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CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development.

Nature genetics | Nov 29, 2012

Charged multivesicular body protein 1A (CHMP1A; also known as chromatin-modifying protein 1A) is a member of the ESCRT-III (endosomal sorting complex required for transport-III) complex but is also suggested to localize to the nuclear matrix and regulate chromatin structure. Here, we show that loss-of-function mutations in human CHMP1A cause reduced cerebellar size (pontocerebellar hypoplasia) and reduced cerebral cortical size (microcephaly). CHMP1A-mutant cells show impaired proliferation, with increased expression of INK4A, a negative regulator of stem cell proliferation. Chromatin immunoprecipitation suggests loss of the normal INK4A repression by BMI in these cells. Morpholino-based knockdown of zebrafish chmp1a resulted in brain defects resembling those seen after bmi1a and bmi1b knockdown, which were partially rescued by INK4A ortholog knockdown, further supporting links between CHMP1A and BMI1-mediated regulation of INK4A. Our results suggest that CHMP1A serves as a critical link between cytoplasmic signals and BMI1-mediated chromatin modifications that regulate proliferation of central nervous system progenitor cells.

Pubmed ID: 23023333 RIS Download

Mesh terms: Animals | Cell Proliferation | Cerebellar Cortex | Cyclin-Dependent Kinase Inhibitor p16 | Endosomal Sorting Complexes Required for Transport | Gene Expression Regulation, Developmental | Genetic Linkage | HEK293 Cells | Humans | Mice | Microcephaly | Mitogen-Activated Protein Kinase 7 | Mutation | NIH 3T3 Cells | Neural Stem Cells | Neurons | Polymorphism, Single Nucleotide | Zebrafish

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Associated grants

  • Agency: FIC NIH HHS, Id: R21TW008223
  • Agency: NIGMS NIH HHS, Id: T32 GM007753
  • Agency: NINDS NIH HHS, Id: R01NS035129
  • Agency: NHLBI NIH HHS, Id: R01 HL048801
  • Agency: NINDS NIH HHS, Id: R01 NS035129
  • Agency: NIMH NIH HHS, Id: T32 MH020017
  • Agency: FIC NIH HHS, Id: R21 TW008223

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UCSC Genome Browser

A collection of genomes which include reference sequences and working draft assemblies, as well as a variety of tools to explore these sequences. The Genome Browser zooms and scrolls over chromosomes, showing the work of annotators worldwide. The Gene Sorter shows expression, homology and other information on groups of genes that can be related in many ways. Blat quickly maps your sequence to the genome. The Table Browser provides access to the underlying database. VisiGene lets you browse through a large collection of in situ mouse and frog images to examine expression patterns. Genome Graphs allows you to upload and display genome-wide data sets. Also provided is a portal to the Encyclopedia of DNA Elements (ENCODE) and Neandertal projects.

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1000 Genomes: A Deep Catalog of Human Genetic Variation

International collaboration producing an extensive public catalog of human genetic variation, including SNPs and structural variants, and their haplotype contexts, in an effort to provide a foundation for investigating the relationship between genotype and phenotype. The genomes of about 2500 unidentified people from about 25 populations around the world were sequenced using next-generation sequencing technologies. Redundant sequencing on various platforms and by different groups of scientists of the same samples can be compared. The results of the study are freely and publicly accessible to researchers worldwide. The consortium identified the following populations whose DNA will be sequenced: Yoruba in Ibadan, Nigeria; Japanese in Tokyo; Chinese in Beijing; Utah residents with ancestry from northern and western Europe; Luhya in Webuye, Kenya; Maasai in Kinyawa, Kenya; Toscani in Italy; Gujarati Indians in Houston; Chinese in metropolitan Denver; people of Mexican ancestry in Los Angeles; and people of African ancestry in the southwestern United States. The goal Project is to find most genetic variants that have frequencies of at least 1% in the populations studied. Sequencing is still too expensive to deeply sequence the many samples being studied for this project. However, any particular region of the genome generally contains a limited number of haplotypes. Data can be combined across many samples to allow efficient detection of most of the variants in a region. The Project currently plans to sequence each sample to about 4X coverage; at this depth sequencing cannot provide the complete genotype of each sample, but should allow the detection of most variants with frequencies as low as 1%. Combining the data from 2500 samples should allow highly accurate estimation (imputation) of the variants and genotypes for each sample that were not seen directly by the light sequencing. All samples from the 1000 genomes are available as lymphoblastoid cell lines (LCLs) and LCL derived DNA from the Coriell Cell Repository as part of the NHGRI Catalog. The sequence and alignment data generated by the 1000genomes project is made available as quickly as possible via their mirrored ftp sites. ftp://ftp.1000genomes.ebi.ac.uk ftp://ftp-trace.ncbi.nlm.nih.gov/1000genomes

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