In recent years, epigenetics has become one of the fastest-growing and hottest subfields of modern genetics. Unlike traditional genetics, epigenetics is a genetic regulatory mechanism that is independent of gene sequences, that is, genetic behaviors that regulate gene expression at the genomic or chromatin level without involving gene sequence alteration. Epigenetics runs through all stages of individual growth and development, and is also involved in the occurrence and development of different diseases, and its importance and research value are no less than those of classical genetics.
From Mendel's laws of inheritance in 1865 to the first isolation of DNA molecules in 1869, and later the proposal of the double helix structure of DNA, the classical theory of genetics was gradually established. A 1930 study reported that the location of the white gene in heterochromatin or euchromatin in Drosophila determined whether its expression was activated or repressed, which researchers thought was related to the local environment of the nucleus. Subsequently, in 1957, developmental biologist Conrad H. Waddington (Conrad HWaddington coined the term epigenetics and became a new branch of biology by summarizing similar phenomena as genes that may interact with the environment and produce corresponding phenotypes. However, due to the backwardness of biochemical molecular technology at that time, the enzymes related to epigenetic modification could not be identified, and they did not receive extensive research and attention. In fact, DNA methylation has been described since 1965; Histone modifications were reported much earlier, beginning in 1962. However, it was not until the 90s that researchers began to pay attention to it. In 1999, the Human Epigenome Society (HEC) was established in the UK, Germany and France, and the Human Epigenome Project was launched immediately after the completion of the Human Genome Sequencing Project. It can be seen that epigenetics has become another major research direction, representing one of the most cutting-edge research fields in life sciences, and has far-reaching significance for human health, diagnosis and treatment of diseases.
Epigenetics has the following characteristics:
, do not changednaSequence:Epigenetics does not involve changes in the genome sequence within the nucleus, mainly through chemical modification of DNA or histones, changes in chromatin structure, or the use of non-coding RNA to regulate gene expression;
, dynamics:Epigenetic modification is a dynamic process, that is, the expression level and pattern of genes can be changed at different developmental stages, tissue types and environmental conditions, so that organisms can adapt to changes in different environments and the needs of individual development.
, heritability:Epigenetic modifications can also be passed on to offspring during cellular** and sexual reproduction like genetic material, but the mechanism is still not fully understood;
, reversibility:Epigenetic modifications are usually performed by corresponding proteases, such as DNA demethylation-related demethylases, which can remove the original DNA methylation modifications. Therefore, it is a reversible process, which opens a new door for disease prevention and control;
, environmental sensitivity:Some environmental factors can alter the genetic material to affect the phenotype of cells and individuals. Similarly, the pattern and degree of epigenetic modification can also be affected by environmental factors, such as dietary Xi, lifestyle, etc., which can change epigenetic modification, which in turn affects ontogeny and health.
The epigenetic modifications found so far usually occur on DNA, histone, or RNA, and the main mechanisms include DNA methylation, RNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation.
Regulatory mechanisms of epigenetics
dnaMethylation
DNA methylation is one of the most well-studied epigenetic modifications. 5'-Methylcytosine (5MC) is the most common mode of DNA methylation, in which DNA methyltransferases (DNMTs) transfer methyl groups to the 5th carbon atom of cytosine in the CPG island. A large number of CG bases are concentrated in certain locations in the genome to form CPG islands, which are involved in the transcriptional regulation of genes. In general, hypermethylation of CPG islands in gene regulatory regions (e.g., promoter regions) leads to transcriptional repression; Conversely, hypomethylation promotes transcription. In the genosome, it is the opposite of the function of the regulatory region. DNA methylation plays a key role in regulating various physiological and pathological processes, such as embryonic development, genomic imprinting, X chromosome inactivation, biological processes such as cell differentiation and proliferation, and aberrant DNA methylation is often associated with the occurrence of a variety of diseases.
Figure 1 Schematic diagram of DNA methylation[1].
rnaMethylation
Similar to DNA methylation, RNA methylation has become a key regulator that regulates the spatiotemporal expression of genes during eukaryotic development. M6A methylation is one of the most common RNA methylation modifications, and it is a very popular research direction in recent years. M6A methylation typically occurs inside mRNA, RRNA, and NCRNA, and is recognized, catalyzed, and removed from RNA by corresponding enzymes. M6A is abundantly concentrated in the vicinity of the stop codon, 3'UTR, long exons, and conserved Drach motifs. Studies have shown that M6A methylation is involved in a series of biological processes such as stem cell self-renewal, tissue differentiation, development and DNA damage response, and once abnormal, it will cause a series of diseases such as cancer, neurological diseases, cardiovascular diseases, and embryonic development retardation.
