%0 Book Section
%A Gotz, Jurgen
%A Ittner, Lars
%A Gotz, Naeman
%A Lam, Hong
%A Nicholas, Hannah
%T Invertebrate and Vertebrate Models of Tauopathies
%B Animal Models for Neurodegenerative Disease
%D 2011
%C Cambridge
%I RSC Publishing
%V 
%N 
%P 69-85
%@ 9781849731843
%E Avila, Jesus
%E Lucas, Jose
%E Hernandez, Felix
%X 
%Z FOR Codes: 60105



%0 Journal Article
%~ Pubmed
%A Nicholas, Hannah R
%A Hodgkin, Jonathan
%T The C. elegans Hox gene egl-5 is required for correct development of the hermaphrodite hindgut and for the response to rectal infection by Microbacterium nematophilum.
%B Developmental Biology
%D 2009
%V 329
%N 1
%P 16-24
%@ 1095-564X
%X Members of the Hox gene family encode transcription factors that specify positional identity along the anterior-posterior axis of nearly all metazoans. One among the Caenorhabditis elegans Hox genes is egl-5. A deletion allele of egl-5 was isolated in a screen for animals which fail to develop swollen tails when exposed to the bacterial pathogen Microbacterium nematophilum. We show that compromised rectal development, which occurs as a result of loss of egl-5 function, results in a failure of rectal epithelial cells to express the ERK MAP kinase mpk-1, which was previously shown to mediate tail-swelling in response to bacterial infection. Tissue-specific rescue experiments demonstrated that egl-5 and mpk-1 act autonomously in rectal cells in the morphological response. The weak egl-5 allele (n1439), which does not compromise rectal development, fails to affect tail-swelling. We find that this allele carries an inserted repeat element approximately 13.8 kb upstream of the egl-5 open reading frame, which specifically disrupts the cell-specific expression of this gene in HSN egg-laying neurons. Together these findings extend the complexity of regulation and function of Hox genes in C. elegans and demonstrate the importance of their tissue-specific expression for correct development and response to infection.
%Z FOR Codes: 60199



%0 Journal Article
%~ Pubmed
%A Eaton, Sally A
%A Funnell, Alister P W
%A Sue, Nancy
%A Nicholas, Hannah
%A Pearson, Richard C M
%A Crossley, Merlin
%T A network of Kr??ppel-like Factors (Klfs). Klf8 is repressed by Klf3 and activated by Klf1 in vivo.
%B Journal of Biological Chemistry
%D 2008
%V 283
%N 40
%P 26937-47
%@ 0021-9258
%X Transcription factors of the Sp/Klf (Kr??ppel-like factor) family regulate biological processes such as hematopoiesis, adipogenesis, and stem cell maintenance. Here we show that Bklf or Klf3 (Basic Kr??ppel-like factor) represses the Klf8 (Kr??ppel-like Factor 8) gene in vivo. Conversely, Eklf or Klf1 (Erythroid Kr??ppel-like factor) activates the Klf8 gene. Klf8 is driven by two promoters, both of which contain multiple CACCC sites. Klf3 can repress Klf1-mediated activation of both promoters. Chromatin immunoprecipitation experiments confirm that Klf3 occupies both Klf8 promoters in vivo. Interestingly, in Klf3 knock-out tissue Klf1 gains access, binds, and activates both Klf8 promoters. These results demonstrate direct competition between activating and repressing Klfs in vivo. Together with previous evidence that Klf1 directly activates the Klf3 gene, the results reveal an elaborate network of cross-talk within the Klf family. The recognition of cross-regulation and potential redundancy between Klf family members is critical to the interpretation of various Klf knock-out mice and the understanding of individual Klfs in particular contexts.
%Z FOR Codes: 1101



