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How does enhancer hypomethylation affect aging/age-related disorders?

How does enhancer hypomethylation affect aging/age-related disorders?

Image credit: Xia, Ji-Han, and Gong-Hong Wei. https://www.mdpi.com/2073-4409/8/10/1281/htm#

By Aohona Datta on Aug 23, 2020

[1] Kundaje, Anshul, et al. “Integrative Analysis of 111 Reference Human Epigenomes.” Nature, vol. 518, Feb. 2015, pp. 317–30.

[2] Peters, Marjolein J., et al. “The Transcriptional Landscape of Age in Human Peripheral Blood.” Nature Communications, vol. 6, Oct. 2015, p. 8570.

[3] Malik, Athar N., et al. “Genome-Wide Identification and Characterization of Functional Neuronal Activity–Dependent Enhancers.” Nature Neuroscience, vol. 17, Oct. 2014, pp. 1330–39.

[4] Thakurela, Sudhir et al. “Dynamics and function of distal regulatory elements during neurogenesis and neuroplasticity.” Genome research vol. 25, 2015 pp. 1309-24.

[5] Joo, Jae-Yeol, et al. “Stimulus-Specific Combinatorial Functionality of Neuronal c-Fos Enhancers.” Nature Neuroscience, vol. 19, Jan. 2016, pp. 75–83.

[6] Li, Peipei et al. “Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer's disease pathology and cognitive symptoms.” Nature communications vol. 10, 2019.

[7] Adam, Rene C., et al. “Pioneer Factors Govern Super-Enhancer Dynamics in Stem Cell Plasticity and Lineage Choice.” Nature, vol. 521, 2015, pp. 366–70.

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CRISPR to interrogate Super Enhancer

CRISPR meets Epigenome Editing CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) has changed the field of genetic engineering. This new kind of molecular scissors – known also as designer nucleases - allows for the precise targeting of a DNA sequence allowing to edit it in a precise manner (https://science.sciencemag.org/content/337/6096/816). The main mechanism by which CRISPR operates relies on a short RNA sequence – known also as guide RNA (gRNA) – which drives the Cas9 nuclease toward the desired target, represented by a sequence complementary to the gRNA. Once that the Cas9 nuclease reaches the target it causes a DNA-double-stranded break (DSB) within the DNA double-helix. Based on this it is possible to inactivate or modify a gene at will (https://doi.org/10.1146/annurev-biochem-060815-014607) . However, CRISPR can be programmed also with the purpose to modulate gene expression by recruitment of specific transcriptional activators - like VP64, P300 - or also transcriptional repressors - LSD1 and KRAB-(https://academic.oup.com/bfg/articleabstract/19/3/215/5670375?redirectedFrom=fulltext methylases ) wich contrary to gene editing, allows for a seamless modification of DNA sequence while actively changing genetic expression. From a clinical point of view, targeted editing of aging-related genes offers novel therapeutic avenues for multiple diseases. Genetic expression is precisely regulated by both elements located close by the respective gene – the promoter - or far away from it – cis-regulatory elements – like transcriptional enhancers which can modulate gene expression over long distances. in an orientation- independent and cell-type-specific manner. CRISPR/Cas9 system, in particular the latest epigenome editors variants like the catalytically inactive variants dead Cas9 (dCas9) fusions and its combinations with other strategies(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5168826/ ) has been recently used to interrogate the regulatory elements – by either promoting activation or repression of the controlled promoter - of the human β-globin locus control region (LCR), oncogenic TAL1 super-enhancer (SE), and hematopoietic lineage-specific enhancers as examples. They proved it was possible to successfully modulate the enhancers across different contests: in vitro, in vivo and xenographs ( https://www.nature.com/articles/s41467-020-14362-5) . Such approach if combined for example with cerebral organoids (https://www.frontiersin.org/articles/10.3389/fcell.2019.00303/full ) to untangle and understand the role of super-enhancers in aging and neurodegenerative disorders as well.

by Antonio Carusillo on Aug 25, 2020

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