PMID- 24465194
OWN - NLM
STAT- MEDLINE
DCOM- 20141112
LR  - 20240323
IS  - 1553-7358 (Electronic)
IS  - 1553-734X (Print)
IS  - 1553-734X (Linking)
VI  - 10
IP  - 1
DP  - 2014 Jan
TI  - Combinatorial modeling of chromatin features quantitatively predicts DNA 
      replication timing in Drosophila.
PG  - e1003419
LID - 10.1371/journal.pcbi.1003419 [doi]
LID - e1003419
AB  - In metazoans, each cell type follows a characteristic, spatio-temporally 
      regulated DNA replication program. Histone modifications (HMs) and chromatin 
      binding proteins (CBPs) are fundamental for a faithful progression and completion 
      of this process. However, no individual HM is strictly indispensable for origin 
      function, suggesting that HMs may act combinatorially in analogy to the histone 
      code hypothesis for transcriptional regulation. In contrast to gene expression 
      however, the relationship between combinations of chromatin features and DNA 
      replication timing has not yet been demonstrated. Here, by exploiting a 
      comprehensive data collection consisting of 95 CBPs and HMs we investigated their 
      combinatorial potential for the prediction of DNA replication timing in 
      Drosophila using quantitative statistical models. We found that while 
      combinations of CBPs exhibit moderate predictive power for replication timing, 
      pairwise interactions between HMs lead to accurate predictions genome-wide that 
      can be locally further improved by CBPs. Independent feature importance and model 
      analyses led us to derive a simplified, biologically interpretable model of the 
      relationship between chromatin landscape and replication timing reaching 80% of 
      the full model accuracy using six model terms. Finally, we show that pairwise 
      combinations of HMs are able to predict differential DNA replication timing 
      across different cell types. All in all, our work provides support to the 
      existence of combinatorial HM patterns for DNA replication and reveal cell-type 
      independent key elements thereof, whose experimental investigation might 
      contribute to elucidate the regulatory mode of this fundamental cellular process.
FAU - Comoglio, Federico
AU  - Comoglio F
AD  - Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
FAU - Paro, Renato
AU  - Paro R
AD  - Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland 
      ; Faculty of Science, University of Basel, Basel, Switzerland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140123
PL  - United States
TA  - PLoS Comput Biol
JT  - PLoS computational biology
JID - 101238922
RN  - 0 (Chromatin)
RN  - 0 (Histones)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Chromatin/*chemistry
MH  - Cluster Analysis
MH  - Computer Simulation
MH  - DNA/chemistry
MH  - *DNA Replication Timing
MH  - Drosophila/*genetics
MH  - Gene Expression Regulation
MH  - Genome
MH  - Histones/chemistry/genetics
MH  - Models, Statistical
PMC - PMC3900380
COIS- The authors have declared that no competing interests exist.
EDAT- 2014/01/28 06:00
MHDA- 2014/11/13 06:00
PMCR- 2014/01/23
CRDT- 2014/01/28 06:00
PHST- 2013/07/15 00:00 [received]
PHST- 2013/11/18 00:00 [accepted]
PHST- 2014/01/28 06:00 [entrez]
PHST- 2014/01/28 06:00 [pubmed]
PHST- 2014/11/13 06:00 [medline]
PHST- 2014/01/23 00:00 [pmc-release]
AID - PCOMPBIOL-D-13-01254 [pii]
AID - 10.1371/journal.pcbi.1003419 [doi]
PST - ppublish
SO  - PLoS Comput Biol. 2014 Jan;10(1):e1003419. doi: 10.1371/journal.pcbi.1003419. 
      Epub 2014 Jan 23.