SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation

被引:6940
作者
Blewitt, Marnie E. [2 ,3 ]
Gendrel, Anne-Valerie [4 ,5 ]
Pang, Zhenyi [1 ]
Sparrow, Duncan B. [6 ]
Whitelaw, Nadia [1 ,7 ]
Craig, Jeffrey M. [8 ]
Apedaile, Anwyn [4 ,5 ]
Hilton, Douglas J. [2 ,3 ]
Dunwoodie, Sally L.
Brockdorff, Neil [4 ,5 ]
Kay, Graham F. [1 ]
Whitelaw, Emma [1 ]
机构
[1] Queensland Inst Med Res, Brisbane, Qld 4006, Australia
[2] Walter & Eliza Hall Inst Med Res, Div Mol Med, Melbourne, Vic 3050, Australia
[3] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3050, Australia
[4] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Clin Sci, London SW7 2AZ, England
[5] Univ London Imperial Coll Sci Technol & Med, MRC, Fac Med, London SW7 2AZ, England
[6] Univ New S Wales, Victor Chang Cardiac Res Inst, Sydney, NSW 2010, Australia
[7] Univ Queensland, Sch Med, Brisbane, Qld 4072, Australia
[8] Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia
基金
英国惠康基金; 英国医学研究理事会;
关键词
D O I
10.1038/ng.142
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
X-chromosome inactivation is the mammalian dosage compensation mechanism by which transcription of X-linked genes is equalized between females and males. In an N-ethyl-N-nitrosourea (ENU) mutagenesis screen on mice for modifiers of epigenetic reprogramming, we identified the MommeD1 (modifier of murine metastable epialleles) mutation as a semidominant suppressor of variegation. MommeD1 shows homozygous female-specific mid-gestation lethality and hypomethylation of the X-linked gene Hprt1, suggestive of a defect in X inactivation(1). Here we report that the causative point mutation lies in a previously uncharacterized gene, Smchd1 (structural maintenance of chromosomes hinge domain containing 1). We find that SmcHD1 is not required for correct Xist expression, but localizes to the inactive X and has a role in the maintenance of X inactivation and the hypermethylation of CpG islands associated with the inactive X. This finding links a group of proteins normally associated with structural aspects of chromosome biology with epigenetic gene silencing.
引用
收藏
页码:663 / 669
页数:7
相关论文
共 28 条
[1]   Mutagenic insertion and chromosome engineering resource (MICER) [J].
Adams, DJ ;
Biggs, PJ ;
Cox, T ;
Davies, R ;
van der Weyden, L ;
Jonkers, J ;
Smith, J ;
Plumb, B ;
Taylor, R ;
Nishijima, I ;
Yu, YJ ;
Rogers, J ;
Bradley, A .
NATURE GENETICS, 2004, 36 (08) :867-871
[2]   Condensin and cohesin display different arm conformations with characteristic hinge angles [J].
Anderson, DE ;
Losada, A ;
Erickson, HP ;
Hirano, T .
JOURNAL OF CELL BIOLOGY, 2002, 156 (03) :419-424
[3]   Mutation of YCS4, a budding yeast condensin subunit, affects mitotic and nonmitotic chromosome behavior [J].
Bhalla, N ;
Biggins, S ;
Murray, AW .
MOLECULAR BIOLOGY OF THE CELL, 2002, 13 (02) :632-645
[4]   An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse [J].
Blewitt, ME ;
Vickaryous, NK ;
Hemley, SJ ;
Ashe, A ;
Bruxner, TJ ;
Preis, JI ;
Arkell, R ;
Whitelaw, E .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (21) :7629-7634
[5]   DPY-27 - A CHROMOSOME CONDENSATION PROTEIN HOMOLOG THAT REGULATES C. ELEGANS DOSAGE COMPENSATION THROUGH ASSOCIATION WITH THE X-CHROMOSOME [J].
CHUANG, PT ;
ALBERTSON, DG ;
MEYER, BJ .
CELL, 1994, 79 (03) :459-474
[6]   Mutations in the Drosophila condensin subunit dCAP-G: Defining the role of condensin for chromosome condensation in mitosis and gene expression in interphase [J].
Dej, KJ ;
Ahn, C ;
Orr-Weaver, TL .
GENETICS, 2004, 168 (02) :895-906
[7]   Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry [J].
Ehrich, M ;
Nelson, MR ;
Stanssens, P ;
Zabeau, M ;
Liloglou, T ;
Xinarianos, G ;
Cantor, CR ;
Field, JK ;
van den Boom, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (44) :15785-15790
[8]   LOCALIZATION OF PLACENTAL LACTOGEN-I IN TROPHOBLAST GIANT-CELLS OF THE MOUSE PLACENTA [J].
FARIA, TN ;
OGREN, L ;
TALAMANTES, F ;
LINZER, DIH ;
SOARES, MJ .
BIOLOGY OF REPRODUCTION, 1991, 44 (02) :327-331
[9]   Transcriptome analysis of human autosomal trisomy [J].
FitzPatrick, DR ;
Ramsay, J ;
McGill, NI ;
Shade, M ;
Carothers, AD ;
Hastie, ND .
HUMAN MOLECULAR GENETICS, 2002, 11 (26) :3249-3256
[10]   Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery [J].
Geiman, TM ;
Sankpal, UT ;
Robertson, AK ;
Chen, Y ;
Mazumdar, M ;
Heale, JT ;
Schmiesing, JA ;
Kim, W ;
Yokomori, K ;
Zhao, YM ;
Robertson, KD .
NUCLEIC ACIDS RESEARCH, 2004, 32 (09) :2716-2729