Anchoring of Heterochromatin to the Nuclear Lamina Reinforces Dosage Compensation-Mediated Gene Repression.
Higher order chromosome structure and nuclear architecture can have profound effects on gene regulation. We analyzed how compartmentalizing the genome by tethering heterochromatic regions to the nuclear lamina affects dosage compensation in the nematode C. elegans. In this organism, the dosage compensation complex (DCC) binds both X chromosomes of hermaphrodites to repress transcription two-fold, thus balancing gene expression between XX hermaphrodites and XO males. X chromosome structure is disrupted by mutations in DCC subunits. Using X chromosome paint fluorescence microscopy, we found that X chromosome structure and subnuclear localization are also disrupted when the mechanisms that anchor heterochromatin to the nuclear lamina are defective. Strikingly, the heterochromatic left end of the X chromosome is less affected than the gene-rich middle region, which lacks heterochromatic anchors. These changes in X chromosome structure and subnuclear localization are accompanied by small, but significant levels of derepression of X-linked genes as measured by RNA-seq, without any observable defects in DCC localization and DCC-mediated changes in histone modifications. We propose a model in which heterochromatic tethers on the left arm of the X cooperate with the DCC to compact and peripherally relocate the X chromosomes, contributing to gene repression.
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
Martha J
MJ
Snyder
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
Alyssa C
http://orcid.org/0000-0002-2946-4883
AC
Lau
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
Elizabeth A
EA
Brouhard
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
Michael B
http://orcid.org/0000-0003-3416-3038
MB
Davis
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
Jianhao
J
Jiang
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
Margarita H
MH
Sifuentes
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
Györgyi
http://orcid.org/0000-0001-5918-034X
G
Csankovszki
Mol Biol Cell. 2000 Nov;11(11):3937-47
11071918
PLoS Genet. 2008 Mar 21;4(3):e1000039
18369458
Nature. 2006 Nov 30;444(7119):614-8
17122774
J Cell Biol. 2015 Jan 5;208(1):33-52
25559185
PLoS Genet. 2012;8(8):e1002873
22956908
Genome Res. 2011 Feb;21(2):227-36
21177964
Science. 1999 Jun 11;284(5421):1800-4
10364546
Genome Biol. 2013 Feb 15;14(2):R14
23414781
Cell. 2013 Mar 14;152(6):1270-84
23498936
Curr Biol. 2011 Oct 11;21(19):1603-14
21962710
Nucleic Acids Res. 2016 May 5;44(8):3618-28
26704981
Cold Spring Harb Symp Quant Biol. 2010;75:555-65
21467137
Curr Opin Cell Biol. 2010 Jun;22(3):320-5
20444586
Nat Genet. 2006 Sep;38(9):1005-14
16878134
Front Genet. 2015 Jan 13;5:473
25628648
J Mol Biol. 2015 Feb 13;427(3):608-25
25280896
Cold Spring Harb Perspect Biol. 2014 Mar 01;6(3):null
24591522
Genetics. 1974 May;77(1):71-94
4366476
PLoS Genet. 2011 Aug;7(8):e1002231
21876678
Development. 2007 Aug;134(16):2991-9
17634190
Genome Biol. 2013;14(10):R112
24125077
Annu Rev Cell Dev Biol. 2012;28:163-87
22905954
Mol Cell. 2010 May 28;38(4):603-13
20513434
Science. 2004 Feb 20;303(5661):1182-5
14976312
PLoS One. 2013;8(2):e51765
23451023
Dev Biol. 2014 Jan 15;385(2):279-90
24252776
Nature. 2015 Jul 9;523(7559):240-4
26030525
Curr Opin Genet Dev. 2013 Apr;23(2):96-103
23312840
Genes Dev. 2009 Mar 1;23(5):602-18
19270160
Elife. 2013 Jun 18;2:e00808
23795297
Genetics. 1980 Nov;96(3):649-64
7262542
Trends Biochem Sci. 2013 Jul;38(7):356-63
23746617
Nat Rev Genet. 2007 Jul;8(7):507-17
17549064
Nature. 2008 Jun 12;453(7197):948-51
18463634
Mol Cell Biol. 2012 May;32(9):1710-9
22393255
PLoS Genet. 2012 Sep;8(9):e1002933
23028348
Front Genet. 2015 Mar 19;6:95
25852741
J Cell Biol. 2008 Jan 14;180(1):51-65
18195101
Genes Dev. 2010 Apr 15;24(8):766-82
20395364
Curr Opin Genet Dev. 2015 Apr;31:50-6
25966908
PLoS Genet. 2015 Dec 07;11(12):e1005698
26641248
Genome Biol. 2010;11(12):R120
21176223
Cell. 2012 Aug 31;150(5):934-47
22939621
Nat Genet. 2007 Mar;39(3):403-8
17293863
PLoS Genet. 2009 Oct;5(10):e1000699
19851459
Nature. 2008 Mar 13;452(7184):243-7
18272965
Dev Biol. 2006 Oct 1;298(1):176-87
16905130
Development. 2010 Sep;137(18):3067-77
20702563
Cell. 2013 Jan 31;152(3):584-98
23374351
Epigenetics Chromatin. 2014 Oct 27;7(1):31
25400696
Cell. 2013 Mar 28;153(1):178-92
23523135
Cell. 2009 Oct 2;139(1):73-86
19781752
J Cell Biol. 2013 Dec 9;203(5):767-83
24297746
Cell. 1994 Nov 4;79(3):459-74
7954812
J Cell Biol. 2013 Apr 1;201(1):49-63
23530065
Curr Biol. 2009 Jan 13;19(1):9-19
19119011
Eur J Hum Genet. 2002 Mar;10(3):157-61
11973618
Genes Dev. 2014 Dec 1;28(23):2591-6
25452271
Science. 2014 Dec 5;346(6214):1238-42
25477464
PLoS Genet. 2010 Jan 22;6(1):e1000830
20107519
Cell. 2015 Dec 3;163(6):1333-47
26607792
RNA. 2015 Sep;21(9):1544-53
26150554
FEBS J. 2013 Jul;280(14):3212-9
23648132