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Turning Genes Off and On Again with CRISPRoff

Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing

Journal ClubJournal Club

The Journal Club hosted by Dr. Oliver Medvedik will return live to our Facebook Page at 12:00 EST on Tuesday 27th of April. This month we will be taking a look at a new paper and technique for the gene editing tool CRISPRcas9. The technique allows researchers to turn epigenetic methylation off and back on again, thus allowing the silencing and unsilencing of certain genes. This could be valuable in combating age-related diseases and reversing the harmful changes in gene expression that accompany aging.

A general approach for heritably altering gene expression has the potential to enable many discovery and therapeutic efforts. Here, we present CRISPRoff—a programmable epigenetic memory writer consisting of a single dead Cas9 fusion protein that establishes DNA methylation and repressive histone modifications. Transient CRISPRoff expression initiates highly specific DNA methylation and gene repression that is maintained through cell division and differentiation of stem cells to neurons. Pairing CRISPRoff with genome-wide screens and analysis of chromatin marks establishes rules for heritable gene silencing. We identify single guide RNAs (sgRNAs) capable of silencing the large majority of genes including those lacking canonical CpG islands (CGIs) and reveal a wide targeting window extending beyond annotated CGIs. The broad ability of CRISPRoff to initiate heritable gene silencing even outside of CGIs expands the canonical model of methylation-based silencing and enables diverse applications including genome-wide screens, multiplexed cell engineering, enhancer silencing, and mechanistic exploration of epigenetic inheritance.


Nuñez, J. K., Chen, J., Pommier, G. C., Cogan, J. Z., Replogle, J. M., Adriaens, C., … & Weissman, J. S. (2021). Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing. Cell.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
  1. Neil
    April 23, 2021

    Excellent choice!

  2. Julie Johnson
    May 3, 2021

    Wow! This is exciting news! My Dad died of Colon Cancer and now my Mom has been diagnosed with it. When testing her tumor they determined she has Lynch Syndrome, a genetic predisposition towards colon and other types of cancer. Since both of my parents have the same cancer, it doesn’t bode well for me. As I get older, I grow more worried and scared. It would be wonderful to know there was a mechanism to keep the mutations from occurring and creating cancers and other diseases. This could save millions of lives!

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