How Does Protein Activation And Silencing Occur Via Chromatin Remodeling?

In eukaryotic cells, gene expressions on chromosome DNA are controlled by a dynamic chromosome structure state that is largely controlled by chromatin-regulating proteins. These proteins regulate chromatin structures, release DNA from the nucleosome, and activate or suppress gene expression by modifying nucleosome histones or mobilizing DNA-histone structure. The complex formed by proteins and DNA is called chromatin.

FACT interacts with DNA repair proteins and chromatin-remodeling factors at DNA damage sites to create a suitable chromatin environment. Chromatin remodeling is a unifying mechanism of chromatin remodelling, which is based on the regulation of DNA translocation. Chromatin-based silencing of sequence information is based on three sequential steps: a decision-making process that targets specific silencing complexes to DNA sequences to be inactivated; a…

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription. Four families of chromatin remodelers provide a means of generating such changes in chromatin structure. ATP-dependent chromatin-remodeling enzymes, often referred to as Snf2- or SWI/SNF-related enzymes, generate changes in chromatin structure.

Chromatin remodeling is an important mechanism of regulating eukaryotic gene expression, making tightly condensed DNA accessible to regulatory transcription. It is involved in the regulation of proper transcriptional activation at the promoter region by altering the histone-DNA contact. Chromatin remodeling also changes chromatin architecture and gene activation. At least nine different types of chromatin remodeling complexes are involved in this process, allowing for extensive remodeling of chromatin, its epigenetic landscape, and transcriptional programs to activate pluripotency and silence certain genes.

How does chromatin Remodelling work?

Chromatin remodeling is a process that involves three dynamic properties of nucleosomes: reconstruction, enzyme-induced covalent modification, and repositioning. Reconstruction involves altering the composition of nucleosomes using canonical histones or special histone variants, which are mediated by histone-exchange complexes like the SWR1 complex. The newly formed variant recruits special regulators to regulate biological functions.

Covalent modification of histones by histone acetyltransferase, deacetylase, methyltransferase, and ATP-dependent protein complexes can also lead to chromatin remodeling. Repositioning of nucleosomes is also facilitated by remodeler complexes.

What kind of activity do chromatin remodeling complexes have?

Chromatin-modifying complexes can be categorized into two main groups: ATP-dependent complexes, which use ATP hydrolysis energy to disrupt or alter the association of histones with DNA, and histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes, which regulate gene transcription by determining the level of acetylation of amino-terminal domains of nucleosomal histones. This review focuses on ATP-dependent remodeling complexes and their relationships between their subunits.

All ATP-dependent chromatin-remodeling complexes contain an ATPase subunit belonging to the SNF2 superfamily of proteins, which are classified into two main groups: the SWI2/SNF2 group and the imitation SWI (ISWI) group. A third class of ATP-dependent complexes with a Snf2-like ATPase and deacetylase activity has been recently described. Tables 1 to 3 classify all complexes and include lists of their known subunits organized by homology, starting with the ATPase subunit.

How is chromatin activated to enable gene transcription?

Transcriptional activation in eukaryotic DNA involves the binding of the basal transcription complex to the transcription start site of a promoter through protein-protein interactions between specific transcription factors and members of the basal transcription complex. However, the accessibility of transcription factors is limited due to eukaryotic DNA being packaged with histones into nucleosomes. To activate transcription, some transcription factors must have the capacity to bind to their binding sites when organized into nucleosomes.

The chromatin structure of the promoter needs to be decondensed to facilitate the binding of the basal transcription machinery. Recent data has demonstrated both binding of transcription factors to their chromatin binding site and transcription factor-induced chromatin remodelling. Factors that mediate chromatin remodelling have been identified and characterized. The ability of a transcription factor to recognize its cognate element in a nucleosome is an inheret property that differs among different transcription factors. The implications of rotational and translational positioning of DNA within a nucleosome on the accessibility of a transcription factor are also discussed.

How does silencing a gene work?

RNA interference (RNAi) is a natural process used by cells to regulate gene expression. It was discovered in 1998 by Andrew Fire and Craig Mello, who won the Nobel Prize for their discovery in 2006. The process begins with the entrance of a double-stranded RNA molecule into the cell, which triggers the RNAi pathway. This molecule is cut into small double-stranded fragments, including small interfering RNAs (siRNA) and microRNA (miRNA), which are approximately 21-23 nucleotides in length. These fragments integrate into a multi-subunit protein called the RNA-induced silencing complex, which contains Argonaute proteins that are essential components of the RNAi pathway.

The guide or antisense strand of the fragment that remains bound to RISC directs the sequence-specific silencing of the target mRNA molecule. Genes can be silenced by siRNA molecules that cause the endonucleatic cleavage of the target mRNA molecules or by miRNA molecules that suppress translation of the mRNA molecule. With the cleavage or translational repression of the mRNA molecules, the genes that form them are rendered essentially inactive.

RNAi is thought to have evolved as a cellular defense mechanism against invaders, such as RNA viruses or transposons within a cell’s DNA. Companies using this approach include Alnylam, Sanofi, Arrowhead, Discerna, and Persomics. The three prime untranslated regions (3’UTRs) of messenger RNAs often contain regulatory sequences that post-transcriptionally cause gene silencing.

What are the mechanisms of action of chromatin modifications?

