11/29/2023 0 Comments Consensus dna![]() 16 However, high nucleosomal occupancy at TSSs rich in binding sites of transcription activators occurs in differentiation, suggesting that TF-binding sites are not unanimous determinants of gene expression. 16 In addition, a balanced state of positive and negative regulators of transcription, all depending on bivalent modifications of histones as nucleosomal components, may maintain genes in a poised state of transcription. Nucleosomes with activating histone modifications interact with and recruit positive regulators of transcription, whereas the histones with repressive marks serve as negative regulators of gene expression by either associating with and recruiting repressors of transcription or by hindering the access of DNA to positive regulators of transcription. 14, 15 Thus, TF-DNA interaction is potentially regulated by nucleosomal occupancy in many different ways: dense nucleosomal occupancy by nucleosomes with repressive histone modifications may render the DNA inaccessible, or the presence of activating histone modifications or simply an absence of nucleosomal occupancy at specific regions may promote TF-DNA interaction. 12, 13 However, the TF-chromatin interaction is also determined by the nucleosome-TFs interaction. Many TFs bind to specific cognate sequences which may be nucleosome-free or occupied by nucleosomes with activating or repressive histone modifications. 10, 11 Nucleosome locations are neither fixed (like binding of sequence-specific transcription factor complexes) nor entirely random. 8 For maintaining the long constitutively nucleosome-rich regions distinct from nucleosome-depleted regions, the DNA sequence plays a key role through binding of boundary element proteins, typified by CCCTC-binding factor (CTCF). 9 Stiff sequences that have GC and AT inter-strand asymmetry provide less favorable sites for nucleosomes. 4 A periodicity of TT and AT at every 10th base pair facilitates the wrapping of DNA around the histone octamer. 8 Positioned nucleosomes flanking the transcription start sites (TSSs) and constitutive heterochromatin serve as strong examples of sequence dependence of nucleosomal occupancy. Sequences with high dA:dT density are nucleosome-depleted. 6, 7 On the other hand, there are regions which have relatively inflexible nucleosomal occupancy due to sequence features. 4, 5 The density of nucleosomes in the vicinity may also determine the choices of DNA sequences a sliding nucleosome settles with. 3 The stabilization of sliding nucleosomes has been proposed to depend on the DNA sequence and may be affected by the histone modification profile of the nucleosomes. 1, 2 To facilitate transcription, replication, and DNA repair, nucleosomes slide short distances and affect local nucleosomal reorganization. Regulation of nucleosomal localization is a complex process. These results indicate that DNA sequence features dictate differential histone occupancy in primary and transformed cells, and the DNA sequence motifs affect transcription through regulation of histone occupancy. Interestingly, TSSs with a motif-linked occupancy of H2AFZ, a component of positioned nucleosomes, showed a distinct pattern of RNA Polymerase II (POLR2A) occupancy and TSS flank transcription in primary and transformed cells. The TSSs associated with transformed or primary cell-specific motifs showed different levels of TSS flank transcription in primary and transformed cells. The motifs for primary and transformed cells showed different levels of GC-richness and proximity to transcription start sites (TSSs). Our results show that DNA sequence motifs are associated with histone occupancy, some of which are different between primary and transformed cells. We have analyzed the presence of DNA sequence motifs in publicly available ChIP-sequence datasets for different histone modifications. However, whether DNA sequence motifs act as an additional effector of histone occupancy is not known. Histone occupancy depends on DNA sequence features like inter-strand symmetry of base composition and periodic occurrence of TT/AT. Genome-wide occupancy of several histone modifications in various cell types has been studied using chromatin immunoprecipitation (ChIP) sequencing.
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