Article

DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Developmental cell (impact factor: 13.36). 12/2011; 22(1):38-51. DOI:10.1016/j.devcel.2011.11.013 pp.38-51
Source: PubMed

ABSTRACT Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression.

0 0
 · 
0 Bookmarks
 · 
415 Views
  • Article: Annotation, nomenclature and evolution of four novel homeobox genes expressed in the human germ line.
    H Anne F Booth, Peter W H Holland
    [show abstract] [hide abstract]
    ABSTRACT: The homeobox genes comprise a large gene superfamily characterised by a conserved DNA motif encoding the homeodomain. Most homeodomain proteins function as transcription factors, and many have important roles in embryonic development and cell differentiation. Here we describe, annotate and name four novel homeobox genes in the human genome: ARGFX, DPRX, TPRX1 and DUXA. Each has generated multiple retrotransposed (processed) pseudogenes; these are reliable indicators of germ-line expression because only in germ-line cells can retrotransposition result in inheritance to the next generation. The retrotransposed sequences were exploited here as a novel means to deduce exon-intron boundaries. All four novel genes show accelerated rates of protein sequence evolution. This fast rate of sequence change may be connected with roles in human reproductive biology. Deducing the evolutionary origins of these genes is not straightforward, but we propose that TPRX1, DPRX and DUXA are highly divergent derivatives of the CRX gene, itself a member of the Otx homeobox gene family.
    Gene 02/2007; 387(1-2):7-14. · 2.34 Impact Factor
  • Article: Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6.
    D Yang, O Chertov, S N Bykovskaia, Q Chen, M J Buffo, J Shogan, M Anderson, J M Schröder, J M Wang, O M Howard, J J Oppenheim
    [show abstract] [hide abstract]
    ABSTRACT: Defensins contribute to host defense by disrupting the cytoplasmic membrane of microorganisms. This report shows that human beta-defensins are also chemotactic for immature dendritic cells and memory T cells. Human beta-defensin was selectively chemotactic for cells stably transfected to express human CCR6, a chemokine receptor preferentially expressed by immature dendritic cells and memory T cells. The beta-defensin-induced chemotaxis was sensitive to pertussis toxin and inhibited by antibodies to CCR6. The binding of iodinated LARC, the chemokine ligand for CCR6, to CCR6-transfected cells was competitively displaced by beta-defensin. Thus, beta-defensins may promote adaptive immune responses by recruiting dendritic and T cells to the site of microbial invasion through interaction with CCR6.
    Science 11/1999; 286(5439):525-8. · 31.20 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

activates LTR elements
 
candidate biomarkers
 
causative gene
 
cell development
 
common
 
controversial
 
direct support
 
disease diagnosis
 
DUX4
 
DUX4 binds
 
DUX4 transcription factor
 
genes
 
human defensin
 
innate immune response
 
leading candidate gene
 
MaLR endogenous primate retrotransposons
 
muscle differentiation
 
pathophysiology unknown
 
progression
 
specific mechanisms