Epigenetics and Noncoding RNA – Principles and Clinical
Impact
Authors: Kornak Uwe , Bischof Oliver , Hesse Eric , Jakob Franz , Ebert Regina , Taipaleenmäki Hanna 
Published: September 2021

Genetics studies the inheritance of genetic information encoded by the base pair
sequence and its variants. Sequence variants can have severe consequences as
seen in genetically inherited diseases (e. g. osteogenesis
Imperfecta, hypophosphatasia). On the other hand, epigenetics deals with
inherited and dynamically reversible modifications of chromatin without changing
the base pair sequence, resulting in a change in phenotype without a change in
genotype. These modifications primarily exert their effects by influencing gene
expression. Initially, the definition of epigenetics exclusively comprised
inherited changes that persist across several generations without changes in the
DNA sequence. This definition has been extended to include also dynamic and
partially reversible changes that occur more short-term. These gene modulatory
effects introduce new levels of complexity and are crucial determinants of cell
fate and organismal development. With its length of approximately two meters,
human DNA has to be compacted to fit into the nuclei and fulfill its functions.
DNA is wrapped around histone octamers into so-called nucleosomes. DNA,
histones, and other DNA-associated proteins together form what is called
chromatin. DNA packaging is achieved by variable degrees of chromatin
condensation depending on cell type and context. Epigenetic transcriptional
regulation modifies the affinity and accessibility of cis-regulatory elements
(CREs) for transcription factors and the basic transcriptional machinery and
governs interaction between CREs. CREs include promoters, enhancers, silencers,
and insulators and are potent modulators of gene expression impacting core cell
biological processes such as proliferation and differentiation. Chromatin
looping and remodeling by differential covalent modifications of DNA
(e. g., methylation or hydroxylation) and histone tails
(e. g., acetylation or methylation) elicit fundamental
changes in CRE accessibility, thus impacting gene expression. Chromatin looping
depends on a specialized machinery including cohesins. Chromatin modifications
are mediated by specific enzymes like DNA methylases (DNMTs), histone-modifying
enzymes, like histone methyl- and acetyltransferases (KMTs, HATs/KATs),
and histone demethylases and deacetylases (KDMs, HDACs). It becomes increasingly
evident that epigenetic (dys)regulation plays a decisive role in physiology and
pathophysiology, impacting many age-related diseases like cancer and
degenerative pathologies (e. g., osteoporosis,
Alzheimer’s, or Parkinson’s) in a significant fashion. Recently,
small-molecule inhibitors of chromatin-modifying enzymes (e. g.,
vorinostat) have been identified and successfully introduced in therapy.
Significant progress in high-throughput sequencing technologies and big data
analysis has broadened our understanding of noncoding (nc) RNAs and DNA sequence
regions in (post-)transcriptional regulation and disease development. Among
ncRNAs that play vital roles in gene expression are micro- (miRs) and long
noncoding RNAs (lncRNAs; e. g., XIST or HOTAIR). By interacting
with the coding genome, these RNAs modulate important genetic programs.
Interfering RNAs can, for example, enhance the post-transcriptional degradation
of transcripts, altering their translation, or assist in the recruitment of
chromatin-modifying enzymes to regulate transcription. They can also be packaged
into extracellular vesicles as cargo and thus deliver critical information to
the microenvironment or even systemically to distant tissues. Therefore, ncRNAs
represent a novel playground for therapeutical investigations and supplement
epigenetic mechanisms of gene regulation while being subject to epigenetic
regulation themselves. Last but not least, dysregulated ncRNAs can also
propagate disease. Until recently, the detection of epigenetic phenomena
necessitated invasive diagnostic interventions. However, with the arrival of
so-called “liquid biopsies” an analysis of circulating cell-free
DNA fragments (cfDNA) and RNAs as well as vesicle-packed RNAs through minimal
invasively drawn blood samples can be obtained. Such
“fragmentomics” and RNAomics approaches on peripheral blood will
ultimately serve as diagnostic tools for personalized clinical
interventions.