Chromatin modification

염색질 변형에 대한 이해는 TATA Box 연구에 가장 핵심적인 부분입니다. 특히 Replication origin에 대한 이해는 중요합니다. Transcriptional activator proteins(TAP) 결합부위와 TATA Box의 기능에 대해서 구체적으로 제시하는 단계이기 때문입니다. 염기비율에 따른 persistence length의 차이는 DNA의 전사와 복제의 전과정에서 대단히 중요한 factor로 작동합니다. 

 

 

In order for DNA transcription or replication to occur, protein enzymes must bind to DNA promoters or replication origins. But the 30nm fiber structure prevents these enzymes from binding to DNA. Therefore, it is necessary to break down the 30nm structure first.

 

The structure of the 30 nm fiber is maintained by the electrostatic coupling of the negative charge of the central histone fold structure and the positive charge of the N-terminal amino tails (+ charge). (particularly the binding between the H4 N-terminal tail and the H2A fold structure is important) Therefore, it was suggested that the structure of 30 nm fibers could be changed by applying modifications such as acetylation, methylation, and phosphorylation to the N-terminal tail. Mainly, Lysine is modified by an acetyl group or a methyl group, but Arginine also often shows this modification. Phosphorylation frequently occurs at serine. It is very important to find out which amino acid of which N-terminal tail is modified, because various results appear depending on which amino acid of which N-terminal tail is modified. For example, acetylation at lysines 8 and 16 of the H4 N-terminal tail triggers gene expression. However, if methylation occurs at lysine 9 or 27 of the H3 N-terminal tail, DNA transcription is rather suppressed.

 

In this section, we will briefly examine the trends that occur when acetylation, methylation, and phosphorylation occur. (There are, of course, many exceptions, as these are only approximate trends.) First, when acetylation of histones occurs, the positive charge of the N-terminal tail is offset. As a result, the 30nm structure is loosened, and in addition to recognizing the acetylation of the N-terminal tail of the central histone, several enzymes gather to modify the structure of the nucleosome.

 

A typical protein domain site that recognizes and binds to the acetylation of the N-terminal tail is the bromodomain, and the enzyme having the bromodomain recognizes and binds the acetylated N-terminal tail, and then performs a certain action. will do

 

 

This is because simply having a bromodomain does not mean that it can bind to all types of acetylated N-terminal tails. Each enzyme has its own site. Next, in the case of methylation, the positive charge of the N-terminal tail becomes stronger. As a result, the structure of the 30nm fiber becomes more compact and the expression of genes is suppressed. This has a very important meaning, because each cell of a multicellular organism must suppress most of its gene expression and express only genes that fit its original role.

 

Representative protein domain sites that recognize and bind methylation of the N-terminal tail include a chromodomain, a TUDOR domain, and a plant homeodomain (PHD)-finger. (Note that the domain that recognizes the unmodified N-terminal tail is the SANT domain) What about phosphorylation? Phosphorylation also counteracts the positive charge of the N-terminal terminal. However, phosphorylation is mainly used as a specific gene marker or induces special cases such as cell division and apoptosis.

 

 

Enzymes called nucleosome-remodeling complexes can take away histones from nucleosome-structured DNA and cause structural modifications, such as forming a nucleosome structure with another DNA chain, or sliding DNA along the surface of histone proteins. there is. However, translocation of the nucleosome structure does not occur easily. In many cases, it is slipped to expose the enzyme binding site, roughly as follows.

It is well shown in the schematic diagram above. In order for transcription to occur, RNA polymerase must recognize and bind to the TATA box-TBP complex located on the DNA sequence. However, since TAP (Transcriptional activator proteins) binding sites or TATA boxes are located in the nucleosome, they were exposed to enzymes by sliding DNA. The method of moving DNA is quite simple. Although only the movement of DNA is shown in the schematic diagram above, it is difficult to see, but first, the enzyme strongly grabs the histone and forcibly rips off a certain part of the DNA. And if you pull the DNA while holding it, the histones around it continuously spin and the DNA slides. And when the pulled DNA is put down as it is, it spins in the opposite direction and the DNA slides like a wave. (Obviously consumes ATP)

 

 

Enzymes appropriately modify the N-terminal tail of histones, catalyzing structural modifications of chromatin and regulation of gene expression. The enzymes that acetylate the N-terminal tail are a family of enzymes called histone acetyltransferases (HATs). Of course, there are many acetylation sites, so there are many types of these enzymes as well. There are enzymes that acetylate and there are enzymes that deacetylate. Histone deacetylases are enzymes called histone deacetylases (HDACs). Likewise, methylation enzymes are enzymes called histone methyltransferases (HMTs).

 

 

 

정리하자면 histone이 메틸화되면서 유전자의 발현을 억제하려는 경향이 나타납니다. 메틸화는 효소가 존재하지만, 탈메틸화 효소 HDMEs(Histone demethylases)는 아직 연구되고 있는 분야인데요. 억제된 유전자를 다시 발현시키는 중요한 도구가 될 것입니다. 이 부분은 Epigenetics에서 다루는데, 저의 biology 지식이 아직 거기까진 미치지 못하는 것 같습니다. 획득형질이 유전되는 부분은 많은 연구자분들께도 어려운 연구주제라고 알고 있습니다.

 

다시한번 제 연구의 conclusion을 보고 오셔도 좋을 것 같군요.

2021.11.12 - [Project/Molecular dynamics and Biology] - 7. Conclusion[Characteristics study of TATA box through comparison of elastic modulus according to DNA sequence]

7. Conclusion[Characteristics study of TATA box through comparison of elastic modulus according to DNA sequence]

위 page에도 잘 정리되어 있겠지만 염기조성에 따른 DNA의 elasticity를 연구했었습니다. 물론 음파를 이용하는 간접적인 방식이나 광집게를 이용하는 선행연구가 있었지만 분자동력학 시뮬레이션을 통해 다른 분자에 대해서도 모델링을 적용할 수 있게끔 활용도를 높였다는 측면이 있습니다. 당연하게도 기존연구들과 달리 염기비율에 따른 elastictiy를 정량적으로 측정할 수 있었죠. Krathy-porod model을 참고하였었는데 이 부분도 나중에 소개할 기회가 있었으면 좋겠습니다. 컴퓨터학과생들이 배우는 공학수학에는 나오지 않는 helix에 대한 부분이라 저도 조금 더 공부가 필요한 부분이긴 합니다. A-T ratio가 높으면 일반적인 DNA structure에서 더 굽어지고 flexible한 것을 보였는데 굽어지기 쉽다는 특성은 number of hydrogen bonds와 관련한 prediction과 일치했습니다. 또한 TATA box에 binding factor가 access할 때 TATA box가 쉽게 bent하고 flexible할수록 binding factor와의 repulsive force를 이겨내고 binding하는 것까지 연결됩니다.

 

최근 약물 후보군을 추려내거나 개발할 때도 전산물리학과 분자동력학 시뮬레이션이 많이 활용되고 있습니다. 최근 코로나 바이러스 백신 개발도 이러한 과정을 거쳤다는 것을 많은 언론에서 주목하기도 했습니다. 저의 연구결과가 DNA에 특정 enzymes등이 attached하거나 생명활동에 관여할 때 DNA의 elasticity로 이해될 수 있는 부분이 아주 많을 것이라고 기대합니다.