CpG islands (CGIs) are short, GC-rich, CpG-rich, and nonmethylated DNA sequences in vertebrates that are often associated with transcription initiation. They are characterized by elevated G+C content, minimal CpG depletion, and frequent absence of DNA methylation. CGIs are the most common promoter type in vertebrate genomes, associated with approximately 70% of annotated gene promoters, including many housekeeping genes and some tissue-specific and developmental regulator genes. Recent studies have identified CGIs that are remote from annotated transcription start sites (TSSs) but still show promoter function. CGIs are generally in a nonmethylated state, which allows them to adopt a transcriptionally permissive chromatin state. However, their promoters can be silenced through dense CpG methylation or polycomb recruitment, which use their distinctive DNA sequence composition. CGIs are evolutionarily conserved across vertebrates, with similar numbers in humans and mice. They are distributed in various genomic regions, including annotated TSSs, gene bodies, and intergenic regions. Many CGIs are sites of transcriptional initiation, with some acting as "orphan" CGIs that may represent novel promoters. Transcriptional initiation at orphan CGIs has been confirmed through various methods, including RNA sequencing and chromatin immunoprecipitation. CGIs are often marked by histone modifications such as H3K4me3, which is a signature of active promoters. CGIs are characterized by unstable nucleosomes and a chromatin structure that facilitates transcription. They are enriched in histone acetylation and H3K4me3, which are associated with transcriptionally active chromatin. The presence of H3K4me3 facilitates transcription by interacting with chromatin remodeling complexes and transcriptional machinery. CGIs can also be silenced by DNA methylation, which is often associated with stable gene silencing. In some cases, CGI methylation is not the initiating event but acts to lock in the silent state. CGIs are also involved in polycomb-mediated silencing, where they can be marked by H3K27me3 and PRC1 complexes, leading to transcriptional repression. CGIs are protected from DNA methylation due to their chromatin structure and transcriptional activity. Transcription factors such as Sp1, Nrf-1, and YY1 bind to CGI promoters and help maintain their unmethylated state. The presence of RNAPII at CGIs is associated with resistance to DNA methylation. Additionally, the chromatin mark H3K4me3 may interfere with DNA methyltransferase activity, further protecting CGIs from methylation. The interplay between transcriptional activity and chromatin modifications ensures that CGIs remain in a transcriptionally permissive state, facilitating gene regulation.CpG islands (CGIs) are short, GC-rich, CpG-rich, and nonmethylated DNA sequences in vertebrates that are often associated with transcription initiation. They are characterized by elevated G+C content, minimal CpG depletion, and frequent absence of DNA methylation. CGIs are the most common promoter type in vertebrate genomes, associated with approximately 70% of annotated gene promoters, including many housekeeping genes and some tissue-specific and developmental regulator genes. Recent studies have identified CGIs that are remote from annotated transcription start sites (TSSs) but still show promoter function. CGIs are generally in a nonmethylated state, which allows them to adopt a transcriptionally permissive chromatin state. However, their promoters can be silenced through dense CpG methylation or polycomb recruitment, which use their distinctive DNA sequence composition. CGIs are evolutionarily conserved across vertebrates, with similar numbers in humans and mice. They are distributed in various genomic regions, including annotated TSSs, gene bodies, and intergenic regions. Many CGIs are sites of transcriptional initiation, with some acting as "orphan" CGIs that may represent novel promoters. Transcriptional initiation at orphan CGIs has been confirmed through various methods, including RNA sequencing and chromatin immunoprecipitation. CGIs are often marked by histone modifications such as H3K4me3, which is a signature of active promoters. CGIs are characterized by unstable nucleosomes and a chromatin structure that facilitates transcription. They are enriched in histone acetylation and H3K4me3, which are associated with transcriptionally active chromatin. The presence of H3K4me3 facilitates transcription by interacting with chromatin remodeling complexes and transcriptional machinery. CGIs can also be silenced by DNA methylation, which is often associated with stable gene silencing. In some cases, CGI methylation is not the initiating event but acts to lock in the silent state. CGIs are also involved in polycomb-mediated silencing, where they can be marked by H3K27me3 and PRC1 complexes, leading to transcriptional repression. CGIs are protected from DNA methylation due to their chromatin structure and transcriptional activity. Transcription factors such as Sp1, Nrf-1, and YY1 bind to CGI promoters and help maintain their unmethylated state. The presence of RNAPII at CGIs is associated with resistance to DNA methylation. Additionally, the chromatin mark H3K4me3 may interfere with DNA methyltransferase activity, further protecting CGIs from methylation. The interplay between transcriptional activity and chromatin modifications ensures that CGIs remain in a transcriptionally permissive state, facilitating gene regulation.