DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina.
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.
Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
Joseph M
JM
Zullo
Ignacio A
IA
Demarco
Roger
R
Piqué-Regi
Daniel J
DJ
Gaffney
Charles B
CB
Epstein
Chauncey J
CJ
Spooner
Teresa R
TR
Luperchio
Bradley E
BE
Bernstein
Jonathan K
JK
Pritchard
Karen L
KL
Reddy
Harinder
H
Singh
D000818:Animals; D001483:Base Sequence; D002843:Chromatin / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004330:Drosophila / Q000378:metabolism; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D051379:Mice; D008938:Mitosis; D041681:NIH 3T3 Cells; D009685:Nuclear Envelope / Q000378:metabolism; D034881:Nuclear Lamina / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3; D008565:Membrane Proteins
D002843:Chromatin; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004247:DNA; D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D007143:Immunoglobulin Heavy Chains; D014157:Transcription Factors; D000099186:Histone Deacetylase 3; C089581:Zfp67 protein, mouse; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins