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#
Aohona DattaAug 23, 2020
How does enhancer hypomethylation affect age-related disorders?
(Enhancer is a short sequence of DNA; about 50-1000bp that can increase the transcription of a particular gene dramatically)
Can we group the gene-targets of dysregulated enhancers across all tissue types in an aging individual according to the cellular processes they affect?
Can modulation of super-enhancers (clusters of enhancers much larger than common enhancers that help specify cell fate) slow down aging?
Enhancers are cis-acting regulatory DNA elements that can strongly stimulate the transcription of a linked transcription unit even when located several thousand base-pairs upstream or downstream of the transcription start site (TSS). Enhancers modulate spatial and temporal expression of genes; are cell-type specific and are usually located outside of their target gene.
Age dependent diseases have an epigenetic basis. Transcriptomic changes that occur with age have been linked to changes in methylation pattern within enhancer regulatory elements. The strongest risk factor for Alzheimer’s disease (AD) is aging.
Epigenetically controlled enhancers influence neuronal differentiation, neuronal plasticity and experience-dependent gene transcription within the brain.
A recent study explored the role of enhancers in AD through a genome-wide analysis of DNA methylation in CpG and CpH sites in neurons from AD brain. It revealed that hypomethylation of enhancer in intron 3 of DSCAML1 gene occurs before the formation of neurofibrillary tangles in the AD brain.
Kundaje, Anshul, et al. “Integrative Analysis of 111 Reference Human Epigenomes.” Nature, vol. 518, Feb. 2015, pp. 317–30.
Peters, Marjolein J., et al. “The Transcriptional Landscape of Age in Human Peripheral Blood.” Nature Communications, vol. 6, Oct. 2015, p. 8570.
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.
Thakurela, Sudhir et al. “Dynamics and function of distal regulatory elements during neurogenesis and neuroplasticity.” Genome research vol. 25, 2015 pp. 1309-24.
Joo, Jae-Yeol, et al. “Stimulus-Specific Combinatorial Functionality of Neuronal c-Fos Enhancers.” Nature Neuroscience, vol. 19, Jan. 2016, pp. 75–83.
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.
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.
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.