Document Detail


Lysine-specific demethylase 1 regulates the embryonic transcriptome and CoREST stability.
MedLine Citation:
PMID:  20713442     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Lysine-specific demethylase 1 (LSD1), which demethylates mono- and dimethylated histone H3-Lys4 as part of a complex including CoREST and histone deacetylases (HDACs), is essential for embryonic development in the mouse beyond embryonic day 6.5 (e6.5). To determine the role of LSD1 during this early period of embryogenesis, we have generated loss-of-function gene trap mice and conditional knockout embryonic stem (ES) cells. Analysis of postimplantation gene trap embryos revealed that LSD1 expression, and therefore function, is restricted to the epiblast. Conditional deletion of LSD1 in mouse ES cells, the in vitro counterpart of the epiblast, revealed a reduction in CoREST protein and associated HDAC activity, resulting in a global increase in histone H3-Lys56 acetylation, but not H3-Lys4 methylation. Despite this biochemical perturbation, ES cells with LSD1 deleted proliferate normally and retain stem cell characteristics. Loss of LSD1 causes the aberrant expression of 588 genes, including those coding for transcription factors with roles in anterior/posterior patterning and limb development, such as brachyury, Hoxb7, Hoxd8, and retinoic acid receptor γ (RARγ). The gene coding for brachyury, a key regulator of mesodermal differentiation, is a direct target gene of LSD1 and is overexpressed in e6.5 Lsd1 gene trap embryos. Thus, LSD1 regulates the expression and appropriate timing of key developmental regulators, as part of the LSD1/CoREST/HDAC complex, during early embryonic development.
Authors:
Charles T Foster; Oliver M Dovey; Larissa Lezina; Jin Li Luo; Timothy W Gant; Nick Barlev; Allan Bradley; Shaun M Cowley
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-16
Journal Detail:
Title:  Molecular and cellular biology     Volume:  30     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-23     Completed Date:  2010-10-28     Revised Date:  2011-07-27    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4851-63     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, University of Leicester, Leicester, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
Cell Differentiation
Cell Line
DNA Primers / genetics
Embryonic Development / genetics,  physiology
Embryonic Stem Cells / cytology,  metabolism
Female
Fetal Proteins / genetics,  metabolism
Gene Expression Profiling*
Gene Expression Regulation, Developmental
Histone Deacetylases / metabolism
Mice
Mice, Knockout
Nerve Tissue Proteins / metabolism*
Oxidoreductases, N-Demethylating / deficiency,  genetics,  metabolism*
Pregnancy
Protein Stability
RNA, Messenger / genetics,  metabolism
Repressor Proteins / metabolism*
T-Box Domain Proteins / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
G0600135//Medical Research Council
Chemical
Reg. No./Substance:
0/Brachyury protein; 0/DNA Primers; 0/Fetal Proteins; 0/Nerve Tissue Proteins; 0/RNA, Messenger; 0/Rcor2 protein, mouse; 0/Repressor Proteins; 0/T-Box Domain Proteins; EC 1.-/Aof2 protein, mouse; EC 1.5.-/Oxidoreductases, N-Demethylating; EC 3.5.1.98/Histone Deacetylases
Comments/Corrections

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