Emerging and evolving concepts in gene essentiality

Rancati, Giulia; Moffat, Jason; Typas, Athanasios; Pavelka, Norman

doi:10.1038/nrg.2017.74

Cited by 230 publications

(252 citation statements)

References 209 publications

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“…The screen we performed spans over several time points, which allowed us to quantify the gRNA decline rate and cluster the essential genes into two groups. We found that genes in the fast declining group are more highly expressed, less likely to have a paralog and are enriched for fundamental cellular functions, all of which are general properties of essential genes (Rancati et al 2017;White et al 2013). While there is possibility that the genes in the fast-declining group are essential for survival whereas the genes in the gradual-declining group are essential for proliferation, our analysis implies that there is a quantitative difference in the level of essentiality between the gene groups.…”

Section: Discussionmentioning

confidence: 58%

Genes essential for embryonic stem cells are associated with neurodevelopmental disorders

Shohat

Shifman

2019

Preprint

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Mouse embryonic stem cells (mESCs) are a key component in generating mouse models for human diseases and performing basic research on pluripotency, but how many genes are essential for mESCs is still unknown. We performed a genome-wide screen for essential genes in mESCs and compared it to human cells. We found that essential genes are enriched for basic cellular functions, are highly expressed in mESCs, and tend to lack paralog genes. Notably, we discovered that genes that are essential specifically in mESCs play a role in pathways associated with their pluripotent state. We show that 25% of human genes that are intolerant to loss-of-function mutations are essential in mouse or human ESCs and that the human phenotypes most significantly associated with essential genes are neurodevelopmental. Our results provide insights into essential genes in the mouse, the pathways which govern pluripotency, and suggest that many genes associated with neurodevelopmental disorders are essential at very early embryonic stages.

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Section: Discussionmentioning

confidence: 58%

Genes essential for embryonic stem cells are associated with neurodevelopmental disorders

Shohat

Shifman

2019

Preprint

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“…In cancer therapeutics, following genetic alteration in a tumor suppressor gene, pharmacologic inhibition of compensatory mechanisms serves as an approach to selectively target malignant cells 1. The poly(ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3, are essential to multiple DNA repair pathways and have been shown to have a potentially lethal interaction when inhibited in the presence of a mutation in BRCA1 or BRCA2 2 3.…”

Section: Introductionmentioning

confidence: 99%

Poly-ADP-ribose polymerase inhibitor use in ovarian cancer: expanding indications and novel combination strategies

Hinchcliff

Westin

Molin

et al. 2019

Int J Gynecol Cancer

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The use of poly(ADP-ribose) polymerase (PARP) inhibition is transforming care for the treatment of ovarian cancer, with three different PARP inhibitors (PARPi) gaining US Food and Drug Administration approval since 2014. Given the rapidly expanding use of PARPi, this review aims to summarize the key evidence for their use and therapeutic indications. Furthermore, we provide an overview of the development of PARPi resistance and the emerging role of PARPi combination therapies, including those with anti-angiogenic and immunotherapeutic agents.

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“…Even when multiple large chromosomal regions can be removed, significant growth defects often result from accumulating losses of 'quasi-essential' genes, defined as genes that are not needed for survival but are required for robust growth (3,8,18,20,21). Given how difficult it is to predict how gene essentiality and quasi-essentiality generalizes across environments (22), it is often necessary to empirically test the viability and performance of many different deletions and combinations of those deletions to create a useful minimal genome organism.…”

Section: Introductionmentioning

confidence: 99%

Rapid and assured genetic engineering methods applied to Acinetobacter baylyi ADP1 genome streamlining

Suárez

Dugan

Renda

et al. 2019

Preprint

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One goal of synthetic biology is to improve the efficiency and predictability of living cells by removing extraneous genes from their genomes. We demonstrate improved methods for engineering the genome of the metabolically versatile and naturally transformable bacterium Acinetobacter baylyi ADP1 and apply them to a genome streamlining project. In Golden Transformation, linear DNA fragments constructed by Golden Gate Assembly are directly added to cells to create targeted deletions, edits, or additions to the chromosome. We tested the dispensability of 55 regions of the ADP1 chromosome using Golden Transformation. The 19 successful multiple-gene deletions ranged in size from 21 to 183 kilobases and collectively accounted for 24.6% of its genome. Deletion success could only be partially predicted on the basis of a single-gene knockout strain collection and a new Tn-Seq experiment. We further show that ADP1's native CRISPR/Cas locus is active and can be retargeted using Golden Transformation. We reprogrammed it to create a CRISPR-Lock, which validates that a gene has been successfully removed from the chromosome and prevents it from being reacquired. These methods can be used together to implement combinatorial routes to further genome streamlining and for more rapid and assured metabolic engineering of this versatile chassis organism.

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Emerging and evolving concepts in gene essentiality

Cited by 230 publications

References 209 publications

Genes essential for embryonic stem cells are associated with neurodevelopmental disorders

Genes essential for embryonic stem cells are associated with neurodevelopmental disorders

Poly-ADP-ribose polymerase inhibitor use in ovarian cancer: expanding indications and novel combination strategies

Rapid and assured genetic engineering methods applied to Acinetobacter baylyi ADP1 genome streamlining

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