch fibre fate.  In slow myoblasts, expression of the Blimp1 protein is transient, and precedes the expression of slow muscle-specific differentiation genes.  In my thesis, I demonstrate that the competence of somitic myoblasts to commit to the slow lineage in response to Blimp1 changes as a function of developmental time. Through in situ hybridization screens, I have identified additional genetic markers of the slow muscle lineage and other genes that may play a role in slow muscle development.  Furthermore, I show that mammalian Blimp1 can recapitulate the slow myogenic program in zebrafish, suggesting that zebrafish Blimp1 can recognize the same consensus DNA sequence that is bound by the mammalian protein.  Functional analysis of the regulatory region of the definitive slow muscle marker, slow myosin heavy chain 1 (smyhc1) reveals that Blimp1 possibly interacts with cis-regulatory elements within this promoter, regulating its expression. 

Finally, I show that zebrafish Blimp1 can repress the expression of fast muscle-specific myosin light chain, mylz2, through direct binding near the promoter of this gene, indicating that an important function of the transcriptional activity of Blimp1 in slow muscle development is the suppression of fast-muscle-specific gene expression.  Taken together, these findings provide new insights into the molecular basis of vertebrate muscle development.

 
 


 
 


Figure Legend:
This work, titled “Specification of vertebrate slow-twitch muscle fibre fate by the transcriptional regulator Blimp1” was published in Developmental Biology. This figure, featuring slow-twitch muscle fibres (in blue, left panel) and fast-twitch fibres (in green, right panel), was selected as the cover image of the issue (Volume 324, Issue 2) of the journal.

For more information on Sudipto Roy’s Lab, Please Click here.

 
 


PhD Gradute: LIM Chiaw Hwee

Thesis Title: Functional study of Zebrafish Udu and its relationship to the Notch signaling Pathway

Abstract
Udu has been shown to play an essential role during blood cell development; however, its roles in other cellular processes remain largely unexplored. We showed that udu mutants exhibited somite and myotome boundary defects. Our FACS analysis showed that the loss of udu function resulted in defective cell cycle progression and comet assay indicated the presence of increased DNA damage in udutu24 mutants. Studies showed that the presence of extensive p53-dependent apoptosis in udutu24 mutant is a consequence of activation in the Atm-Chk2 pathway. Yeast two hybrid and coimmunoprecipitation data indicated that PAH-L (Paired Amphipathic α-Helix like) repeats and SANT-L (SW13, ADA2, N-Cor and TFIIIB like) domain of Udu interacts with MCM3 and MCM4. Furthermore, Udu is co-localized with BrdU and heterochromatin during DNA replication, suggesting a role in maintaining genome integrity.


 
 



 
 


Figure Legend:
(A-C) Comet assay of dissociated cells from zebrafish embryos. (A) Untreated wild-type cells, (B) UV irradiated wild-type cells as positive control, (C) untreated udutu24 cells. The head is composed of intact DNA, while the tail consists of damaged DNA.

For more information on Yun-Jin JIANG’s Lab, Please Click here.


 
 


PhD Gradute: Tan Hwee Hong

Thesis Title: Regulation of DNA (Cytosine-5) Methyltransferase 1 and its role in doxorubicin-induced genotoxicity

Abstract

The expression of DNA Methyltransferase 1 (DNMT1), the major maintenance DNA methyltransferases in mammalian cells, is critical in coordinating DNMT1 activity with biological processes and therefore must be tightly regulated in the cell cycle. Several studies have shown that DNMT1 expression level is inversely correlated with the cell cycle inhibitor p21WAF1 protein, but the exact mechanism remained unresolved. Using a series of experimental approaches, I identified p21WAF1 as a novel upstream regulator of DNMT1 expression in mammalian cell lines. The histone acetyltransferase p300, which serves as a crucial transcription co-activator for DNMT1, emerged as an important mediator for the negative regulation of DNMT1 by p21WAF1. Collectively, my work illustrated a novel p21WAF1-p300-DNMT1 pathway which may provide the molecular basis for understanding the coordination of DNMT1 expression and DNA methylation with critical biological processes in mammalian cell division.

Aside from elucidating the mechanism involved in regulating DNMT1, the involvement of DNMT1 in DNA damage response induced by treatment with chemotherapeutic drugs was studied. Several DNA damaging agents can induce the formation of extranuclear bodies during mitosis termed micronuclei. The anti-cancer drug doxorubicin also induces such chromosomal impairments but the underlying causes remain unknown. Interestingly, my work provides strong evidence for the involvement of DNMT1 in promoting genomic instability in the form of micronuclei formation in human cancer cells upon sub-lethal exposure to doxorubicin. The ability of DNMT1 to mediate such chromosomal aberrations, and possibly cellular demise, may act as a fail safe mechanism against carcinogenicity of sustained DNMT1 expression in human cancer cells. Indeed, DNMT1, recently identified as a candidate for mediating doxorubicin-induced cytotoxicity, is dysregulated in various cancer cell types. My novel findings enhance our understanding of drug response during doxorubicin administration in cancer therapy and the potential involvement of DNMT1 in drug-induced genotoxicity.

Hwee Hong’s PhD was completed in A/Prof Benjamin Li’s group (2004 to 2008) and Prof Alan Porter’s group (2008 to 2009).


 
 

PhD Gradute: Sharon Ling Hee Ming
Thesis Title: Crystal structure of human Edc3, an enhancer of decapping in mRNA decay, and its functional implications

Abstract
Edc3 protein functions as an enhancer of decapping in mRNA decay. It has multiple domains, an N-terminal Lsm domain, a central FDF domain and a C-terminal YjeF-N domain. Edc3 serves as a scaffold protein, allowing aggregation of mRNAs and mRNA decay machineries, for P-body formation. The crystal structure of an N-terminally truncated human Edc3 protein is solved at a resolution of 2.2Å. The structure shows that the Edc3 YjeF-N domain is dimeric and adopts a divergent Rossmann fold. Dimerization of Edc3 is confirmed by sedimentation velocity and equilibrium studies. The dimer interface of Edc3 is well conserved in eukaryotes and structure based site-directed mutagenesis revealed that Edc3 dimerization is important for its functions in mRNA decay, namely in RNA binding, P-body formation and regulation of yeast Rps28B mRNA stability.


 
 



 
 


Figure Legend:
This work, titled “Specification of vertebrate slow-twitch muscle fibre fate by the transcriptional regulator Blimp1” was published in Developmental Biology. This figure, featuring slow-twitch muscle fibres (in blue, left panel) and fast-twitch fibres (in green, right panel), was selected as the cover image of the issue (Volume 324, Issue 2) of the journal.

For more information on Haiwei SONG’s Lab, Please Click here.