TY - JOUR
T1 - DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina
AU - Zullo, Joseph M.
AU - Demarco, Ignacio A.
AU - Piqué-Regi, Roger
AU - Gaffney, Daniel J.
AU - Epstein, Charles B.
AU - Spooner, Chauncey J.
AU - Luperchio, Teresa R.
AU - Bernstein, Bradley E.
AU - Pritchard, Jonathan K.
AU - Reddy, Karen L.
AU - Singh, Harinder
N1 - Funding Information:
We acknowledge support from the University of Chicago Functional Genomics Facility for genome-wide expression and DamID analyses. We thank Lázló Kömüves and Allison Bruce at Genentech for assistance with confocal imaging and graphics art, respectively. We are grateful to members of the Singh laboratory for critical input. J.M.Z. was supported by an NIH training grant. I.A.D. acknowledges support by the Cancer Research Institute. H.S. acknowledges support by the Howard Hughes Medical Institute and the Chicago Biomedical Consortium and from NIH GM086213. H.S. and C.J.S. are employees of Genentech Inc.
PY - 2012/6/22
Y1 - 2012/6/22
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2012.04.035
DO - 10.1016/j.cell.2012.04.035
M3 - Article
C2 - 22726435
AN - SCOPUS:84862639469
SN - 0092-8674
VL - 149
SP - 1474
EP - 1487
JO - Cell
JF - Cell
IS - 7
ER -