Identification of CTCF as a master regulator of the clustered protocadherin genes.
The brain is a large and complex network of neurons. Specific neuronal connectivity is thought to be based on the combinatorial expression of the 52 protocadherins (Pcdh) membrane adhesion proteins, whereby each neuron expresses only a specific subset. Pcdh genes are arranged in tandem, in a cluster of three families: Pcdhα, Pcdhβ and Pcdhγ. The expression of each Pcdh gene is regulated by a promoter that has a regulatory conserved sequence element (CSE), common to all 52 genes. The mechanism and factors controlling individual Pcdh gene expression are currently unknown. Here we show that the promoter of each Pcdh gene contains a gene-specific conserved control region, termed specific sequence element (SSE), located adjacent and upstream to the CSE and activates transcription together with the CSE. We purified the complex that specifically binds the SSE-CSE region and identified the CCTC binding-factor (CTCF) as a key molecule that binds and activates Pcdh promoters. Our findings point to CTCF as a factor essential for Pcdh expression and probably governing neuronal connectivity.
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Michal
M
Golan-Mashiach
Moshe
M
Grunspan
Rafi
R
Emmanuel
Liron
L
Gibbs-Bar
Rivka
R
Dikstein
Ehud
E
Shapiro
D001483:Base Sequence; D000076246:CCCTC-Binding Factor; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D017124:Conserved Sequence; D006801:Humans; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D005810:Multigene Family; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D015820:Cadherins; D012097:Repressor Proteins