%0 Journal Article
%~ Pubmed
%A Nicholas, Hannah R
%A Lowry, Jason A
%A Wu, Tina
%A Crossley, Merlin
%T The Caenorhabditis elegans protein CTBP-1 defines a new group of THAP domain-containing CtBP corepressors.
%B Journal of Molecular Biology
%D 2007
%V 375
%N 1
%P 1-11
%@ 1089-8638
%X The C-terminal binding proteins (CtBPs) play roles in diverse cellular processes including transcriptional regulation, Golgi membrane fission, and synaptic ribbon formation. In the context of transcriptional regulation, they function as corepressors, interacting with promoter-bound transcription factors and recruiting a large protein complex that contains chromatin-modifying enzymes. We recently described the structure of a Thanatos-associated protein (THAP) domain that is found in a new member of the CtBP family, the Caenorhabditis elegans CTBP-1 protein. We have identified additional THAP domain-containing CtBPs in the nematode, echinoderm, and cephalochordate lineages. The distribution of these lineages within the animal kingdom suggests that the ancestral form of the animal CtBPs may have contained a THAP domain that was subsequently lost in the vertebrate and arthropod lineages. We also provide functional data indicating that CTBP-1 represses gene expression and homodimerizes and interacts with PXDLS-containing partner proteins, three key features of the previously characterized animal CtBPs. CTBP-1 is therefore the founding member of a new subgroup within the CtBP corepressor family, the THAP domain-containing CtBPs.
%Z FOR Codes: 110106



%0 Journal Article
%~ Pubmed
%A Liew, Chu Kong
%A Crossley, Merlin
%A Mackay, Joel P
%A Nicholas, Hannah R
%T Solution structure of the THAP domain from Caenorhabditis elegans C-terminal binding protein (CtBP).
%B Journal of Molecular Biology
%D 2006
%V 366
%N 2
%P 382-90
%@ 0022-2836
%X The THAP (Thanatos-associated protein) domain is a recently discovered zinc-binding domain found in proteins involved in transcriptional regulation, cell-cycle control, apoptosis and chromatin modification. It contains a single zinc atom ligated by cysteine and histidine residues within a Cys-X(2-4)-Cys-X(35-53)-Cys-X(2)-His consensus. We have determined the NMR solution structure of the THAP domain from Caenorhabditis elegans C-terminal binding protein (CtBP) and show that it adopts a fold containing a treble clef motif, bearing similarity to the zinc finger-associated domain (ZAD) from Drosophila Grauzone. The CtBP THAP domain contains a large, positively charged surface patch and we demonstrate that this domain can bind to double-stranded DNA in an electrophoretic mobility-shift assay. These data, together with existing reports, indicate that THAP domains might exhibit a functional diversity similar to that observed for classical and GATA-type zinc fingers.



%0 Journal Article
%~ Pubmed
%A Turner, Jeremy
%A Nicholas, Hannah
%A Bishop, David
%A Matthews, Jacqueline M
%A Crossley, Merlin
%T The LIM protein FHL3 binds basic Kr?ppel-like factor/Kr?ppel-like factor 3 and its co-repressor C-terminal-binding protein 2.
%B Journal of Biological Chemistry
%D 2003
%V 278
%N 15
%P 12786-95
%@ 0021-9258
%X The ability of DNA-binding transcription factors to recruit specific cofactors is central to the mechanism by which they regulate gene expression. BKLF/KLF3, a member of the Kr?ppel-like factor family of zinc finger proteins, is a potent transcriptional repressor that recruits a CtBP co-repressor. We show here that BKLF also recruits the four and a half LIM domain protein FHL3. Different but closely linked regions of BKLF mediate contact with CtBP2 and FHL3. We present evidence that CtBP2 also interacts with FHL3 and demonstrate that the three proteins co-elute in gel filtration experiments. CtBP and FHL proteins have been implicated in both nuclear and cytoplasmic functions, but expression of BKLF promotes the nuclear accumulation of both FHL3 and CtBP2. FHL proteins have been shown to act predominantly as co-activators of transcription. However, we find FHL3 can repress transcription. We suggest that LIM proteins like FHL3 are important in assembling specific repression or activation complexes, depending on conditions such as cofactor availability and promoter context.
%Z FOR Codes: 1101