Figure 2 RNA methylation modification[2].
, histone modifications
Histones are the basic structures that make up eukaryotic chromatin and are alkaline due to their rich in basic amino acids such as arginine and lysine, which can bind tightly to acidic DNA. Histone modification refers to the modification process of methylation, acetylation, phosphorylation, ubiquitination, ADP ribosylation, etc., of histones catalyzed by related proteases, and can also be reversed under the action of the corresponding reverse modification enzyme system. Histone methylation, which typically adds methyl groups to the Lys residues of histones H3 and H4, is one of the most important post-transcriptional modifications. Another of the most common post-transcriptional modifications is phosphorylation, which occurs primarily on histone ser and tyr residues and is widely involved in cellular processes including gene expression, cell cycle regulation, DNA damage repair, and asymmetric cell**.
Fig. 3 Histone modifications[1].
and chromatin remodeling
Chromatin remodeling is a process of dynamic change in chromatin structure. The chromatin structure is uneven, with some areas being loose and others being compact. In the relaxed region of chromatin, the DNA is in an "open" state, allowing transcription factors and RNA polymerases to bind to the DNA, activating or promoting gene expression; Dense areas of chromatin, on the other hand, hinder this process and hinder gene expression. Chromatin remodeling occurs mainly by two mechanisms, one is the histone modification described above, and the second is ATP-dependent modification, which disrupts the binding between DNA and histones by using the energy of ATP hydrolysis, resulting in a change in nucleosome position. Therefore, when there is a change in chromatin structure, i.e., chromatin remodeling, it affects the expression of nearby genes.
Fig. 4 Schematic diagram of chromatin remodeling[3].
, non-codingrnaRegulation
In addition to proteases being involved in epigenetic regulation, they are also regulated by non-coding RNAs. The functional non-coding RNAs we are familiar with, including mirna, lncRNA, circRNA, and pirna, are basically involved in epigenetic modification, and they mainly play a role in the mRNA of the target gene, down-regulating the expression of the target gene by degrading the mRNA or inhibiting its translation, and the adsorption of miRNA by the Cerna mechanism of LNCRNA and circRNA, which also belong to the category of epigenetic modification. In addition, piRNA is mainly found in mammalian germ cells and stem cells, and binds to the transcription site of the transposon by binding to the PIWI protein to recognize the primary transcription product of the transposon, and recruits histone methyltransferases to promote histone methylation, which in turn leads to chromatin tightening and inhibition of gene expression.
Fig.5 Non-coding RNA regulation [1].
In general, epigenetic modification is a non-gene sequence-related genetic regulation mechanism, which has the characteristics of DNA sequence invariance, dynamics, heritability, reversibility and environmental sensitivity, and has a variety of mechanisms involved in epigenetic modification from different levels, especially DNA RNA methylation, histone modification, chromatin remodeling, and regulation of functional non-coding RNA. It plays an important role in ontogeny, adaptation to the environment, and disease occurrence, providing new perspectives and methods for research in the fields of biology and medicine. In the follow-up, Xiaoheng will introduce the mechanism in epigenetics one by one, and interested partners are welcome to pay attention and discuss exchanges. Hanheng Biotech has been focusing on virus packaging for more than ten years, and can consult the gene regulatory vectors of off-the-shelf or customized epigenetic modification-related enzymes, as well as DNA methylation and demethylation-related dcas9 adenovirus
References:
1] prasher, dimple et al. “the impact of epigenetics on cardiovascular disease.” biochemistry and cell biology = biochimie et biologie cellulaire vol. 98,1 (2020): 12-22. doi:10.1139/bcb-2019-0045
2] song, peizhe et al. “rna methylation in mammalian development and cancer.” cell biology and toxicology vol. 37,6 (2021): 811-831. doi:10.1007/s10565-021-09627-8
3] clapier, cedric r, and bradley r cairns. “the biology of chromatin remodeling complexes.” annual review of biochemistry vol. 78 (2009): 273-304. doi:10.1146/annurev.biochem.77.062706.153223