Chromatin remodeling is an important mechanism for regulating eukaryotic gene expression. It enables tightly packed DNA to be approached by various regulatory factors such as transcription factors and DNA replication components. In the nucleus, the DNA double helix is tightly wrapped around nucleoproteins called histones. The complex formed by proteins and DNA is called chromatin. Histones are tightly packed around DNA, preventing it from coming into contact with various chromosomal regulatory proteins, leading to gene silencing.
Chromatin comes in two forms: euchromatin, which is less condensed and can participate in transcription; and heterochromatin, which is highly condensed and not transcriptable. The basic unit of chromatin is the nucleosome, which consists of 147 base pairs of DNA, each wrapped around two copies of the four histone proteins H2A, H2B, H3, and H4 (histone octomers).The basic mechanism of chromatin remodeling depends on three dynamic characteristics of nucleosomes: remodeling, enzyme-induced covalent modification and repositioning. For reconstruction, nucleosomes can be compositional altered using standard histone or specific histone variants. This change in compositions is mediated by histone exchange complexes, such as the SWR 1 complex, which replace standard histones with histone variants.
Moreover, remodeling complexes mediate the reorientation of nucleosomes. All of these processes eventually lead to DNA exposure to transcriptional regulatory proteins and subsequent activation of DNA.
There are multiple chromatin remodeling complexes in the nucleus which follow different chromatin remodeling mechanisms. Reassortants mobilize and reposition nucleosomes, introduce histone octamers, and remove or replace h2a-h2b dimers.
To perform these functions, a plasticizer requires about 12 to 14 kcal/mol energy, which is obtained by hydrolysis of ATP. In contrast to the ATP-dependent mechanism, chromatin remodeling can also occur ATP-independent. Relocalization of nucleosomes as a result of transcription factor-DNA binding or histone chaperone mediated histone removal from chromatin is an example of an ATP-independent mechanism.
Histone modifications (through methylation/demethylation, acetylation/deacetylation, phosphorylation, ubiquitination, etc.) are another important aspect of chromatin remodeling. Specifically, histone modifications are covalent bonds between various functional groups and lysine residues at the tail end of histone. Histone modification allows the binding of various regulatory factors that have specialized domains for recognizing modified histones.
Wrapping DNA around histones to form chromatin structures serves two main purposes: first, to cause the aggregation of large (several meters) strands of DNA so that they can be properly embedded in the nucleus; second, it prevents DNA from being continuously transcribed. In order to initiate gene expression, chromatin must unfold, a process called chromatin remodeling. Remodeling of visible chromatin is an absolute requirement for gene expression. Therefore, it is an important process to regulate important physiological functions and maintain the stability of intracellular environment. Scientific studies have shown that histone modifications (deacetylation and methylation) and DNA methylation play an important role in regulating the promoters of immune-related genes, which are crucial for disease prevention. Chromatin remodeling is also known to be critical for building long-lasting transgenic immune memories in plants.
Chromatin remodeling is a component of epigenetic changes in the body that result from changes in gene expression rather than changes in the gene sequence itself. Impaired chromatin remodeling leads to the accumulation of epigenetic abnormalities that subsequently lead to the development and progression of cancer.
Mutations in genes involved in chromatin remodeling are frequently observed in many types of cancer. In particular, post-translational histone modifications of n-terminal sequences of histones 3 and 4 can be genetically influenced, including acetylation and methylation. This transmission is known to strongly influence chromatin structure and gene expression.
Chromatin remodeling plays an integral role in cardiac gene expression not only during neonatal development, but also throughout maturation and disease. This eventually led to profound changes in the epigenetic landscape of cardiomyocytes.
Chromatin modulators have been suggested to inhibit the expression of fetal genes in the infant's heart after birth. Studies of chromatin remodeling complexes, particularly the SWI/SNF family, have identified unique roles of chromatin remodeling in cardiac tissue development. The SWI/SNF chromatin recombinant is composed of 8-14 subunits derived from saccharomyces cerevisiae and is involved in the proliferation, differentiation and apoptosis of heart-derived cell lines.
In addition, chromatin remodeling is known to play an important role in regulating the proliferation and differentiation of mouse embryonic stem cells, suggesting its importance in the self-renewal and maintenance of pluripotency of stem cells.
The SWI/SNF complexes, initially identified in yeast 20 years ago, are a family of multi-subunit complexes that use the energy of adenosine triphosphate (ATP) hydrolysis to remodel nucleosomes. Chromatin remodeling processes mediated by the SWI/SNF complexes are critical to the modulation of gene expression across a variety of cellular processes, including stemness, differentiation, and proliferation. The first evidence of the involvement of these complexes in carcinogenesis was provided by the identification of biallelic, truncating mutations of the SMARCB1 gene in malignant rhabdoid tumors, a highly aggressive childhood cancer. Subsequently, genome-wide sequencing technologies have identified mutations in genes encoding different subunits of the SWI/SNF complexes in a large number of tumors. SWI/SNF mutations, and the subsequent abnormal function of SWI/SNF complexes, are among the most frequent gene alterations in cancer. The mechanisms by which perturbation of the SWI/SNF complexes promote oncogenesis are not fully elucidated; however, alterations of SWI/SNF genes obviously play a major part in cancer development, progression, and/or resistance to therapy.