Chromatin remodeling regulates the activation or repression of genes within cells, which has important implications for the development of disease or the emergence of beneficial mutations in organisms. The key players in chromatin remodeling are chromatin remodelers, which are considered the primary drivers of chromatin activation. Working in conjunction with histone modification, DNA methylation, and RNA interference, chromatin remodelers facilitate the reorganization of chromatin structure, leading to epigenetic changes that are distinct from the traditional genetic code. These remodelers utilize the energy derived from ATP hydrolysis to increase the accessibility of transcription factors to DNA, enabling the regulation of gene expression. This process is achieved through two main mechanisms. The first involves shifting the positioning of nucleosomes to expose or conceal DNA sequences. The second, also known as nucleosome remodeling, involves establishing specific configurations near the core histones on the DNA surface, allowing transcription factors to access DNA more easily.
Fig.1 Chromatin structural remodeling during aging.1
Chromatin remodelers typically comprise a core ATPase subunit, which plays a vital role in catalyzing the ATP-dependent chromatin remodeling process, along with various other subunits that assist in regulating chromatin structure. Chromatin remodelers can be classified into four categories based on the structural domains present in the core ATPase subunit.
SWI/SNF remodelers play a critical role in regulating gene transcriptional activity through chromatin remodeling. These remodelers are recruited to transcriptional regulatory regions by sequence-specific DNA-binding proteins. This family includes important subunits such as SWI2/SNF2 in the yeast SWI/SNF complex, Sth1 in the yeast RSC complex, Brahma in the Drosophila SWI/SNF complex, as well as BRG1 and BRM in human SWI/SNF.
This family, also known as the SNF2L family, can alter nucleosome localization and structure to regulate gene expression. Within the ISWI remodelers, there are three main categories: RSF, HucHRAC, and CAF1. RSF is primarily composed of Hsnf-h subunits and is responsible for transcription initiation. HucHRAC, on the other hand, includes subunits like Hsnf-2h and Hacfl, which are essential for maintaining heterochromatin replication. Lastly, the function of CAF1 is to participate in the assembly of chromatin.
The CHD family (CHD1-9) is categorized into three subfamilies, which have the hallmark features of the presence of double chromodomains at the N-terminus and an SNF2 helicase-like ATPase structural domain at the core. CHDs operate individually or as part of multimeric enzymatic complexes, facilitating chromatin binding through interactions with various molecular components such as modified histones, transcription factors, methylated DNA, RNA, and poly(ADP-ribose). The nucleosome remodeling complex (NuRD) encompasses CHD3/4 (Mi2-α/β) chromatin remodelers along with HDAC1 and HDAC2 subunits, orchestrating processes of histone deacetylation, chromatin compaction, and transcriptional inhibition.
The INO80 subfamily consists of two complexes, INO80 and SWR1, which are composed of ATPases, actin modules, and other accessory proteins. INO80 complex is found in various eukaryotic organisms such as yeast, human, Arabidopsis thaliana, and Drosophila. It plays a key role in moving nucleosomes and localizing gene promoter regions and ORF regions. The INO80 complex globally regulates gene transcription and is involved in signal transduction pathways and environmental stress response in Saccharomyces cerevisiae.
Chromatin remodeling interacts and collaborates with epigenetic modifications like DNA methylation and histone modifications in a sophisticated manner, influencing various physiopathological processes including embryonic development, cancer, and cardiovascular diseases. An illustrative case is observed in cancer research, where decreased levels of histone H3K9 methylation weaken chromatin compaction, stimulating the actions of the chromatin remodeling complex SWI/SNF. This alteration subsequently impacts the transcription of oncogenes, fostering the progression of cancer. Moreover, aberrant chromatin remodeling also plays a crucial role in neuronal impairment, facilitating the pathogenesis of neurodegenerative disorders like Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis.
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