Modifications can be divided into two main categories, each with distinct mechanisms of action. The first category involves disrupting the interactions between nucleosomes, a process known as “unraveling” of the chromatin. The second category involves the recruitment of non-histone proteins. The second function has been the subject of the most extensive characterization to date. ScienceDirect employs the use of cookies, and all rights are reserved for text and data mining, AI training, and similar technologies. The open access content is licensed under Creative Commons terms.

How does histone modification silence transcription?

Post-translational modification (PTM) of histone proteins affects their interactions with DNA. Some modifications disrupt histone-DNA interactions, causing nucleosomes to unwind, allowing DNA to be accessible for transcriptional machinery and gene activation. Others strengthen histone-DNA interactions, creating a tightly packed chromatin structure called heterochromatin. This results in gene silencing.

At least nine types of histone modifications have been discovered, including acetylation, methylation, phosphorylation, ubiquitylation, GlcNAcylation, citrullination, krotonilation, and isomerization.

These modifications are added or removed from histone amino acid residues by specific enzymes. Histone proteins control chromatin architecture, nucleosomal positioning, and access to DNA for gene transcription. Each nucleosome consists of two identical subunits with four histones: H2A, H2B, H3, and H4. The H1 protein stabilizes internucleosomal DNA and is not part of the nucleosome itself.

How do chromatin modifying proteins modify DNA?

In eukaryotic cells, gene expressions on chromosome DNA are controlled by a dynamic chromosome structure state, largely controlled by chromatin-regulating proteins. These proteins regulate chromatin structures, release DNA from the nucleosome, and activate or suppress gene expression by modifying nucleosome histones or mobilizing DNA-histone structure. There are two classes of chromatin-regulating proteins: enzymes that modify histones through methylation, acetylation, phosphorylation, adenosine diphosphate–ribosylation, glycosylation, sumoylation, or ubiquitylation, and enzymes that remodel DNA-histone structure with energy from ATP hydrolysis.

Chromatin-regulating proteins have major functions in nuclear processes, including gene transcription, DNA replication, repair, and recombination. The basic unit of DNA packaging in chromatin is the nucleosome, a structure that comprises 147 bp of double-strand DNA tightly wrapped around an octamer of histone protein cores. The wrapped DNA contacts the histone octamer at 14 different sites at intervals of approximately 10 bp, harboring various types of noncovalent interactions between the histones and DNA.

Genome DNA also needs to be accessed by protein complexes for gene transcription, DNA replication, and DNA repair. The state of chromatin is dynamic, switching between a DNA-packaging status, where nucleosomes are highly compacted, and a DNA-unpacking status, where nucleosomes are loosened to allow protein complexes necessary for molecular processes that use DNA as a template.

How do chromatin remodeling complexes and histone modifying enzymes activate transcription?

This review discusses the study of histone-modifying and remodeling complexes, which are the main coregulators that affect transcription by changing chromatin structure. Coordinated action by these complexes is essential for the transcriptional activation of any eukaryotic gene. The review covers the functional impact of transcriptional proteins/complexes, remodeling and modification of non-histone proteins by transcriptional complexes, the supplementary functions of non-catalytic subunits of remodelers, and the participation of histone modifiers in the “pause” of RNA polymeraseII. It also includes a scheme illustrating the recruitment of the main classes of remodelers and chromatin modifiers to various sites in the genome and their functional activities.

What are the two major mechanisms of chromatin modifications?

Histone modifications have two main mechanisms: directly influencing the overall structure of chromatin and regulating the binding of effector molecules. These modifications are relevant in the regulation of other DNA processes such as repair, replication, and recombination.

Histone acetylation and phosphorylation reduce the positive charge of histones, potentially disrupting electrostatic interactions between histones and DNA. This leads to a less compact chromatin structure, facilitating DNA access by protein machineries. Acetylation occurs on numerous histone tail lysines, such as H3K9, H3K14, H3K18, H4K5, H4K8, and H4K12. This high number of potential sites indicates that in hyper-acetylated regions of the genome, the charge on histone tails can be effectively neutralized, having profound effects on the chromatin structure.

Evidence for this can be found at the β-globin locus, where genes reside within a hyper-acetylated and transcriptionally competent chromatin environment that displays DNase sensitivity and general accessibility.

Histone phosphorylation is site-specific and has fewer sites compared to acetylated sites. These single-site modifications can be associated with gross structural changes within chromatin. For example, phosphorylation of H3S10 during mitosis occurs genome-wide and is associated with chromatin becoming more condensed. This may be due to the displacement of heterochromatin protein 1 (HP1) from heterochromatin during metaphase by uniformly high levels of H3S10ph, which promotes the detachment of chromosomes from the interphase scaffolding and facilitates chromosomal remodeling essential for its attachment to the mitotic spindle.

What is the function of the chromatin remodeling protein?

Chromatin remodeling is the process of rearranging chromatin from a condensed state to a transcriptionally accessible state, enabling transcription factors or DNA binding proteins to access DNA and control gene expression. This process is crucial for various applications, including text and data mining, AI training, and similar technologies. Copyright © 2024 Elsevier B. V., its licensors, and contributors.

What is the mechanism of action of chromatin remodeling complexes?

The RSC chromatin-remodeling complex, as studied biochemically and structurally, is proposed to release DNA from the histone surface, initiate DNA translocation, and complete the remodeling process through ATP binding.