Transcriptional regulation

2주일이 다되어가는데 개학을 해 바빠서 그랬는지 티스토리 포스팅을 거의 안했습니다ㅠㅠ 뭔가 블로그를 만들면서 생각했던 포부가 무너져가는 느낌이 들긴 합니다만... 계속 TATA box review를 해나가려고 합니다. 무언가 연구를 했으면 거기서 그치는 것이 아니라 꾸준히 발전시키는 것이 중요하다고 생각하기 때문입니다. 발전시켜 나가기 위해서는 무작정 깊이 파는 것이 아니라 기반지식을 넓혀서 다시 깊이 팔 수 있는 구멍을 찾는 것이 중요합니다. 마치 석유를 시추하기 전에 기반암조사를 하는 것처럼요.

 

 

As research on JUNK DNA continues, sequences that control DNA expression are coming out, but many parts of DNA are still interpreted as if meaningless. Of course, this is something that needs to be researched...

However, in some gene clusters, expression is controlled by a group of regulatory sequences. An example is the globin gene.

 

There are five types of globin genes, but these genes are not expressed simultaneously. (It has the order of ε, γG, γA, δ, β from the 3' end) Different genes are expressed in the order of ε to β at the developmental stage. If the gene is artificially altered, it is expressed in the order in which it was changed.

 

The regulatory sequence that controls this gene group is a long region of several regulatory sequences located upstream called a locus control region (LCR). Here, not only amplifiers that promote transcription but also insulators and promoter regions that suppress transcription are mixed. Gene expression is regulated by an appropriate combination of these sequences, and there is a model that induces transcription so that the appropriate gene is expressed by changing the chromatin according to the level of LCR activity.

Similar to the globin gene, there is a group of HoxD genes in mice, which are regulated by a factor called a global control region (GCR). HoxD gene is a gene that makes proteins that play a very important role in the formation of limbs (limbs) during development. Likewise, protein expression is regulated according to the combination of several regulatory sequences present in GCR. In general, when several activators work together, a synergistic effect occurs and strongly promotes transcription. Conversely, even if one repressor inhibits an activator, the effect of the activator is greatly reduced, which means that transcription can be repressed. The synergistic effect of the activators can be easily understood by considering how the activators interact with the mediator complex.

 

 

There are a lot of subunits in the mediator complex, and they can interact with several activators at the same time. Each activator can attract different proteins, and the proteins can functionally cooperate to bring about a great effect. There may be several methods for cooperative binding of activators. Binding of one activator may be facilitated simply by binding of one activator, but as one activator binds, the chromatin structure is altered, and the binding site of the other activator may be exposed. An example of the latter is the expression of the HO gene in yeast. Both SW15 and an activator called SBF are required for the expression of the HO gene. The activator that directly promotes transcription of the HO gene is SBF. SBF has a binding site near the promoter, and when SBF binds, transcription of the HO gene occurs. However, the binding site of SW15 is also quite far from the promoter and does not directly promote transcription.

 

The reason why SBF is not enough is that the SBF binding site on DNA is not normally exposed to the outside, so that SBF cannot bind to DNA. SW15 induces the nucleosome remodeling complex and histone acetyltransferase to modify the chromatin structure to expose the SBF binding site, thereby promoting the binding of SBF, and thereby transcription of the HO gene.

 

Several activators may cooperatively bind to one region of an enhancer sequence, which is called an enhancer complex.

 

 

The β-interferon gene, which is activated when infected, is activated by three activators. They cooperatively bind to an amplifier located about 1 kb upstream of the β-interferon gene to form an amplifier complex. However, before they bind, a protein called HMGA1 binds to the amplifier first. This protein binds to the minor groove side of the DNA and straightens the bent DNA to facilitate the formation of the amplifier complex. After the amplifier complex is formed, the HMGA1 protein is dropped because there is no more binding site left at the amplifier site. The amplifier complex induces the binding of CBP (CREB-binding protein) and p300 coactivators, which not only promote transcription by modifying the histone structure, but also directly collect and activate transcription machinery.

 

 

위에서 가장 중요한 단계는 DNA를 곧게 피는 것이다. TATA Box와 관련한 연구에서 persistence length를 주목한 이유이기도 했다.

 

 

As such, several activators work cooperatively to regulate gene expression. Interestingly, there is also an example in which a single regulator regulates the expression of several genes.

 

An example is the expression of a gene that determines the mating type of yeast. Yeast is a single-celled organism that reproduces by budding, but it also reproduces sexually when the environment is bad. Common diploid (2n) yeast divides into two haploid (n) yeasts through meiosis when the environment is bad, and these two yeasts have different genetic makeup. Each haploid yeast is called type a and type α, and this is called a hybridization of yeast. Haploid yeast can reproduce asexually through budding and reproduce by itself, and two yeasts with different mating types join to form diploid yeast, which is the sexual reproduction method of yeast. The two crosses are genotyped different.

In yeast, the MAT gene of the two mating types is different. The MAT gene encodes a regulator, and the expression of each mating type-specific gene is regulated by the regulator. All yeasts have a-specific genes, α-specific genes, and haploid-specific genes, and these genes are target genes of regulators. becomes A-type-specific genes and α-type-specific genes are expressed only when an activator binds to them, but haploid-specific genes can be expressed even in the absence of a specific activator. As a result of the expression of the MAT gene in type a yeast, an activator called a1 is produced, but this activator does nothing in type a yeast. Mcm1 protein present in yeast is an activator that induces transcription of a target gene, and promotes the expression of type a-specific genes. However, since the Mcm1 protein alone cannot bind to the α-specific gene, the expression of the α-specific gene does not occur.

 

On the other hand, α-type yeast produces two proteins, α1 and α2, instead of a1, where α1 is an activator and α2 is a suppressor. Mcm1 protein can also bind to type a-specific genes in α-type yeast, but in this case, α2 protein suppresses transcription. On the other hand, the α1 protein can promote the expression of the α-type-specific gene through cooperative binding with Mcm1.

 

When haploid yeast forms a diploid through conjugation, it has both a blood and α-type MAT genes. However, the α1 protein is not expressed in diploid cells. As a result, both the a-type-specific gene and the α-type-specific gene expression are suppressed. And interestingly, the expression of the haploid gene is suppressed through the cooperative binding of the a1 protein and the α2 protein.