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SUMMARY:Spatio-temporal organization of replication: On genome evolution a
 nd large-scale chromatin folding - Benjamin Audit\, Laboratoire de Physiqu
 e de l'Ecole Normale Supérieure de Lyon\, France
DTSTART:20151104T140000Z
DTEND:20151104T150000Z
UID:TALK61841@talks.cam.ac.uk
CONTACT:38916
DESCRIPTION:Taking advantage of the recent availability of high resolution
  timing data\, we show for seven human cell\ntypes that about half of the 
 genome is divided in megabase-sized domains that display a characteristic 
 Ushaped replication timing profile with early initiation zones at borders 
 and late replication at centers. Significant overlap is observed between U
 -domains of different cell types and also with germline replication domain
 s exhibiting a N-shaped nucleotide compositional skew confirming that the 
 putative origins at Ndomains borders are likely to be active in different 
 cell lines. From the demonstration that the average fork polarity is direc
 tly reflected by both the compositional skew and the derivative of the rep
 lication timing\nprofile\, we argue that the fact that this derivative dis
 plays a N-shape in U-domains sustains the existence of large-scale gradien
 ts of replication fork polarity in somatic and germline cells. When invest
 igating further the large scale organization of human genes with respect t
 o replication\, we show that the replication origins at U/N-domain borders
 \, gene orientation and gene expression are not randomly distributed but o
 n the opposite are at the heart of a strong organization of human chromoso
 mes. In particular highly expressed genes in a given cell type are over-re
 presented close to the corresponding replication U/N-domain borders. When 
 mapping experimental and numerical chromatin mark data in replication U/N-
 domains\, we find\, surrounding most of the putative replication origins t
 hat replicate early in the S phase\, regions of a few hundred kbp wide tha
 t are hypersensitive to DNase cleavage\, that are hypomethylated and that 
 present a significant enrichment in epigenetic marks of open and transcrip
 tionally active chromatin. Analysis of\nchromatin interaction (Hi-C) data 
 further reveals that replication domains actually correspond to high-order
  chromatin structural units that likely contribute to the compartmentaliza
 tion of the genome into autonomous domains of gene transcription and repli
 cation. We propose a cascade model for replication where replication of N/
 U-domains preferentially initiates at master replication origins located a
 t their open chromatin borders\nand that secondary origins within each dom
 ain subsequently fire stimulated by approaching forks from\nearlier-activa
 ted origins.
LOCATION:MR4\, Centre for Mathematical Sciences\, Wilberforce Road\, Cambr
 idge
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