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PREditOR: a synthetic biology approach to removing heterochromatin from cells.

ABSTRACT: It is widely accepted that heterochromatin is necessary to maintain genomic stability. However, direct experimental evidence supporting this is slim. Previous studies using either enzyme inhibitors, gene knockout or knockdown studies all are subject to the caveat that drugs may have off-target effects and enzymes that modify chromatin proteins to support heterochromatin formation may also have numerous other cellular targets as well. Here, we describe PREditOR (protein reading and editing of residues), a synthetic biology approach that allows us to directly remove heterochromatin from cells without either drugs or global interference with gene function. We find that removal of heterochromatin perturbs mitotic progression and causes a dramatic increase in chromosome segregation defects, possibly as a result of interfering with the normal centromeric localization of the chromosomal passenger complex.

SUBMITTER: Molina O

PROVIDER: S-EPMC5167778 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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PREditOR: a synthetic biology approach to removing heterochromatin from cells.

Molina Oscar O Carmena Mar M Maudlin Isabella E IE Earnshaw William C WC

Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 20161206 4

It is widely accepted that heterochromatin is necessary to maintain genomic stability. However, direct experimental evidence supporting this is slim. Previous studies using either enzyme inhibitors, gene knockout or knockdown studies all are subject to the caveat that drugs may have off-target effects and enzymes that modify chromatin proteins to support heterochromatin formation may also have numerous other cellular targets as well. Here, we describe PREditOR (protein reading and editing of res ...[more]

PMID: 27924426

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Project description:We present a software tool, called cMatch, to reconstruct and identify synthetic genetic constructs from their sequences, or a set of sub-sequences-based on two practical pieces of information: their modular structure, and libraries of components. Although developed for combinatorial pathway engineering problems and addressing their quality control (QC) bottleneck, cMatch is not restricted to these applications. QC takes place post assembly, transformation and growth. It has a simple goal, to verify that the genetic material contained in a cell matches what was intended to be built - and when it is not the case, to locate the discrepancies and estimate their severity. In terms of reproducibility/reliability, the QC step is crucial. Failure at this step requires repetition of the construction and/or sequencing steps. When performed manually or semi-manually QC is an extremely time-consuming, error prone process, which scales very poorly with the number of constructs and their complexity. To make QC frictionless and more reliable, cMatch performs an operation we have called "construct-matching" and automates it. Construct-matching is more thorough than simple sequence-matching, as it matches at the functional level-and quantifies the matching at the individual component level and across the whole construct. Two algorithms (called CM_1 and CM_2) are presented. They differ according to the nature of their inputs. CM_1 is the core algorithm for construct-matching and is to be used when input sequences are long enough to cover constructs in their entirety (e.g., obtained with methods such as next generation sequencing). CM_2 is an extension designed to deal with shorter data (e.g., obtained with Sanger sequencing), and that need recombining. Both algorithms are shown to yield accurate construct-matching in a few minutes (even on hardware with limited processing power), together with a set of metrics that can be used to improve the robustness of the decision-making process. To ensure reliability and reproducibility, cMatch builds on the highly validated pairwise-matching Smith-Waterman algorithm. All the tests presented have been conducted on synthetic data for challenging, yet realistic constructs - and on real data gathered during studies on a metabolic engineering example (lycopene production).

Dataset Information

PREditOR: a synthetic biology approach to removing heterochromatin from cells.

Publications

PREditOR: a synthetic biology approach to removing heterochromatin from cells.

Similar Datasets

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