Research Awards
Sanford Leuba, Ph.D. & Jordanka Zlatanova, Ph.D.
University of Pittsburgh & Polytechnic University
Rett Syndrome: MeCP2 action in chromatin
$100,000
Lay Progress Report (August 2005)
Mutations in the MeCP2 protein are associated with Rett Syndrome. MeCP2 binds methylated DNA, is associated with chromatin, is found in densely methylated regions of the genome and represses transcription. Our research aims to understand the mechanism of action of MeCP2 in chromatin and in transcription. A better understanding of the mechanism of MeCP2 should lead to a rational design of therapies to maintain normal functioning of MeCP2 even when the gene is mutated, and thus prevent the onset of Rett Syndrome in patients identified at risk for the disease or treat an already progressing disease.
We show that MeCP2 binds unusual DNA structures including nucleosomes in which the DNA is wrapped around core histone proteins and Holliday junction DNA, which is an intermediate in DNA recombination. We also show that a histone chaperone protein, nucleosome assembly protein 1 (NAP1), removes MECP2 on nucleosomes.
NAP1 is the first protein ever shown to displace MeCP2 from its natural binding site and suggests a mechanism of how MeCP2 binding to methylated nucleosomes may be regulated in vivo.
Sanford Leuba, Ph.D. & Jordanka Zlatanova, Ph.D.University of Pittsburgh & Polytechnic University
Rett Syndrome: MeCP2 action in chromatin
$100,000
Lay Progress Report (August 2005)
Mutations in the MeCP2 protein are associated with Rett Syndrome. MeCP2 binds methylated DNA, is associated with chromatin, is found in densely methylated regions of the genome and represses transcription. Our research aims to understand the mechanism of action of MeCP2 in chromatin and in transcription. A better understanding of the mechanism of MeCP2 should lead to a rational design of therapies to maintain normal functioning of MeCP2 even when the gene is mutated, and thus prevent the onset of Rett Syndrome in patients identified at risk for the disease or treat an already progressing disease.
We show that MeCP2 binds unusual DNA structures including nucleosomes in which the DNA is wrapped around core histone proteins and Holliday junction DNA, which is an intermediate in DNA recombination. We also show that a histone chaperone protein, nucleosome assembly protein 1 (NAP1), removes MECP2 on nucleosomes.
NAP1 is the first protein ever shown to displace MeCP2 from its natural binding site and suggests a mechanism of how MeCP2 binding to methylated nucleosomes may be regulated in vivo.