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Related Concept Videos

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Before a cell can divide, it must accurately replicate all of its chromosomes, including the DNA and its associated histone and non-histone proteins.  This process begins at numerous origins of replication during the S phase of the cell cycle in each of a cell’s chromosomes simultaneously. Certain nucleotides can act as origins of replication, but these sequences are not well defined - especially in complex, multi-cellular, eukaryotic species. The length of DNA that spans an origin...
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A functional eukaryotic chromosome must contain three elements: a centromere, telomeres, and numerous origins of replication.
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In eukaryotic cells, DNA replication is highly conserved and tightly regulated. Multiple linear chromosomes must be duplicated with high fidelity before cell division, so there are many proteins that fulfill specialized roles in the replication process. Replication occurs in three phases: initiation, elongation, and termination, and ends with two complete sets of chromosomes in the nucleus.
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DNA replication is carried out by a large complex of proteins that act in a coordinated matter to achieve high-fidelity DNA replication. Together this complex is known as the DNA replication machinery or the replisome.
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Single molecule MATAC-seq reveals key determinants of DNA replication origin efficiency.

Anna Chanou1, Matthias Weiβ1, Karoline Holler1,2,3

  • 1Institute of Epigenetics and Stem Cells, Helmholtz Zentrum München, Munich, Germany.

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New Methylation Accessibility of TArgeted Chromatin domain Sequencing (MATAC-Seq) reveals cell-to-cell DNA replication differences. This single-molecule assay uncovers chromatin states predicting efficient origin activation.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Epigenetics

Background:

  • Cell-to-cell variability in genome replication patterns arises from stochastic origin activation.
  • The molecular mechanisms underlying heterogeneity in DNA replication origin efficiency and timing remain incompletely understood.

Purpose of the Study:

  • To develop a novel single-molecule assay for chromatin accessibility.
  • To investigate the heterogeneity of chromatin states at specific DNA replication origins.
  • To establish a mechanistic link between chromatin states and replication origin activation efficiency.

Main Methods:

  • Methylation Accessibility of TArgeted Chromatin domain Sequencing (MATAC-Seq) was developed to assess single-molecule chromatin accessibility.
  • MATAC-Seq utilizes methyltransferase modification of accessible DNA followed by Nanopore Sequencing for direct readout.
  • The method was applied to early-efficient and late-inefficient yeast replication origins.

Main Results:

  • MATAC-Seq revealed significant heterogeneity in chromatin states at individual replication origins.
  • Disruption of INO80 or ISW2 chromatin remodeling complexes altered nucleosomal positions, correlating with replication efficiency changes.
  • An accessible nucleosome-free region with specific +1 and +2 nucleosome positioning predicted efficient origin activation.

Conclusions:

  • MATAC-Seq uncovers a spectrum of chromatin states at specific loci, resolving heterogeneity previously masked by population-based studies.
  • The findings provide a mechanistic basis for heterogeneity in eukaryotic DNA replication origin activation.
  • This single-molecule assay is applicable to studying heterogeneity in other fundamental biological processes like transcription and DNA repair.