Cohesinopathy mutations disrupt the subnuclear organization of chromatin.
In Saccharomyces cerevisiae, chromatin is spatially organized within the nucleus with centromeres clustering near the spindle pole body, telomeres clustering into foci at the nuclear periphery, ribosomal DNA repeats localizing within a single nucleolus, and transfer RNA (tRNA) genes present in an adjacent cluster. [corrected] Furthermore, certain genes relocalize from the nuclear interior to the periphery upon transcriptional activation. The molecular mechanisms responsible for the organization of the genome are not well understood. We find that evolutionarily conserved proteins in the cohesin network play an important role in the subnuclear organization of chromatin. Mutations that cause human cohesinopathies had little effect on chromosome cohesion, centromere clustering, or viability when expressed in yeast. However, two mutations in particular lead to defects in (a) GAL2 transcription and recruitment to the nuclear periphery, (b) condensation of mitotic chromosomes, (c) nucleolar morphology, and (d) tRNA gene-mediated silencing and clustering of tRNA genes. We propose that the cohesin network affects gene regulation by facilitating the subnuclear organization of chromatin.
Gard
Scarlett
S
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Light
William
W
Xiong
Bo
B
Bose
Tania
T
McNairn
Adrian J
AJ
Harris
Bethany
B
Fleharty
Brian
B
Seidel
Chris
C
Brickner
Jason H
JH
Gerton
Jennifer L
JL
D000123:Acetyltransferases / Q000235:genetics* / Q000502:physiology; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000502:physiology; D000097722:Cohesins; D000098550:Structural Maintenance of Chromosome Protein 1
D000123:Acetyltransferases; D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D000097722:Cohesins; D000098550:Structural Maintenance of Chromosome Protein 1; C410592:SCC2 protein, S cerevisiae; C108312:condensin complexes; C118076:ECO1 protein, S cerevisiae