DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina.
Cell, 2012/6/22;149(7):1474-87.
Zullo JM[1], Demarco IA, Piqué-Regi R, Gaffney DJ, Epstein CB, Spooner CJ, Luperchio TR, Bernstein BE, Pritchard JK, Reddy KL, Singh H
Affiliations
PMID: 22726435DOI: 10.1016/j.cell.2012.04.035
Impact factor: 66.85
Abstract
A large fraction of the mammalian genome is organized into inactive chromosomal domains along the nuclear lamina. The mechanism by which these lamina associated domains (LADs) are established remains to be elucidated. Using genomic repositioning assays, we show that LADs, spanning the developmentally regulated IgH and Cyp3a loci contain discrete DNA regions that associate chromatin with the nuclear lamina and repress gene activity in fibroblasts. Lamina interaction is established during mitosis and likely involves the localized recruitment of Lamin B during late anaphase. Fine-scale mapping of LADs reveals numerous lamina-associating sequences (LASs), which are enriched for a GAGA motif. This repeated motif directs lamina association and is bound by the transcriptional repressor cKrox, in a complex with HDAC3 and Lap2β. Knockdown of cKrox or HDAC3 results in dissociation of LASs/LADs from the nuclear lamina. These results reveal a mechanism that couples nuclear compartmentalization of chromatin domains with the control of gene activity.
MeSH terms
Animals; Base Sequence; Chromatin; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; DNA; DNA-Binding Proteins; Drosophila; Gene Silencing; Histone Deacetylases; Immunoglobulin Heavy Chains; Mice; Mitosis; NIH 3T3 Cells; Nuclear Envelope; Nuclear Lamina; Transcription Factors; Transcription, Genetic
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