Dynamics of chromatin accessibility and epigenetic state in response to UV damage

Abstract

Epigenetic mechanisms determine the access of regulatory factors to DNA during events such as transcription and the DNA damage response. However, the global response of histone modifications and chromatin accessibility to UV exposure remains poorly understood. Here, we report that UV exposure results in a genome-wide reduction in chromatin accessibility, while the distribution of the active regulatory mark H3K27ac undergoes massive reorganization. Genomic loci subjected to epigenetic reprogramming upon UV exposure represent target sites for sequence-specific transcription factors. Most of these are distal regulatory regions, highlighting their importance in the cellular response to UV exposure. Furthermore, UV exposure results in an extensive reorganization of super-enhancers, accompanied by expression changes of associated genes, which may in part contribute to the stress response. Taken together, our study provides the first comprehensive resource for genome-wide chromatin changes upon UV irradiation in relation to gene expression and elucidates new aspects of this relationship.

Continuous transcription initiation guarantees robust repair of transcribed genes and regulatory regions in response to DNA damage

“…Moreover, finding active transcription at these loci complies with prior reports suggesting that increase in gene expression are associated with surges in chromatin accessibility 57,58 and that the presence of nRNA is known to inhibit 51,59 the recruitment of H3K27me3-catalysing Polycomb Repressive complex 2 (PRC2) at active genes. Our data contrast the drastic chromatin remodeling observed in mice at a later time during recovery (6 h) when much higher doses of UV-B were used 60 . This suggests that when cells deal with unmanageable levels of damages they need to implement completely different expression changes required for the associated fate of programmed death, a protective mechanism limiting the risk of malignant transformation [61][62][63] .…”

Choreography of parental histones in damaged chromatin

“…In agreement with this hypothesis, a reduction in chromatin accessibility was reported following UV irradiation in mouse cells, 26 and chromatin compaction was observed in response to DSBs in human cells. 27 Further investigations using superresolution microscopy for instance could help decipher the relative distribution of parental and new histones and the overall chromatin structure at repair sites.…”

Genome-wide kinetics of DNA excision repair in relation to chromatin state and mutagenesis

“…The current "accessrepair-restore" model for excision repair in chromatin suggests active removal of nucleosomes to allow repair (31). Given that the sequencing data is normalized to read depth, we cannot distinguish whether elevated repair levels at later time points are a result of completion of repair in other regions or the result of an active process, including histone modification, chromatin remodeling, or gene activation in response to UV, that makes these regions more accessible (32,33). However, our assay will be a powerful tool to test for candidates involved in facilitating repair of tightly packed chromatin.…”